Search

Presents a letter to the editor about late cystic fibrosis caused by homozygous IVS8-5T CFTR polymorphism.

The aim of this study was to compare anti-Mullerian hormone (AMH) plasma levels in patients with azoospermia according to the physiopathology. In a prospective clinical study from April 2008 to March 2009 in University Hospital, we measured AMH levels in 49 consecutive patients with azoospermia. AMH plasma levels were correlated with FSH, inhibin B, bioavailable testosterone plasma levels and testicular volume and compared between nonobstructive azoospermia (NOA) and obstructive azoospermia (OA) and within four physiopathological subgroups of NOA: genetic, cryptorchidism, cytotoxic and unexplained. AMH, FSH, inhibin B, bioavailable testosterone plasma levels and testicular volumes were all related to each other. AMH plasma levels were lower in NOA relatively to OA. Lowest values were observed in cases of genetic NOA and on the other hand, the values observed in case of cytotoxic NOA were as high as the values observed in OA. FSH, inhibin B, bioavailable testosterone and testicular volume were not different between genetic and cytotoxic NOA. These results suggest that the decrease in AMH plasma levels is related to the origin of NOA, with low values in genetic NOA and values similar to OA in cytotoxic NOA. Further studies will be useful to understand the fine regulation of AMH production. [ABSTRACT FROM AUTHOR]

Abstract: We investigate the influence of bottom topography on the formation and trapping of long upwelling filaments using a 2-layer shallow water model on the f-plane. A wind forced along-shore current, associated with coastal upwelling along a vertical wall, encounters a promontory of finite width and length, perpendicular to the coast. In the lower layer, topographic eddies form, which are shown to drive the formation of a filament on the front. Indeed, as the upwelling current and front develop along the coast, the along shore flow crosses the promontory, re-arranging the potential vorticity structure and generating intense vortical structures: water columns with high potential vorticity initially localized upon the promontory are advected into the deep ocean, forming cyclonic eddies, while water columns from the deep ocean with low potential vorticity climb on the topography forming a trapped anticyclonic circulation. These topographic eddies interact with the upper layer upwelling front and form an elongated, trapped and narrow filament. Sensitivity tests are then carried out and it is shown that: [•] baroclinic instability of the front does not play a major role on the formation of long trapped filaments; [•] increasing the duration of the wind forcing increases the upwelling current and limits the offshore growth of the filament; [•] modifying the promontory characteristics (width, length, height and slopes) has strong impact on the filament evolution, sometimes leading to a multipolarisation of the potential vorticity anomaly structure which results in much more complicated patterns in the upper layer (numerous shorter and less coherent filaments). This shows that only specific promontory shapes can lead to the formation of well defined filaments; [•] adding bottom friction introduces a slight generation of potential vorticity in the bottom layer over the promontory, but does not significantly alter significantly the formation of the filament along the outcropped front in the present configuration; [•] modifying the stratification characteristics, in particular the density jump between the layers, has only a weak influence on the dynamics of topographic eddies and on filament formation; [•] the influence of capes is also modest in our simulations, showing that topography plays the major role in the formation of long and trapped upwelling filaments. [Copyright &y& Elsevier]

We study mesoscale eddy characteristics in the tropical Atlantic Ocean, using 23 years of daily altimetry sea level anomalies. Eddies are mainly generated in the eastern boundary upwelling systems and in the Brazil Current region. Their westward propagation speed reaches 20 cm/s in equatorial areas, decreasing with latitudes. They present typical amplitudes of 1‐5 cm. The largest and most energetic eddies are observed in the equatorial region, especially in the North Brazil Current (NBC) retroflection. The seasonal cycle of the eddy characteristics shows higher amplitudes along the NBC retroflection and the western part of the North Equatorial Countercurrent. A new criterion, based on altimetry data, determines the probability that barotropic instability of mean surface currents is responsible for eddy generation. We find a strong likelihood that the latter plays a key role along the North Equatorial Countercurrent, whereas other mechanisms must be invoked for the NBC region. Key Points: Mesoscale eddies in the tropical Atlantic ocean have amplitudes, radii, and kinetic energies of 1–5 cm, 30–100 km, and 50–100 cm2/s 2, respectivelySeasonal cycle of eddy properties has the highest amplitude in the NBC retroflection and in the western part of the NECCBarotropic instability is the main mechanism for eddy generation in the western part of the NECC [ABSTRACT FROM AUTHOR]

Pubertal gynecomastia is a common condition observed in up to 65% of adolescent males. It is usually idiopathic and tends to regress within 1-2 years. In this descriptive cross-sectional study, we investigated 25 adolescent males with prominent (>B3) and/or persistent (>2 years) pubertal gynecomastia (P/ PPG) to determine whether a hormonal/genetic defect might underline this condition. Endocrine investigation revealed the absence of hormonal disturbance for 18 boys (72%). Three patients presented Klinefelter syndrome and three a partial androgen insensitivity syndrome ( PAIS) as a result of p.Ala646Asp and p.Ala45Gly mutations of the androgen receptor gene. The last patient showed a 17α-hydroxylase/17,20-lyase deficiency as a result of a compound heterozygous mutation of the CYP17A1 gene leading to p.Pro35Thr(P35T) and p.Arg239Stop(R239X) in the P450c17 protein. Enzymatic activity was analyzed: the mutant protein bearing the premature stop codon R239X showed a complete loss of 17α-hydroxylase and 17,20-lyase activity. The mutant P35T seemed to retain 15-20% of 17α-hydroxylase and about 8-10% of 17,20-lyase activity. This work demonstrates that P/ PPG had an endocrine/genetic cause in 28% of our cases. PAIS may be expressed only by isolated gynecomastia as well as by 17α-hydroxylase/17,20-lyase deficiency. Isolated P/ PPG is not always a 'physiological' condition and should thus be investigated through adequate endocrine and genetic investigations, even though larger studies are needed to better determine the real prevalence of genetic defects in such patients. [ABSTRACT FROM AUTHOR]

Summary: Neonatal salt-wasting syndromes are rare but potentially serious conditions. Isolated hypoaldosteronism is an autosomal recessive inherited disorder of terminal aldosterone synthesis, leading to selective aldosterone deficiency. Two different biochemical forms of this disease have been described, called aldosterone synthase deficiency or corticosterone methyl oxydase, types I and II. In type I, there is no aldosterone synthase activity and the 18 hydroxycorticosterone (18 OHB) level is low, whereas in type II, a residual activity of aldosterone synthase persists and 18 OHB is overproduced. We report on four patients with isolated hypoaldosteronism. In 2 of them, who were recently diagnosed with aldosterone synthase deficit, we discuss the symptoms and treatment. The 2 other patients are now adults. We discuss the long-term outcome, the quality of adult life, aldosterone synthase deficits, as well as the pathophysiology and molecular analysis. [Copyright &y& Elsevier]

Kharrat M, Trabelsi S, Chaabouni M, Maazoul F, Kraoua L, Ben Jemaa L, Gandoura N, Barsaoui S, Morel Y, M’rad R, Chaabouni H. Only two mutations detected in 15 Tunisian patients with 11β-hydroxylase deficiency: the p.Q356X and the novel p.G379V. Steroid 11β-hydroxylase deficiency is the second most common cause of congenital adrenal hyperplasia, resulting in virilization, glucocorticoid deficiency and hypertension. The 11β-hydroxylase enzyme is encoded by the CYP11B1 gene and mutations in this gene are responsible for this disease. The aim of this study was to characterize mutations in the CYP11B1 gene and to determine their frequencies in a cohort of Tunisian patients. The molecular genetic analysis was performed by direct nucleotide sequencing of the CYP11B1 gene in 15 unrelated Tunisian patients suffering from classical 11β-hydroxylase deficiency. Only two mutations were detected in homozygous state in the CYP11B1 gene of all patients, the p.Q356X in exon 6 (26.6%) and the novel p.G379V in exon 7 with large prevalence (73.3%). This is the first report of screening for mutations of CYP11B1 gene in the Tunisian population and even in the Arab population. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that discusses the pseudoexon activation in the PKHD1 gene: a French founder intronic mutation IVS46+653>G causing severe autosomal recessive polycystic kidney disease.

Waves propagate in a free-surface ocean due to compressibility and gravity (and surface tension at much smaller scale). Analytical solutions have long been derived independently for acoustic and gravity waves, i.e., acoustic waves or internal-gravity waves in an unbounded ocean, surface-gravity waves in a free-surface-ocean, and acoustic or internal modes in a bounded ocean. In the present study, surface tension and earth-rotation are neglected and a simple, unified model based on inner and boundary dispersion relations is derived for waves propagating in a compressible, stratified, free-surface ocean. Branches of acoustic gravity wave solutions are identified and visually analysed in phase-space. Taylor developments are then carried out with respect to small parameters describing stratification and compressibility and are compared with numerical approximations of the intersection of inner and boundary dispersion surfaces. Finally, the model recovers the known approximations for swell, long-surface waves, internal-gravity waves, internal modes, acoustic waves or acoustic modes, and also provides information on the modifications of these solutions due to stratification and compressibility and on the coupling of acoustic and gravity waves. Two peculiar regions of the acoustic-gravity wave phase-space are more specifically highlighted and studied in detail: one for long waves shedding new light on the distinction between surface waves and low-order internal modes, the other for marginally stable surface waves of intermediate length-scale. [ABSTRACT FROM AUTHOR]

Abstract: Adrenal hypoplasia congenita (AHC) is an extremely uncommon disease of early onset. This condition can be lethal in the absence of adapted treatment. Some of these diseases are related to changes in the gene DAX1 that encodes a member of the superfamily of hormone nuclear receptors. It is a transcriptional repressor that is central in the morphogenesis of the adrenals and the gonadic differentiation. Here we report on four cases of X- linked AHC. In the first two familial cases, mutations were identified and mothers were heterozygotes. Abnormally low levels of estriol were evidenced during the pregnancy leading to an early diagnosis and adapted care of the affected male neonates. These children are doing well with a 21-and 20 months follow-up with hormone replacement at the present time. The two last cases corresponded to a contiguous gene syndrome associating AHC to glycerol-kinase deficiency that was revealed respectively at six days and seven years of age by acute adrenal insufficiency. [Copyright &y& Elsevier]

Aim. – Chronic fatigue is the more frequent symptom identified in the course of hereditary haemochromatosis. A screening for this disorder was carried out in 120 primary care patients consulting for unexplained chronic fatigue.Subjects and methods. – Transferrin saturation and serum ferritin were determined in all patients. If transferrin saturation was ≥ 45% and serum ferritin ≥ 300 μg/l, HFE1 genotyping for mutations C282Y and H63D was completed.Results. – One hundred and twenty patients were recruited, 19–86 years old, including 62 males and 58 females. 45 patients (38%) presented with serum ferritin ≥ 300 μg/l. Thirty two patients (27%) presented with transferrin saturation ≥ 45%. Twenty two patients (18%) presented with these two pathological values. Four C282Y/H63D compound heterozygous, one H63D/H63D homozygous, and eight simplex heterozygous (6 H63D and 2 C282Y) genotypes were found. Patients with serum ferritin ≥ 300 μg/l were predominantly male (89%), older (57 year) and plethoric (BMI: 26.4) corresponding mainly to dysmetabolic hyperferritinemia.Conclusion. – None of these 120 patients consulting for unexplained chronic fatigue was found with hereditary haemochromatosis. Therefore observed prevalence is 0, with upper limit of 95% confidence interval at 2.5%. But the high prevalence (38%) of serum ferritin ≥ 300 μg/l must be emphasized, corresponding usually to dysmetabolic hyperferritinemia. [Copyright &y& Elsevier]

Focuses on the association of hormones in the virilization of female fetuses. Causes of virilization in female fetuses; Factors influencing gender identity; Role of aromatase on the conversion of androgens to estrogens.

In this paper, we report on the fabrication and characterization of the dynamic behavior of circular micromembranes integrating a piezoelectric thin film for actuation and a boron-doped silicon piezoresistor for sensing purposes. Resonant frequencies corresponding to high-order modes of vibration are measured, respectively, in air and deionized water. The measurements are compared with theoretical values calculated using the extended Lamb’s model [H. Lamb, Proc. R. Soc. London 98, 205 (1920)] adapted to the microscale. Moreover, label-free detection of Bacillus atrophaeus (or B. atrophaeus) with a concentration of 108 spores/mL is repeatedly performed in real-time which assesses the biosensing potential of microscale circular membranes bearing actuation and sensing elements. [ABSTRACT FROM AUTHOR]

Objectifs: Présentation de 3 patients 46XX présentant une anomalie de la différenciation sexuelle (ADS), virilisation et présence de tissu testiculaire en l’absence de SRY détectable. Patients: Les 3 enfants 46XX SRY- pris en charge à l’Hôpital Debrousse à Lyon présentent un aspect clinique assez similaire : micropénis, hypos-pade périnéal, hémiscrotum bien développé d’un coté contenant une gonade (testicule en anatomie pathologique) et hypoplasie de l’autre hémiscrotum (streak gonade inguinale ou intra abdominale). Résultats: Le premier patient était déclaré garçon à la naissance – le diagnostic a été réalisé à l’âge de 9 mois et l’intervention chirurgicale pour son hypos-pade postérieur (Koyanagi) a été réalisée à 17 mois. Le deuxième enfant a été déclaré garçon à la naissance mais le diagnostic a été fait rapidement (15 jours de vie). Après changement du sexe civil, la féminisation a été effectuée à l’âge de 7 mois. Le troisième enfant a été vu à la naissance, la déclaration du sexe à l’état civil a été différée pour attendre l’ensemble des résultats (caryotype, biologie, génitoscopie et génitographie, biopsie des gonades) et, après discussion avec les parents, l’orientation a été décidée dans le sexe féminin. L’intervention de féminisation est prévue vers l’âge de 5 mois. Discussion: Le rôle du SRY est considéré comme primordial pour permettre la différenciation testiculaire à partir de la gonade dite indifférenciée chez les mammifères. Chez ces 3 patients, l’absence de SRY détectable soulève plusieurs hypothèses : 1) Le SRY a existé et a disparu (« Y vanishing syndrome ») ; 2) Le SRY existe mais n’a pas été détectés ; 3) la présence d’autres gènes (SOX 9, gènes répresseurs) peut être suffisante pour remplacer SRY. Conclusion: En cas d’ADS, l’assignement d’un genre c’est-à-dire l’attribution d’une identité sociale relève de plusieurs facteurs que sont : le sexe intérieur (gènes, gonades et hormones), le sexe extérieur (phénotype des organes génitaux externes et internes), le sexe fonctionnel (possibilités de relations sexuelles et fertilité) et enfin le sexe social et culturel (milieu d’élevage, regard de la mère etc…) Les démarches diagnostiques et la prise en charge chirurgicale sont discutées, ainsi qu’une revue de la littérature actuelle. [Copyright &y& Elsevier]

NK cells offer a promising alternative to T cell therapies in cancer. We evaluated IPH6501, a clinical-stage, tetraspecific NK cell engager (NKCE) armed with a non-alpha IL-2 variant (IL-2v), which targets CD20 and was developed for treating B cell non-Hodgkin lymphoma (B-NHL). CD20-NKCE-IL2v boosts NK cell proliferation and cytotoxicity, showing activity against a range of B-NHL cell lines, including those with low CD20 density. Whereas it presented reduced toxicities compared with those commonly associated with T cell therapies, CD20-NKCE-IL2v showed greater killing efficacy over a T cell engager targeting CD20 in in vitro preclinical models. CD20-NKCE-IL2v also increased the cell surface expression of NK cell-activating receptors, leading to activity against CD20-negative tumor cells. In vivo studies in nonhuman primates and tumor mouse models further validated its efficacy and revealed that CD20-NKCE-IL2v induces peripheral NK cell homing at the tumor site. CD20-NKCE-IL2v emerges as a potential alternative in the treatment landscape of B-NHL.

Reactive aldehydes are a class of electrophilic low molecular weight compounds that play an essential role in physiological function and lipid peroxidation. These molecules are implicated in many diseases, especially cardiovascular and neurodegenerative diseases, and are potential endogenous markers of lipid peroxidation. However, there are limited options to accurately quantify multiple reactive aldehydes in brain tissue. This study developed and validated a 3-nitrophenylhydrazine derivatization-based LC-MS/MS method to quantify four reactive aldehydes: malondialdehyde, acrolein, 4-hydroxy-2-hexenal and 4-hydroxy-2-nonenal. Method development involved comparing the sensitivity of detection between widely used derivatization reagents: 2,4-dinitrophenylhydrazine and 3-nitrophenylhydrazine. Our data showed that 3-nitrophenylhydrazine resulted in greater sensitivity. Additional method development included evaluation of hydrolysis sample pretreatment, selection of protein precipitation reagent, and optimization of derivatization conditions. The optimized conditions included no hydrolysis and use of 20 % trichloroacetic acid as the protein precipitation reagent. The optimized derivatization condition was 25 mM 3-nitrophenylhydrazine reacted at 20 °C for 30 min. The chromatographic conditions were optimized to reduce matrix effects, ion suppression, and efficient analysis time (<7-minute analytical run). The four aldehyde species were accurately quantified in brain tissue using stable-labeled internal standards. Application of this assay to a traumatic brain injury mouse model revealed significant accumulation of acrolein, 4-hydroxy-2-hexenal, and 4-hydroxy-2-nonenal at 28 days post injury. Overall, a validated method was developed to rapidly quantify the most prominent reactive aldehydes associated with lipid peroxidation during injury progression following acute brain trauma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

CD123, the alpha chain of the IL-3 receptor, is an attractive target for acute myeloid leukemia (AML) treatment. However, cytotoxic antibodies or T cell engagers targeting CD123 had insufficient efficacy or safety in clinical trials. We show that expression of CD64, the high-affinity receptor for human IgG, on AML blasts confers resistance to anti-CD123 antibody-dependent cell cytotoxicity (ADCC) in vitro. We engineer a trifunctional natural killer cell engager (NKCE) that targets CD123 on AML blasts and NKp46 and CD16a on NK cells (CD123-NKCE). CD123-NKCE has potent antitumor activity against primary AML blasts regardless of CD64 expression and induces NK cell activation and cytokine secretion only in the presence of AML cells. Its antitumor activity in a mouse CD123 + tumor model exceeds that of the benchmark ADCC-enhanced antibody. In nonhuman primates, it had prolonged pharmacodynamic effects, depleting CD123 + cells for more than 10 days with no signs of toxicity and very low inflammatory cytokine induction over a large dose range. These results support clinical development of CD123-NKCE., (© 2023. The Author(s).)

Lipid peroxidation is a key component in the pathogenesis of numerous disease states, where the oxidative damage of lipids frequently leads to membrane dysfunction and subsequent cellular death. Glycerophosphoethanolamine (PE) is the second most abundant phospholipid found in cellular membranes and, when oxidized, has been identified as an executor of ferroptotic cell death. PE commonly exists in the plasmalogen form, where the presence of the vinyl ether bond and its enrichment in polyunsaturated fatty acids make it especially susceptible to oxidative degradation. This results in a multitude of oxidized products complicating identification and often requiring several analytical techniques for interpretation. In the present study, we outline an analytical approach for the structural characterization of intact oxidized products of arachidonate-containing diacyl and plasmalogen PE. Intact oxidized PE structures, including structural and positional isomers, were identified using complementary liquid chromatography techniques, drift tube ion mobility, and high-resolution tandem mass spectrometry. This work establishes a comprehensive method for the analysis of intact lipid peroxidation products and provides an important pathway to investigate how lipid peroxidation initially impacts glycerophospholipids and their role in redox biology.

Disorders of isolated mineralocorticoid deficiency, which cause potentially life-threatening salt-wasting crisis early in life, have been associated with gene variants of aldosterone biosynthesis or resistance; however, in some patients no such variants are found. WNT/β-catenin signaling is crucial for differentiation and maintenance of the aldosterone-producing adrenal zona glomerulosa (zG). Herein, we describe a highly consanguineous family with multiple perinatal deaths and infants presenting at birth with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Whole exome sequencing revealed a homozygous splice variant in the R-SPONDIN receptor LGR4 gene (c.618-1G>C) regulating WNT signaling. The resulting transcripts affected protein function and stability and resulted in loss of Wnt/β-catenin signaling in vitro. The impact of LGR4 inactivation was analyzed by adrenal cortex-specific ablation of Lgr4, using Lgr4fl/fl mice mated with Sf1:Cre mice. Inactivation of Lgr4 within the adrenal cortex in the mouse model caused decreased WNT signaling, aberrant zonation with deficient zG, and reduced aldosterone production. Thus, human LGR4 mutations establish a direct link between LGR4 inactivation and decreased canonical WNT signaling, which results in abnormal zG differentiation and endocrine function. Therefore, variants in WNT signaling and its regulators should systematically be considered in familial hyperreninemic hypoaldosteronism.

High levels of loneliness are prominent in teenagers ranging from ages 14-19. The 4-week Self-Care program, offered by the Heartfulness Institute, is designed to develop social-emotional skills and self-observation. This study examined the impact of the Self-Care program on loneliness in high school students in the United States in a randomized, wait-list control trial with baseline and postintervention assessments. High school participants, aged 14-19, were randomized into a control-wait-listed group (n = 54) and a Heartfulness group (n = 54). Both the groups completed the intervention and the presurveys and postsurveys online, assessing their loneliness with the UCLA Loneliness Scale. The initial analysis noted the baseline equivalence of the data. A repeated measures ANOVA found a significant time * group interaction, with a significant decrease in loneliness reported in the Heartfulness Intervention group but no significant pre-post difference in the control group. In summary, the short online intervention program consisting of self-care tools decreased loneliness scores in the participants. This study opens up a new valley of possibilities, apart from existing research, and demonstrates that the online intervention used might be helpful to decrease loneliness levels in teens., (© 2022 The Authors. Applied Psychology: Health and Well-Being published by John Wiley & Sons Ltd on behalf of International Association of Applied Psychology.)

Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson disease protein), maintain Cu homeostasis in the tissue. Atp7a mediates Cu entry into the brain and activates Cu-dependent enzymes, whereas the role of Atp7b is less clear. We show that during postnatal development Atp7b is necessary for normal morphology and function of choroid plexus (ChPl). Inactivation of Atp7b causes reorganization of ChPl' cytoskeleton and cell-cell contacts, loss of Slc31a1 from the apical membrane, and a decrease in the length and number of microvilli and cilia. In ChPl lacking Atp7b, Atp7a is upregulated but remains intracellular, which limits Cu transport into the brain and results in significant Cu deficit, which is reversed only in older animals. Cu deficiency is associated with down-regulation of Atp7a in locus coeruleus and catecholamine imbalance, despite normal expression of dopamine-β-hydroxylase. In addition, there are notable changes in the brain lipidome, which can be attributed to inhibition of diacylglyceride-to-phosphatidylethanolamine conversion. These results identify the new role for Atp7b in developing brain and identify metabolic changes that could be exacerbated by Cu chelation therapy., Competing Interests: Authors declare no competing interests., (Copyright: © 2023 Washington-Hughes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Harnessing innate immunity is emerging as a promising therapeutic approach in cancer. We report here the design of tetraspecific molecules engaging natural killer (NK) cell-activating receptors NKp46 and CD16a, the β-chain of the interleukin-2 receptor (IL-2R), and a tumor-associated antigen (TAA). In vitro, these tetraspecific antibody-based natural killer cell engager therapeutics (ANKETs) induce a preferential activation and proliferation of NK cells, and the binding to the targeted TAA triggers NK cell cytotoxicity and cytokine and chemokine production. In vivo, tetraspecific ANKETs induce NK cell proliferation and their accumulation at the tumor bed, as well as the control of local and disseminated tumors. Treatment of non-human primates with CD20-directed tetraspecific ANKET leads to CD20 + circulating B cell depletion, with minimal systemic cytokine release and no sign of toxicity. Tetraspecific ANKETs, thus, constitute a technological platform for harnessing NK cells as next-generation cancer immunotherapies., Competing Interests: Declaration of interests Innate Pharma has filed patent applications relating to ANKETs and its use of ANKETs in the treatment of tumors (US patent no. 10,113,003, together with other patents and patent applications), as well as applications for use of ANKETs as a trademark. With the exception of E.L., N.F., S.S., J.-L.D., and R.L.G., all the authors are employees of Innate Pharma., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: 3β-hydroxysteroid dehydrogenase 2 (3βHSD2) deficiency is a rare form of congenital adrenal hyperplasia (CAH), with fewer than 200 cases reported in the world literature and few data on outcomes., Patients and Methods: We report a mixed longitudinal and cross-sectional study from a single Algerian center between 2007 and 2021. Virilization and under-masculinization were assessed using Prader staging and the external masculinization score (EMS), pubertal development staged according to the system of Tanner. Adrenal steroids were measured using mass spectrophotometry (LC-MS/MS). A genetic analysis of HSD3B2 was performed using Sanger sequencing., Results: A 3βHSD2 defect was confirmed in 6 males and 8 females from 10 families (8 consanguineous), with p.Pro222Gln mutation in all but two siblings with a novel deletion: c.453&#95;464del or p.(Thr152&#95;Pro155del). Probable 3βHSD2 deficiency was diagnosed retrospectively in a further 6 siblings who died, and in two patients from two other centers. In the genetically confirmed patients, the median (range) age at presentation was 20 (0-390) days, with salt-wasting (n = 14) and genital anomaly (n = 10). The Prader stage for female patients was 2 (1-2) with no posterior fusion of the labia. The EMS for males was 6 (3-9). Median (range) values at diagnosis for 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulfate (DHEA-S), and 17-hydroxypregnenolone (17OHPreg) were elevated: 73.7 (0.37-164.3) nmol/L; 501.2(9.4-5441.3) nmol/L, and 139.7 (10.9-1500) nmol/l (NB >90 nmol/L diagnostic of 3βHSD2 defect). Premature pubarche was observed in four patients (3F:1M). Six patients (5F:1M) entered puberty spontaneously, aged 11 (5-13) years in 5 girls and 11.5 years in one boy. Testicular adrenal rest tumors were found in three boys. Four girls reached menarche at 14.3 (11-14.5) years, with three developing adrenal masses (surgically excised in two) and polycystic ovary syndrome (PCOS), with radiological evidence of ovarian adrenal rest tumor in one. The median IQ was 90 (43-105), >100 in only two patients and <70 in three., Conclusions: The prevalence of 3βHSD2 deficiency in Algeria appears high, with p.Pro222Gln being the most frequent mutation. Mortality is also high, with significant morbidity from adrenal tumors and PCOS in adolescence and an increased risk of learning disability. The finding of adrenal tumors in older patients with 3βHSD2 indicates under-replacement, requiring effective hydrocortisone and fludrocortisone treatment rather than surgical removal., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ladjouze, Donaldson, Plotton, Djenane, Mohammedi, Tardy-Guidollet, Mallet, Boulesnane, Bouzerar, Morel and Roucher-Boulez.)

Objectives: Congenital adrenal hyperplasia (CAH) remains one of the most challenging endocrine disorders to diagnose, manage, and treat, especially in Africa where there is lack of neonatal screening program, and limited access to care. Data on biomolecular anomaly are sparse, therefore type of mutations are unknown, increasing management challenges and genetic counseling. The present study aims to describe clinical, biomolecular aspects of a group of Cameroonian patients., Methods: We did an observational retrospective study at the pediatric endocrinology unit of the Mother and Child Centre of the Chantal Biya Foundation in Yaounde from May 2013 to December 2019, including all patients diagnosed with CAH., Results: We consecutively included 31 patients aged less than 21 years, diagnosed CAH. Median age at diagnosis was 1.71 years (IQR 0.08-2.57 years). Abnormal genitalia was the main complain in 48.4%(n=15). The most prevalent genetic anomaly found in our study population (n=24) was on CYP11, found in 16 patients (66.6%) followed by CYP21A2 mutation found in 8 patients. Homozygous mutation of p.Q356X was found in half of patients with 11 hydroxylase deficiency. This mutation was mostly found in people from semi-Bantu tribes, declared non consanguineous., Conclusions: 11 hydroxylase deficiency is the most prevalent form of CAH found in this group of Cameroonian children., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Changes in plasmalogen glycerophosphoethanolamine (PE-P) composition (structure and abundance) are a key indicator of altered lipid metabolism. Differential changes in the levels of PE-P have been reported in different disease states, including neurodegenerative diseases. Of particular interest, traumatic brain injury (TBI) has resulted in altered expression of glycerophospholipid profiles, including PE-P. To date, most analytical assays assessing PE-P have focused on general lipidomic workflows to evaluate the relative, semi-quantitative abundance of PE-P during disease progression. This approach provides a broad evaluation of PE-P, yet often lacks specificity and sensitivity for individual PE-P structures which is a necessity for robust quantitative data. The present study highlights the development of a targeted, quantitative method using a HILIC separation and selective reaction monitoring mass spectrometry for the confident identification and accurate quantitation of PE-P. Our innovative method incorporates both the sn-1 alkyl vinyl ether and sn-2 acyl chain as product ion transitions, for specific and sensitive quantitation of 100 PE-P structures. Our method also uniquely allowed for the unambiguous assignment and quantitation of di-unsaturated sn-1 PE-P structures, which to date have not been conclusively quantified. Application of this assay to a TBI mouse model resulted in distinct temporal profiles for plasma PE-P up to 28 days post injury. Plasma PE-P were significantly increased 24 h after induced TBI, followed by a gradual reduction to sham concentrations by day 28. Overall, we established a structure-specific, quantitative assay for identification and quantitation of a comprehensive set of PE-P structures with demonstrated relevance to brain injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: MICA and MICB are tightly regulated stress-induced proteins that trigger the immune system by binding to the activating receptor NKG2D on cytotoxic lymphocytes. MICA and MICB are highly polymorphic molecules with prevalent expression on several types of solid tumors and limited expression in normal/healthy tissues, making them attractive targets for therapeutic intervention., Methods: We have generated a series of anti-MICA and MICB cross-reactive antibodies with the unique feature of binding to the most prevalent isoforms of both these molecules., Results: The anti-MICA and MICB antibody MICAB1, a human IgG1 Fc-engineered monoclonal antibody (mAb), displayed potent antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) of MICA/B-expressing tumor cells in vitro . However, it showed insufficient efficiency against solid tumors in vivo , which prompted the development of antibody-drug conjugates (ADC). Indeed, optimal tumor control was achieved with MICAB1-ADC format in several solid tumor models, including patient-derived xenografts (PDX) and carcinogen-induced tumors in immunocompetent MICAgen transgenic mice., Conclusions: These data indicate that MICA and MICB are promising targets for cytotoxic immunotherapy., Competing Interests: Competing interests: M.M-K., A.M., D.B., C.B., L.G., B.R., R.R., C.P., S.C., N.A., N.V., S.T., A.J-G., G.G., Y.M., I.P., E.V are employees of Innate Pharma. A.S. had research contracts with Innate Pharma, and PDI Therapeutics, as well as consulting and stock ownership of PDI Therapeutics. The other authors have no competing financial interests to declare.

Coronavirus disease 2019 (COVID-19) is a disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic 1 . The C5a complement factor and its receptor C5aR1 (also known as CD88) have a key role in the initiation and maintenance of several inflammatory responses by recruiting and activating neutrophils and monocytes 1 . Here we provide a longitudinal analysis of immune responses, including phenotypic analyses of immune cells and assessments of the soluble factors that are present in the blood and bronchoalveolar lavage fluid of patients at various stages of COVID-19 severity, including those who were paucisymptomatic or had pneumonia or acute respiratory distress syndrome. The levels of soluble C5a were increased in proportion to the severity of COVID-19 and high expression levels of C5aR1 receptors were found in blood and pulmonary myeloid cells, which supports a role for the C5a-C5aR1 axis in the pathophysiology of acute respiratory distress syndrome. Anti-C5aR1 therapeutic monoclonal antibodies prevented the C5a-mediated recruitment and activation of human myeloid cells, and inhibited acute lung injury in human C5aR1 knock-in mice. These results suggest that blockade of the C5a-C5aR1 axis could be used to limit the infiltration of myeloid cells in damaged organs and prevent the excessive lung inflammation and endothelialitis that are associated with acute respiratory distress syndrome in patients with COVID-19.

The interdisciplinary field of neurorobotics looks to neuroscience to overcome the limitations of modern robotics technology, to robotics to advance our understanding of the neural system's inner workings, and to information technology to develop tools that support those complementary endeavours. The development of these technologies is still at an early stage, which makes them an ideal candidate for proactive and anticipatory ethical reflection. This article explains the current state of neurorobotics development within the Human Brain Project, originating from a close collaboration between the scientific and technical experts who drive neurorobotics innovation, and the humanities and social sciences scholars who provide contextualising and reflective capabilities. This article discusses some of the ethical issues which can reasonably be expected. On this basis, the article explores possible gaps identified within this collaborative, ethical reflection that calls for attention to ensure that the development of neurorobotics is ethically sound and socially acceptable and desirable.

Purpose: Urethral fistula and dehiscence are common after hypospadias surgery. Preoperative androgens have been considered to reduce these complications although this consideration is not evidence-based. Dermatologists have reported the benefits of topical estrogens on skin healing. We investigated whether the preoperative use of topical promestriene could reduce healing complications in hypospadias surgery. Our primary objective was to demonstrate a reduction of healing complications with promestriene vs placebo. Impact on reoperations and other complications, clinical tolerance, bone growth, and biological systemic effects of the treatment were also considered., Methods: We conducted a prospective, randomized, placebo-controlled, double-blind, parallel group trial between 2011 and 2015 in 4 French centers. One-stage transverse preputial island flap urethroplasty (onlay urethroplasty) was selected for severe hypospadias. Promestriene or placebo was applied on the penis for 2 months prior to surgery. The primary outcome was the presence of postoperative urethral fistula or dehiscence in the first year postsurgery. For safety reasons, hormonal and anatomical screenings were performed., Results: Out of 241 patients who received surgery, 122 patients were randomized to receive placebo, and 119 patients received promestriene. The primary outcome was unavailable for 11 patients. Healing complications were assessed at 16.4% (19/116) in the placebo vs 14.9% (17/114) in the promestriene arm, and the odds ratio adjusted on center was 0.93 (95% confidence interval 0.45-1.94), P = 0.86., Conclusions and Relevance: Although we observed an overall lower risk of complications compared to previous publications, postsurgery complications were not different between promestriene and placebo, because of a lack of power of the study or the inefficacy of promestriene., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)