Chapter 5: The roles of genetics in primary hyperparathyroidism.

Around 10% of cases of primary hyperparathyroidism are thought to be genetic in origin, some of which are part of a syndromic form such as multiple endocrine neoplasia types 1, 2A or 4 or hyperparathyroidism-jaw tumor syndrome, while the remainder are cases of isolated familial primary hyperparathyroidism. Recognition of these genetic forms is important to ensure appropriate management according to the gene and type of variant involved, but screening for a genetic cause is not justified in all patients presenting primary hyperparathyroidism. The indications for genetic analysis have made it possible to propose a decision tree that takes into account whether the presentation is familial or sporadic, syndromic or isolated, patient age, and histopathological type of parathyroid lesion.

Fgfr3 enhancer deletion markedly improves all skeletal features in a mouse model of achondroplasia.

Achondroplasia, the most prevalent short-stature disorder, is caused by missense variants overactivating the fibroblast growth factor receptor 3 (FGFR3). As current surgical and pharmaceutical treatments only partially improve some disease features, we sought to explore a genetic approach. We show that an enhancer located 29 kb upstream of mouse Fgfr3 (-29E) is sufficient to confer a transgenic mouse reporter with a domain of expression in cartilage matching that of Fgfr3.

Human genetic diseases of phosphate and pyrophosphate metabolism.

In humans, physiological bone and tooth mineralization is a complex cell-mediated process. Prerequisites for proper mineralization include sufficient amounts of minerals (calcium and phosphate [Pi]) to initiate the formation and the growth of apatite crystals and adequate amounts of mineralization inhibitors, such as pyrophosphate (PPi), to prevent uncontrolled extraskeletal mineralization. In this review, we provide an overview of the genetics of human disorders of mineralization, focusing on Pi and PPi metabolism and transport diseases, as the Pi/PPi ratio is an important determinant of crystal production in vivo.

Development of fast 2.5 MeV neutron detectors for high-intensity stray magnetic field environments.

Several small to medium-scale magnetic confinement fusion devices operate using deuterium as fuel. These low neutron rate (108-1010 n/s) devices rely on 2.45 MeV neutron measurements to validate physical models and to assess their performance.

Design solutions for the hodoscope of the magnetic proton recoil neutron spectrometer of the SPARC tokamak.

A new 14 MeV neutron spectrometer utilizing the magnetic proton recoil (MPR) technique is under development for the SPARC tokamak. This instrument measures neutrons by converting them into protons, whose momenta are subsequently analyzed using a series of magnets before detection by an array of scintillators known as the hodoscope. In this work, we explore various solutions for the hodoscope detectors through laboratory tests with radioactive sources and simulations.

COSMONAUT: A COmpact spectrometer for measurements of neutrons at the ASDEX upgrade tokamak.

A COmpact Spectrometer for Measurements Of Neutrons at the ASDEX Upgrade Tokamak (COSMONAUT) has been developed for spectroscopy measurements of the 2.45 MeV neutron emission from deuterium plasmas at the ASDEX Upgrade. The instrument is based on a CLYC-7 inorganic scintillator, whereby the detection of fusion neutrons occurs via their interaction with 35Cl nuclei in the detector crystal, leading to a peak in the detector response function and providing excellent neutron/gamma-ray discrimination capabilities.

Sensitized Triplet-Triplet Annihilation in Nanostructured Polymeric Scintillators Allows for Pulse Shape Discrimination.

Scintillating materials emit light when exposed to ionizing radiation or particles and are used for the detection of nuclear threats, medical imaging, high-energy physics, and other usages. For some of these applications, it is vital to distinguish neutrons and charged particles from γ-rays. This is achievable by pulse shape discrimination (PSD), a time-gated technique, which exploits that the scintillation kinetics can depend on the nature of the incident radiation.

An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes.

Skeletal growth is enhanced by a shared role for SOX8 and SOX9 in promoting reserve chondrocyte commitment to columnar proliferation.

SOX8 was linked in a genome-wide association study to human height heritability, but roles in chondrocytes for this close relative of the master chondrogenic transcription factor SOX9 remain unknown. We undertook here to fill this knowledge gap. High-throughput assays demonstrate expression of human and mouse in growth plate cartilage.

Functional relevance of circRNA aberrant expression in pediatric acute leukemia with KMT2A::AFF1 fusion.

Circular RNAs (circRNAs) are emerging molecular players in leukemogenesis and promising therapeutic targets. In KMT2A::AFF1 (MLL::AF4)-rearranged leukemia, an aggressive disease compared with other pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), data about circRNAs are limited. Here, we disclose the circRNA landscape of infant patients with KMT2A::AFF1 translocated BCP-ALL showing dysregulated, mostly ectopically expressed, circRNAs in leukemia cells.

Phenotypic and genotypic characterization of 1q21.1 copy number variants: A report of 34 new individuals and literature review.

Recurrent 1q21.1 copy number variants (CNVs) have been associated with a wide spectrum of clinical features, ranging from normal phenotype to moderate intellectual disability, with congenital anomalies and dysmorphic features. They are often inherited from unaffected parents and the pathogenicity is difficult to assess.

Reassuring Data on the Cardiovascular Risk in Adults With X-linked Hypophosphatemia Receiving Conventional Therapy.

Context: X-linked hypophosphatemia (XLH) is a rare genetic disorder that results in increased plasma levels of fibroblast growth factor 23 (FGF23). Several studies have demonstrated a direct association between FGF23 and cardiovascular mortality in cohorts of patients with chronic renal failure. However, in patients with XLH, studies on the cardiovascular impact of the disease are rare, with contradictory results.

Effectiveness of short peripheral intravenous catheter educational programmes to improve clinical outcomes protocol for a systematic review.

The placement of a short peripheral intravenous catheter (sPIVC) is the most common invasive clinical procedure for patients requiring fluid infusion and multiple blood draws. Phlebitis and infiltration represent the most common catheter-related complications. Occlusions, dislocations, and infections are less frequent.

Gustavson syndrome is caused by an in-frame deletion in RBMX associated with potentially disturbed SH3 domain interactions.

RNA binding motif protein X-linked (RBMX) encodes the heterogeneous nuclear ribonucleoprotein G (hnRNP G) that regulates splicing, sister chromatid cohesion and genome stability. RBMX knock down experiments in various model organisms highlight the gene's importance for brain development. Deletion of the RGG/RG motif in hnRNP G has previously been associated with Shashi syndrome, however involvement of other hnRNP G domains in intellectual disability remain unknown.

Emotion recognition accuracy only weakly predicts empathic accuracy in a standard paradigm and in real life interactions.

The relationship between decoding ability (Emotion recognition accuracy, ERA) for negative and positive emotion expressions from only video, only audio and audio-video stimuli and the skill to understand peoples' unspoken thoughts and feelings (Empathic accuracy, EA) was tested. Participants ( = 101) from three groups (helping professionals with and without therapy training as well as non-helping professionals) saw or heard recordings of narrations of a negative event by four different persons. Based on either audio-video or audio-only recordings, the participants indicated for given time points what they thought the narrator was feeling and thinking while speaking about the event.

Genotype-phenotype Description of Vitamin D-dependent Rickets 1A: CYP27B1 p.(Ala129Thr) Variant Induces a Milder Disease.

Introduction: Vitamin D-dependent rickets type 1A (VDDR1A) is a rare genetic disease associated with loss-of-function variations in the gene encoding the vitamin D-activating enzyme 1α-hydroxylase (CYP27B1). Phenotype-genotype correlation is unclear. Long-term outcome data are lacking.

Fusion product measurements by nuclear diagnostics in the Joint European Torus deuterium-tritium 2 campaign (invited).

A new deuterium-tritium experimental, DTE2, campaign has been conducted at the Joint European Torus (JET) between August 2021 and late December 2021. Motivated by significant enhancements in the past decade at JET, such as the ITER-like wall and enhanced auxiliary heating power, the campaign achieved a new fusion energy world record and performed a broad range of fundamental experiments to inform ITER physics scenarios and operations. New capabilities in the area of fusion product measurements by nuclear diagnostics were available as a result of a decade long enhancement program.

Critical Role for Macrophages in the Developmental Programming of Pancreatic β-Cell Area in Offspring of Hypertensive Pregnancies.

Preeclampsia is a pregnancy-specific complication with long-term negative outcomes for offspring, including increased susceptibility to type 2 diabetes (T2D) in adulthood. In a rat reduced uteroplacental perfusion pressure (RUPP) model of chronic placental ischemia, maternal hypertension in conjunction with intrauterine growth restriction mimicked aspects of preeclampsia and resulted in female embryonic day 19 (e19) offspring with reduced β-cell area and increased β-cell apoptosis compared with offspring of sham pregnancies. Decreased pancreatic β-cell area persisted to postnatal day 13 (PD13) in females and could influence whether T2D developed in adulthood.

Pulmonary vein isolation alone versus pulmonary vein isolation with additional extensive ablation for paroxysmal and persistent atrial fibrillation.

Background: The value of additional ablation beyond pulmonary vein isolation for atrial fibrillation (AF) ablation is unclear, especially for persistent AF. It is uncertain whether substrate modification with additional extensive ablation improves outcomes. We reviewed our experience to determine whether pulmonary vein isolation with additional extensive ablation (PVIEA) improves outcomes compared to pulmonary vein isolation alone (PVIA) for AF ablation.

Fluconazole in hypercalciuric patients with increased 1,25(OH)D levels: the prospective, randomized, placebo-controlled, double-blind FLUCOLITH trial.

Background: Hypercalciuria is one of the most frequent metabolic disorders associated with nephrolithiasis and/or nephrocalcinosis possibly leading to chronic kidney disease (CKD) and bone complications in adults. Orphan diseases with different underlying primary pathophysiology share inappropriately increased 1,25(OH)D levels and hypercalciuria, e.g.