GnRH replacement rescues cognition in Down syndrome.

At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction-gonadotropin-releasing hormone (GnRH)-and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.

A variant in the CASR gene (c.368T>C) causing hypocalcemia refractory to standard medical therapy.

SUMMARY: Hypoparathyroidism is characterized by low or inappropriately normal parathormone production, hypocalcemia and hyperphosphatemia. Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene. Current treatments for ADH type 1 include supplementation with calcium and active vitamin D. We report a case of hypoparathyroidism in an adolescent affected by syncope without prodrome. The genetic testing revealed a variant in the CASR gene. Due to standard therapy ineffectiveness, the patient was treated with recombinant human parathyroid hormone (1-34), magnesium aspartate and calcitriol. He remained asymptomatic and without neurological sequelae until adulthood. Early diagnosis and treatment are important to achieve clinical stability. LEARNING POINTS: Autosomal dominant hypocalcemia (ADH) type 1 is one of the genetic etiologies of hypoparathyroidism caused by heterozygous activating mutations in the calcium-sensing receptor (CASR) gene. The variant c.368T>C (p.Leu123Ser) in heterozygosity in the CASR gene is likely pathogenic and suggests the diagnosis of ADH type 1. Teriparatide (recombinant human parathyroid hormone 1-34) may be a valid treatment option to achieve clinical stability for those individuals whose condition is poorly controlled by current standard therapy.

Naturally occurring radioactive material and risk assessment of tailings of polymetallic and Ra/U mines from legacy sites.

Old mine tailings from Northern and Central Portugal were studied in order to perform a radiological and chemical characterization. The evaluation of massic activity of natural radionuclides and concentrations in tailings of polymetallic and Ra/U mines was performed by gamma spectrometry and neutron activation analysis. Iron speciation was carried out by Mössbauer spectroscopy. In polymetallic tailings with physical ore processing (Cumieira and Verdes - exploited for Sn, Nb-Ta) higher contents of Th, 228Ra and 226Ra in the coarser materials occur, probably due to their presence in host rock and ore fragments. In finer tailings, washing may explain the lower 226Ra and 210Pb massic activity. In tailings with physical/chemical ore processing (Covas - exploited for W and Sn) high U contents and a tendency for higher 226Ra and 210Pb massic activity in the fine materials is observed, probably due to their incorporation in nano-sized particles of iron oxides. A high variation of the 210Pb/226Ra ratio occurs in polymetallic tailings; a deficit of 210Pb can be observed particularly in deposits of settling tanks drained from dumps of chemically treated ore. In Ervideira-Mestras tailings (Ra/U exploitation) where no ore process in situ was performed, a near equilibrium between 210Pb and 226Ra occurs. Dose risk assessment was carried out by calculating external outdoor Annual Effective Dose Rate; the dose rates in air due to terrestrial gamma radiation are low for the polymetallic tailings (<47 nGy/h), and higher for tailings of Ra/U (up to 4130 nGy/h), in the worst scenario.

The yin and yang of α-synuclein-associated epigenetics in Parkinson's disease.

Parkinson's disease is the second most prevalent neurodegenerative disorder. The main neuropathological hallmarks of the disease are the degeneration of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of protein inclusions known as Lewy bodies. Recently, great attention has been given to the study of genes associated with both familial and sporadic forms of Parkinson's disease. Among them, the α-synuclein gene is believed to play a central role in the disease and is, therefore, one of the most studied genes. Parkinson's disease is a complex disorder and, as such, derives from the interaction between genetic and environmental factors. Here, we offer an update on the landscape of epigenetic-mediated regulation of gene expression that has been linked with α-synuclein and associated with Parkinson's disease. We also provide an overview of how epigenetic modifications can influence the transcription and/or translation of the α-synuclein gene and, on the other hand, how α-synuclein function/dysfunction can, per se, affect the epigenetic landscape. Finally, we discuss how a deeper understanding of the epigenetic profile of α-synuclein may enable the development of novel therapeutic approaches for Parkinson's disease and other synucleinopathies.