Calcimimetic agents: Review and perspectives

Calcimimetic agents: Review and perspectives.BackgroundRecognition of the role of the extracellular calcium-sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The activation of this receptor by small changes in the extracellular ionized calcium (ec(Ca2+)) regulates PTH, calcitonin secretion, urinary calcium excretion, and, ultimately, bone turnover.MethodsThe cloning of the CaR and the discovery of mutations that make the receptor less or more sensitive to calcium have allowed a better understanding of several hereditary disorders characterized by either hyperparathyroidism or hypoparathyroidism. The CaR, able to amplify the sensitivity of the CaR to Ca++ and suppress PTH levels with a resulting decrease in blood Ca++, became an ideal target for the development of compounds, the calcimimetics. Experience with the calcimimetic R-568 in patients with primary and secondary hyperparathyroidism and parathyroid carcinoma are summarized.ResultsThe first clinical studies with the first-generation calcimimetic agents have demonstrated their efficacy in lowering plasma intact PTH concentration in uremic patients with secondary hyperparathyroidism. However, the low bioavailability of these first calcimimetics predicts a difficult clinical utilization. The second-generation calcimimetic, AMG 073, having a better pharmacokinetic profile, appears to be effective and safe for the treatment of secondary hyperparathyroidism, suppressing PTH levels while simultaneously reducing serum phosphorus levels and the calcium x phosphorus product.ConclusionThe advantage of controlling PTH secretion without the complications related to hypercalcemia, hyperphosphatemia, and increased calcium x phosphorus product is very promising

A multivariate approach for multi-step demand forecasting in assembly industries: Empirical evidence from an automotive supply chain

PreprintDemand forecasting works as a basis for operating, business and production planning decisions in many supply chain contexts. Yet, how to accurately predict the manufacturer's demand for components in the presence of end-customer demand uncertainty remains poorly understood. Assigning the proper order quantities of components to suppliers thus becomes a nontrivial task, with a significant impact on planning, capacity and inventory-related costs. This paper introduces a multivariate approach to predict manufacturer's demand for components throughout multiple forecast horizons using different leading indicators of demand shifts. We compare the autoregressive integrated moving average model with exogenous inputs (ARIMAX) with Machine Learning (ML) models. Using a real case study, we empirically evaluate the forecasting and supply chain performance of the multivariate regression models over the component's life-cycle. The experiments show that the proposed multivariate approach provides superior forecasting and inventory performance compared with traditional univariate benchmarks. Moreover, it reveals applicable throughout the component's life-cycle, not just to a single stage. Particularly, we found that demand signals at the beginning of the life-cycle are predicted better by the ARIMAX model, but it is outperformed by ML-based models in later life-cycle stages.INCT-EN - Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção(UIDB/00319/2020

Receiver Calibration and Quantum Random Number Generation for Continuous-variable Quantum Key Distribution

The desire for secure communications and the advent of quantum computing has spurred innovation into key-distribution technologies that are secure against future quantum computers. Computationally secure solutions based on post quantum algorithms and physically-secure solutions using either discrete-variable or continuous-variable quantum key distribution (CV-QKD) have been proposed. The attraction with CV-QKD systems in particular is the potential to leverage the vast knowledge base and access scaling benefits of photonic integration for conventional coherent optical communication for key distribution. CV-QKD requires detailed characterization of coherent receiver hardware, specifically noise generated by electronics and shot noise caused by the local oscillator (LO) laser. This work investigates the temporal stability of the receiver noise power which defines the amount of trusted noise in the quantum link used to compute the secret key rate (SKR). Depending on the noise power’s stability, this characterization must be repeated often, typically in the order of seconds. Therefore, this work explores the possibility of using the shot noise measurement as a source of quantum random numbers, which is required by a CV-QKD transceiver. This work enables further integration of the CV-QKD hardware, removing the need for a separate quantum random number generator (QRNG)

Blueprint for a european calciphylaxis registry initiative. the european calciphylaxis network (eucalnet)

Calcific uraemic arteriolopathy (CUA) is a rare disease and continues to be a clinical challenge. The typical course of CUA is characterized by painful skin discolouration and induration evolving to necrotic ulcerations. Medial calcification of cutaneous arterioles and extensive extracellular matrix remodelling are the hallmarks of CUA. The epidemiology and risk factors associated with this disease are still not fully understood. Moreover, CUA treatment strategies vary significantly among centres and expert recommendations are heterogeneous. Registries may provide important insights and information to increase our knowledge about epidemiology and clinical aspects of CUA and may help to optimize its therapeutic management. In 2006, we established an internet-based registry in Germany (www.calciphylaxie.de) to allow online notification of patients with established or suspected CUA. The registry includes a comprehensive database with questions covering >70 parameters and items regarding patient-related and laboratory data, clinical background and presentation as well as therapeutic strategies. The next phase will be to allow international patient registration via www.calciphylaxis.net as part of the multinational EuCalNet (European Calciphylaxis Network) initiative, which is supported by the ERA-EDTA scientific working group 'CKD-MBD'. Based on the valuable experience with the previous German CUA registry, EuCalNet will be a useful tool to collect data on the rare disease CUA and may become a basis for prospective controlled trials in the near future

Microcystin-LR detection in water by the Fabry–Pérot interferometer using an optical fibre coated with a sol–gel imprinted sensing membrane

Cyanobacteria deteriorate the water quality and are responsible for emerging outbreaks and epidemics causing harmful diseases in Humans and animals because of their toxins. Microcystin-LR (MCT) is one of the most relevant cyanotoxin, being the most widely studied hepatotoxin. For safety purposes, the World Health Organization recommends a maximum value of 1 μg L−1 of MCT in drinking water. Therefore, there is a great demand for remote and real-time sensing techniques to detect and quantify MCT. In this work a Fabry–Pérot sensing probe based on an optical fibre tip coated with a MCT selective thin film is presented. The membranes were developed by imprinting MCT in a sol–gel matrix that was applied over the tip of the fibre by dip coating. The imprinting effect was obtained by curing the sol–gel membrane, prepared with (3-aminopropyl) trimethoxysilane (APTMS), diphenyl-dimethoxysilane (DPDMS), tetraethoxysilane (TEOS), in the presence of MCT. The imprinting effect was tested by preparing a similar membrane without template. In general, the fibre Fabry–Pérot with a Molecular Imprinted Polymer (MIP) sensor showed low thermal effect, thus avoiding the need of temperature control in field applications. It presented a linear response to MCT concentration within 0.3–1.4 μg L−1 with a sensitivity of −12.4 ± 0.7 nm L μg−1. The corresponding Non-Imprinted Polymer (NIP) displayed linear behaviour for the same MCT concentration range, but with much less sensitivity, of −5.9 ± 0.2 nm L μg−1. The method shows excellent selectivity for MCT against other species co-existing with the analyte in environmental waters. It was successfully applied to the determination of MCT in contaminated samples. The main advantages of the proposed optical sensor include high sensitivity and specificity, low-cost, robustness, easy preparation and preservation

Modulation of blood redox status by the progression of induced apical periodontitis in rats

This study aimed to investigate if apical periodontitis in different periods changes systemic levels of the antioxidant and pro-oxidant parameters in Wistar rats. Twenty-four rats were randomly allocated into healthy animals, apical periodontitis at 14 days (AP14) and apical periodontitis at 28 days (AP28). The first mandibular molars were accessed in the AP groups, and the pulp chamber was exposed to the oral environment, inducing the apical lesion. After 14 and 28 days, the animals were anesthetized, euthanized, and hemimandibles were collected for micro-computed tomography (micro-CT) analysis to measure lesion volume, bone volume (BV), percent of bone to total tissue volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), and trabecular space (Tb.Sp). A histological examination of the remaining bone was also performed. Finally, blood samples were collected for oxidative biochemistry analysis, investigating glutathione (GSH), Trolox equivalent antioxidant capacity (TEAC), and lipid peroxidation (TBARS). The lesion volume was greater at 28 than at 14 days, as shown by micro-CT. AP14 and AP28 had decreased BV and Tb.Th, but only AP28 showed a reduction in BV/TV. Tb.N and Tb. Sp were increased in apical periodontitis at 28 days. In the histopathological analysis, AP14 had focal regions of moderate mononuclear inflammatory infiltrate, and AP28 had an intense inflammatory infiltrate with bacterial colonies. In the biochemical evaluation, GSH, TEAC, and TBARS were increased after 14 days. However, GSH returned to control levels, TEAC was similar to AP14, and TBARS increased significantly after 28 days. Therefore, the oxidative biochemistry response was modulated according to the progression of periapical damage. After 14 days, the organism could still react to the injury. However, at 28 days, the antioxidant response decreased, associated with an increase in TBAR

estudos artísticos

A revista Gama prossegue o aprofundamento da sua linha editorial específica e dentro do projeto mais alargado de desafiar criadores a debaterem e apresentar a obra de outros criadores, dentro do espaço descentrado que é o universo dos idiomas ibéricos. Trata-se de, dentro deste tema mais abrangente, revisitar arquivos, autores de épocas um pouco recuadas, de resgatar do esquecimento o património que existe e urge apresentar, discutir, colocar em ação, fazer funcionar, pela voz dos artistas. A arte necessita de ser ativada por intermédio do pensamento, e com ele, do discurso. Há vozes silenciosas que aguardam olhos, ouvidos, inquietações, deslumbramentos. Quando uma peça é descoberta é como se voltasse a ser feita: esse é o paradoxo do documento. A arte é vestígio e ao mesmo tempo universalidade, eternidade. É local e total. É sempre, em simultâneo, sem contradição, facto e possibilidade, presença e ausência. Os vinte e quatro artigos apresentados neste número cinco da Revista Gama oferecem outros tantos pontos de vista sobre os discursos artísticos. Recupera-se obra desconhecida, mostram-se obras, descobrem-se autores desaparecidos. Aqui a arte depositou-se, precipitou-se, tornou-se visível ao resgate. O resgate, operação de amor, é feito por artistas. Os públicos estão no futuro, à nossa espera.info:eu-repo/semantics/publishedVersio