Search Results (11)

Generalized arterial calcification of infancy (GACI) is a rare disease characterized by arterial calcification. GACI is caused by a mutation in the ENPP1 or ABCC6 genes. GACI causes severe hypertension and heart failure, and approximately 50% of patients die within the first 6 months. In particular, preterm infants with GACI often die due to immature cardiac function. Bisphosphonates are effective in treating GACI; however, no standardized treatment regimen is available. We experienced a case of a preterm infant with GACI born at 30 weeks gestation. Ultrasonography showed high-intensity lesions in the arteries, and computed tomography revealed calcification of the arteries throughout the body, leading to the diagnosis of GACI. We administered intravenous pamidronate, and her cardiac contraction improved. The initial scheduled interval between drug administrations was 2 months. However, the cardiac contraction worsened 1 month after the pamidronate administration. Therefore, we decreased the dosing interval and administered a second course of pamidronate, which improved her cardiac function. We then switched to oral etidronate. To improve the morbidity and mortality rates of preterm infants with GACI, it is important to obtain an early diagnosis of GACI by investigating high-intensity lesions in the arteries and performing early administration of an appropriate type of bisphosphonate. Full article

The Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) ectoenzyme regulates vascular intimal proliferation and mineralization of bone and soft tissues. ENPP1 variants cause Generalized Arterial Calcification of Infancy (GACI), a rare genetic disorder characterized by ectopic calcification, intimal proliferation, and stenosis of large- and medium-sized arteries. ENPP1 hydrolyzes extracellular ATP to pyrophosphate (PP_i) and AMP. AMP is the precursor of adenosine, which has been implicated in the control of neointimal formation. Herein, we demonstrate that an ENPP1-Fc recombinant therapeutic inhibits proliferation of vascular smooth muscle cells (VSMCs) in vitro and in vivo. Addition of ENPP1 and ATP to cultured VSMCs generated AMP, which was metabolized to adenosine. It also significantly decreased cell proliferation. AMP or adenosine alone inhibited VSMC growth. Inhibition of ecto-5′-nucleotidase CD73 decreased adenosine accumulation and suppressed the anti-proliferative effects of ENPP1/ATP. Addition of AMP increased cAMP synthesis and phosphorylation of VASP at Ser157. This AMP-mediated cAMP increase was abrogated by CD73 inhibitors or by A_2aR and A_2bR antagonists. Ligation of the carotid artery promoted neointimal hyperplasia in wild-type mice, which was exacerbated in ENPP1-deficient ttw/ttw mice. Prophylactic or therapeutic treatments with ENPP1 significantly reduced intimal hyperplasia not only in ttw/ttw but also in wild-type mice. These findings provide the first insight into the mechanism of the anti-proliferative effect of ENPP1 and broaden its potential therapeutic applications beyond enzyme replacement therapy. Full article

Pseudoxanthoma Elasticum (PXE) is an inherited disease characterized by elastic fiber calcification in the eyes, the skin and the cardiovascular system. PXE results from mutations in ABCC6 that encodes an ABC transporter primarily expressed in the liver and kidneys. It took nearly 15 years after identifying the gene to better understand the etiology of PXE. ABCC6 function facilitates the efflux of ATP, which is sequentially hydrolyzed by the ectonucleotidases ENPP1 and CD73 into pyrophosphate (PPi) and adenosine, both inhibitors of calcification. PXE, together with General Arterial Calcification of Infancy (GACI caused by ENPP1 mutations) as well as Calcification of Joints and Arteries (CALJA caused by NT5E/CD73 mutations), forms a disease continuum with overlapping phenotypes and shares steps of the same molecular pathway. The explanation of these phenotypes place ABCC6 as an upstream regulator of a purinergic pathway (ABCC6 → ENPP1 → CD73 → TNAP) that notably inhibits mineralization by maintaining a physiological Pi/PPi ratio in connective tissues. Based on a review of the literature and our recent experimental data, we suggest that PXE (and GACI/CALJA) be considered as an authentic “purinergic disease”. In this article, we recapitulate the pathobiology of PXE and review molecular and physiological data showing that, beyond PPi deficiency and ectopic calcification, PXE is associated with wide and complex alterations of purinergic systems. Finally, we speculate on the future prospects regarding purinergic signaling and other aspects of this disease. Full article

Generalized arterial calcification of infancy (GACI) is a rare autosomal-recessive disease characterized by extensive arterial calcification in infancy, with clinical manifestations such as arterial stenoses and heart failure. The ENPP1 inactivation mutation has been identified as a potential defect in most of the cases of GACI, while mutations in ABCC6 are demonstrated in patients who are genotyped as pseudoxanthoma elasticum and only limited cases of GACI are reported. Whole-exome sequencing was applied for the detection of pathogenic variants. Copy-number variants of pathogenic genes were also evaluated through a bioinformatic process and were further validated by real-time quantitative PCR. In this report, we described the clinical information and treatment of a patient with extensive arterial calcification. We have identified the underlying cause as biallelic mutations in ABCC6 (NM_00117: exon30, c.4223_4227dupAGCTC p.(Leu1410Serfs*56)) and a unique exonic deletion that spans from the first to the fourth exons of ABCC6 (chr16:16313388-16330869)). This discovery was made by utilizing a combined genetic testing approach. With the review of previously reported GACI patients with ABCC6 mutation, our work contributed to enriching the mutation spectrum of GACI and providing further information on this rare form of inherited disorder. Full article

The methanogenic strain Mx-05^T was isolated from the human fecal microbiome. A phylogenetic analysis based on the 16S rRNA gene and protein marker genes indicated that the strain is affiliated with the order Methanomassiliicoccales. It shares 86.9% 16S rRNA gene sequence identity with Methanomassiliicoccus luminyensis, the only member of this order previously isolated. The cells of Mx-05^T were non-motile cocci, with a diameter range of 0.4–0.7 μm. They grew anaerobically and reduced methanol, monomethylamine, dimethylamine, and trimethylamine into methane, using H₂ as an electron donor. H₂/CO₂, formate, ethanol, and acetate were not used as energy sources. The growth of Mx-05^T required an unknown medium factor(s) provided by Eggerthella lenta and present in rumen fluid. Mx-05^T grew between 30 °C and 40 °C (optimum 37 °C), over a pH range of 6.9–8.3 (optimum pH 7.5), and between 0.02 and 0.34 mol.L⁻¹ NaCl (optimum 0.12 mol.L⁻¹ NaCl). The genome is 1.67 Mbp with a G+C content of 55.5 mol%. Genome sequence annotation confirmed the absence of the methyl branch of the H₄MPT Wood–Ljungdahl pathway, as described for other Methanomassiliicoccales members. Based on an average nucleotide identity analysis, we propose strain Mx-05^T as being a novel representative of the order Methanomassiliicoccales, within the novel family Methanomethylophilaceae, for which the name Methanomethylophilus alvi gen. nov, sp. nov. is proposed. The type strain is Mx-05^T (JCM 31474T). Full article

Recent literature reflects the substantial progress in combining spatial, temporal and spectral capacities for remote sensing applications. As a result, new issues are arising, such as the need for methodologies that can process simultaneously the different dimensions of satellite information. This paper presents PLS regression extended to three-way data in order to integrate multiwavelengths as variables measured at several dates (time-series) and locations with Sentinel-2 at a regional scale. Considering that the multi-collinearity problem is present in remote sensing time-series to estimate one response variable and that the dataset is multidimensional, a multiway partial least squares (N-PLS) regression approach may be relevant to relate image information to ground variables of interest. N-PLS is an extension of the ordinary PLS regression algorithm where the bilinear model of predictors is replaced by a multilinear model. This paper presents a case study within the context of agriculture, conducted on a time-series of Sentinel-2 images covering regional scale scenes of southern France impacted by the heat wave episode that occurred on 28 June 2019. The model has been developed based on available heat wave impact data for 107 vineyard blocks in the Languedoc-Roussillon region and multispectral time-series predictor data for the period May to August 2019. The results validated the effectiveness of the proposed N-PLS method in estimating yield loss from spectral and temporal attributes. The performance of the model was evaluated by the R² obtained on the prediction set (0.661), and the root mean square of error (RMSE), which was 10.7%. Limitations of the approach when dealing with time-series of large-scale images which represent a source of challenges are discussed; however, the N–PLS regression seems to be a suitable choice for analysing complex multispectral imagery data with different spectral domains and with a clear temporal evolution, such as an extreme weather event. Full article

The Hölderian regularity is an important mathematical feature of a signal, connected with the physical nature of the measured parameter. Many algorithms have been proposed in literature for estimating the local Hölder exponent value, but all of them lead to biased estimates. This paper attempts to apply the grey system theory (GST) on the raw signal for improving the accuracy of Hölderian regularity estimation. First, synthetic logs data are generated by the successive random additions (SRA) method with different types of Hölder functions. The application on these simulated signals shows that the Hölder functions estimated by the GST are more precise than those derived from the raw data. Additionally, noisy signals are considered for the same experiment, and more accurate regularity is obtained using signals processed using GST. Second, the proposed technique is implemented on well log data measured at an Algerian exploration borehole. It is demonstrated that the regularity determined from the well logs analyzed by the GST is more reliable than that inferred from the raw data. In addition, the obtained Hölder functions almost reflect the lithological discontinuities encountered by the well. To conclude, the GST is a powerful tool for enhancing the estimation of the Hölderian regularity of signals. Full article

Generalized Arterial Calcification of Infancy (GACI) is a rare disease inherited in a recessive manner, with severe and diffuse early onset of calcifications along the internal elastic lamina in large and medium size arteries. The diagnosis results are from clinical manifestations, imaging, histopathologic exams, and genetic tests. GACI is predominantly caused by biallelic pathogenic variant in the ENPP1 gene (GACI1, OMIM#208000) and, to a lesser extent, by pathogenic variants in the ABCC6 gene (GACI2, OMIM#614473). We present a novel variation in the ENPP1 gene identified in a patient clinically diagnosed with GACI and confirmed by genetic investigation and autopsy as GACI type 1. The sequence analysis of the patient’s ENPP1 gene detected two heterozygous variants c.1412A>G (p.Tyr471Cys) and c.1715T>C (p.Leu572Ser). The variant c.1715T>C (p.Leu572Ser) has not been described yet in the literature and in mutation databases. A genetic analysis was also carried out for the parents of the newborn; the heterozygous pathogenic variant c.1412A>G (p.Tyr471Cys) was detected in the mother’s ENPP1 gene, and a sequence analysis of the father’s ENPP1 gene revealed the novel heterozygous variant c.1715T>C (p.Leu572Ser). Our results showed that the variant c.1715T>C (p.Leu572Ser) may have a pathogenic role in the development of GACI type1 (GACI1, OMIM#208000), at least when associated with the pathogenic c.1412A>G (p.Tyr471Cys) variant. The identification of novel mutations potentially enabled genotype/phenotype associations that will ultimately have an impact on clinical management and prognosis for the disease. Full article

Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds. Full article

Pseudoxanthoma elasticum (PXE), the prototype of heritable ectopic mineralization disorders, manifests with deposition of calcium hydroxyapatite crystals in the skin, eyes and arterial blood vessels. This autosomal recessive disorder, due to mutations in ABCC6, is usually diagnosed around the second decade of life. In the spectrum of heritable ectopic mineralization disorders are also generalized arterial calcification of infancy (GACI), with extremely severe arterial calcification diagnosed by prenatal ultrasound or perinatally, and arterial calcification due to CD73 deficiency (ACDC) manifesting with arterial and juxta-articular mineralization in the elderly; the latter disorders are caused by mutations in ENPP1 and NT5E, respectively. The unifying pathomechanistic feature in these three conditions is reduced plasma levels of inorganic pyrophosphate (PPi), a powerful endogenous inhibitor of ectopic mineralization. Several on-going attempts to develop treatments for these conditions, either with the goal to normalize PPi plasma levels or by means of preventing calcium hydroxyapatite deposition independent of PPi, are in advanced preclinical levels or in early clinical trials. This overview summarizes the prospects of treatment development for ectopic mineralization disorders, with PXE, GACI and ACDC as the target diseases, from the 2020 vantage point. Full article

This exploratory study analyzed how three serial killers (i.e., Bundy, Gacy, and Dahmer) potentially rationalized and justified their murders by applying techniques of neutralization. This paper discusses how the use of these neutralizations also functions as a form of stigma management assisting in the maintenance of a positive presentation of self, thus mitigating responsibility for their crimes. This study conducted a content analysis of data comprised from interviews and case histories of these three serial killers. Based on these analyses, the impression is conveyed that these killers used neutralizations to manage their identities (i.e., present “normal” selves), mitigate responsibility for their actions, and minimize the stigma associated with being labeled a serial killer. Full article