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To correlate the presence of calcifications in alveolar echinococcosis (AE) hepatic lesions to the metabolic activity in 18 fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT). Our institutional review board approved this study. 61 patients (29 women, 32 men, aged from 15 to 86 years) were included in the study. Images of FDG-PET/CT were interpreted by two independent nuclear medicine physicians. AE hepatic lesions were classified as AE lesions with or without hypermetabolic activity. The presence of calcifications was assessed on unenhanced CT scans by two independent radiologists blinded with regard to the metabolic activity of the AE hepatic lesions. Every single calcification the size of which was

Introduction Tumoral calcinosis (TC) is a difficult-to-treat complication that can occur during several diseases such as dermatomyositis or genetic hyperphosphatemia. It is a painful and disabling condition that can lead to local complications including joint mobility reduction, cutaneous ulceration and superinfection. For the largest lesions, the treatment relies essentially on surgery. Intravenous sodium thiosulfate (STS) is efficient to treat calciphylaxis in patients undergoing hemodialysis. Local injections of STS seem efficient in superficial calcifications. Objective To report the efficacy and safety of intra-lesional injections of STS in tumoral calcinosis. Results We report two cases of successful intra-lesional injections of STS. A 44-year-old woman, with a history of dermatomyositis, presenting large subcutaneous calcifications in the right elbow, and a 42-year-old man, with a history of familial tumoral calcinosis, presenting large intramuscular calcifications in the right buttock, received weekly intra-lesional of 1–3 g STS injections for 12 and 21 months, respectively. In both cases, the treatment relieved pain and greatly reduced the tumoral calcinosis with a very significant functional improvement without specific adverse effects. In case 1, TC size decreased from 28.7*56.0 mm at baseline to 21.5*30.6 mm at M12 treatment (59% reduction). In case 2, TC reduced from 167.5*204.3 mm at baseline to 86.2*85.2 mm at M21 treatment (79% reduction). Conclusion Local injection of STS could be a promising therapeutic strategy for large and deep TC lesions and could therefore be an alternative to surgery.

Meuwissen and collaborators define a novel genetic cause of pseudo-TORCH syndrome, which resembles the sequelae of congenital infection and represents a novel type I interferonopathy., Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders.

International audience; In this review we consider diseases associated with pathological mineralization/ossification, namely, ankylosing spondylitis (AS), osteoarthritis (OA), generalized artery calcification of infancy (GACI), vascular calcification as well as chondrocalcinosis (CC) and pseudo gout. Deciphering the key enzymes implicated in the calcification process is an objective of prime importance and the ultimate goal is to synthesize inhibitors of these enzymes in order to provide efficient alternate therapeutic strategies that will slow down the pathologic mineralization and complement the arsenal of anti-inflammatory drugs. One of the difficulties in the definition of diseases associated with pathologic mineralization/ossification lies in the controversial relationship between the type of calcification and the nature of the disease. Here, we propose to clarify this relationship by making a distinction between diseases associated with hydroxyapatite (HA) and calcium pyrophosphate dihydrate (CPPD) deposits. AS, OA, GACI and vascular calcification are usually characterized by mineralization/ossification associated with HA deposits, while CC and pseudo gout are mostly characterized by CPPD deposits. Although both HA and CPPD deposits may occur concomitantly, as in chronic pyrophosphate arthritis or in OA with CPPD, they are formed as a result of two antagonistic processes indicating that treatment of distinct diseases can be only achieved by disease-specific drug therapies. The hydrolysis of PPi, an inhibitor of HA formation, is mostly controlled by tissue non-specific alkaline phosphatase TNAP, while PPi production in the extracellular medium is controlled by ANK, a PPi transporter, and/or NPP1 which generates PPi from nucleotide triphosphates. Low PPi concentration may lead to a preferential deposition of HA while high PPi concentration will favor the formation of CPPD deposits. Thus, HA and CCPD deposition cannot occur concomitantly because they are determined by the Pi/PPi ratio which, in turn, depends on the relative activities of antagonistic enzymes, TNAP hydrolyzing PPi or ANK and NPP1 producing PPi. TNAP inhibitors could prevent HA formation in AS, in late OA, in GACI, as well as in vascular calcifications, while ANK or NPP1 inhibitors could slow down CCPD deposition in CC and pseudo gout.

International audience; Widespread endochondral and intramembranous ectopic bone formation is mediated by extracellular PP(i) deficiency that develops in ank/ank mice. Herein we report on the rapid condensation into chondrogenic nodules of cultured ank/ank bone marrow stromal cells (BMSCs). We compared the roles of increased chondrogenic potential versus altered osteoblast function in the ank/ank phenotype. To do so, we crossbred ank/ank mice with mice lacking Vanin-1 pantetheinase, which inhibits synthesis of the chondrogenesis regulator glutathione, since we observed increased Vanin-1 expression and pantetheinase activity and decreased glutathione in ank/ank BMSCs. Vnn1(-/-) BMSCs demonstrated delayed chondrogenesis mediated by increased glutathione. Moreover, increased chondrogenesis of ank/ank BMSCs and increased chondrogenic transdifferentiation and calcification by ank/ank aortic smooth muscle cells and explants were corrected by Vanin-1 knockout. Osteoblastogenesis was accelerated in ank/ank mesenchymal stem cells. However, in cultured ank/ank osteoblasts, Vanin-1 knockout actually increased specific alkaline phosphatase activity and lowered extracellular PP(i), and did not correct increased calcification. Moreover, Vanin-1 knockout failed to correct the ank/ank skeletal soft tissue phenotype. Therefore, ank/ank periskeletal soft tissue calcification appears more dependent on altered osteoblastic function than enhanced chondrogenic potential and is not dependent on Vanin-1; however, Vanin-1 regulates chondrogenesis via glutathione metabolism and is critical for accelerated chondrogenesis of ank/ank mesenchymal precursors and P(i) donor-driven chondrogenic transdifferentiation and calcification of aortic smooth muscle cells.

International audience; We report a 12-year-old boy who presented with abdominal pain and who was found to have an aneurysm of the abdominal aorta (AAA). The patient was born from a quadruplet pregnancy induced by in vitro fertilization. Postnatal transient respiratory distress required assisted ventilation that had been monitored by two consecutive umbilical arterial catheters (UAC). AAA is a rare condition in childhood. Infection and/or trauma are known to be the most frequent causes. Most of the reported cases have occurred in children in whom a UAC had been placed during the neonatal period. In this patient the delay between UAC placement and diagnosis was considerable. At the time of this report the patient had remained well during a follow-up of 8 years after treatment.

International audience; BACKGROUND AND AIM OF THE STUDY: Transcatheter valve-in-valve implantation is an emerging option for patients with structural deterioration of an aortic bioprosthesis and who are at a high surgical risk. The present case underlines the need for dedicated imaging to accurately understand the mechanism of valve failure, and the feasibility of a valve-in-valve procedure. METHODS: A patient with structural bioprosthetic deterioration at echocardiography was investigated using computed tomography (CT) scanning and novel 3D slicer software. The findings were compared with those revealed at intraoperative pathology. RESULTS: Post-processed CT images showed the bulk of calcifications to be located at the subvalvular level, suggesting the presence of calcified pannus. Pathology of the explanted valve confirmed that the valve stenosis was due primarily to pannus. Misdiagnosed calcified pannus represents a major threat during valve-in-valve procedures, due mainly to embolic risk. CONCLUSION: The 3D slicer elaboration of CT images may be invaluable in providing a precise definition of the mechanism of valve failure, and also to establish the feasibility of either a valve-in-valve procedure or conventional surgery.

International audience; This paper gathers different investigations dedicated to pathological calcifications made of apatite in order to define the structural characteristics, which display a clinical significance. Such approach helps the clinician to define the characterisation tools, which have to be combined to obtain such structural characteristics in order to establish a possible relationship between the structural characteristics of the pathological calcifications and the disease. The fact that it is now possible to perform such experiments at the subcellular scale gives new opportunities for a large number of diseases associated to pathological calcification. Moreover, new diagnostic tools based on these characterisation techniques, quite sensitive to analyze microcrystals, can be defined.

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Background and Purpose— Although intracranial artery calcification (IAC) has been reported to be a risk factor for ischemic stroke, the prognostic implications of IAC in stroke outcome are unknown. The purpose of this study was to determine the association between IAC and risk of vascular events and death in patients with stroke after hospital discharge. Methods— All patients with ischemic stroke over a 1-year period were included (n=302). IAC, assessed by multidetector CT, was defined as hyperdense foci (peak density >130 Hounsfield units) and assessed in the 7 major cerebral arteries. The IAC scores ranged from 0 (no calcification) to 7. Follow-up information on major clinical events (including fatal or nonfatal ischemic stroke, cardiac and peripheral artery events, and all-cause death) was obtained by means of a structured phone interview. Results— IAC was present in 260 patients (83%). With a mean follow-up of 773±223 days, 88 major clinical events occurred in 67 patients (22%): 45 new ischemic vascular events (ischemic stroke: n=22; cardiac event: n=15; peripheral artery event: n=8) and 43 deaths from any cause. Patients with the highest IAC scores had significantly higher rates of death and vascular events than those with the lowest IAC scores (log rank test, P =0.029). In the Cox proportional hazards regression model, the IAC score was significantly associated with major clinical events (hazard ratio, 1.34; 95% CI, 1.11–1.61; P =0.002). Conclusions— In patients with ischemic stroke, IAC detection may constitute a simple marker of a high risk of future major clinical events.

International audience; Cysticercosis has been reported in Muslim countries in workers coming from endemic regions for Taenia solium. For the first time in Mali, the authors report a case of autochtonous neurocysticercosis where Muslim religion is predominent. The patient was a woman student with fever, arthralgia, headaches, consciousness troubles followed by partial motor epilepsy. Diagnosis was confirmed by clinic, serology ELISA and Western blotting and cephalic tomodensitometry analysis. The medical treatment was successfully based on combination of albendazole and praziquantel. The origin of contamination remains unknown and further investigations are needed, particularly with veterinary research team and the National League against epilepsy recently founded in Mali.

International audience; In children, pseudohypoparathyroidism (PHP) is a rare but classical cause of basal ganglia calcifications. It is caused by resistance to parathormone (PTH). Hypocalcemia, which may be symptomatic, is its main feature. We report the case of a 13-year-old boy, affected by type Ib PHP revealed by hypocalcemia and seizures, with basal ganglia calcifications on the CT scan. We describe the characteristics of the 2 main types of PHP and emphasize the search for this disease when basal ganglia calcifications are discovered, even fortuitously, on a cerebral CT scan.

BACKGROUND: Hypertension and chronic renal failure (CRF) are considered models of accelerated arterial stiffening. Arterial stiffness increases further when CRF is associated with hypertension. We hypothesized that, in patients with mild CRF, aortic gene expression profile would include genes involved in arterial calcifications and enlargement. METHOD: We analysed human aorta with the 'GeneChip Microarray' technology, in patients with or without CRF, scheduled for a coronary artery bypass graft. RESULTS: Nine of 25 patients had high-quality RNA and were included in the study. Among the 101 transcripts differentially expressed between CRF patients and controls, 97 transcripts were overexpressed in CRF patients. Two genes had the highest overexpression in CRF patients: lumican (LUM), involved in the regulation of collagen fibrillogenesis; and ornithine decarboxylase (ODC1), involved in polyamine biosynthesis, smooth muscle cell growth and proliferation. Immunohistochemical staining revealed an increased amount of LUM and ODC1 in the vascular smooth muscle cells (VSMCs) of CRF compared to non-CRF aortic sections. Eight genes were implicated in the regulation of the cytoskeleton (including capping protein muscle Z-line 1 alpha and moesin) and cell migration, and five genes were implicated in extracellular matrix function and apoptosis. A trend towards an upregulation of candidate genes involved in arterial calcifications was observed in CRF patients, but did not reach statistical significance. Carotid-femoral pulse wave velocity was not correlated with gene expression level. CONCLUSION: In conclusion, these results show that patients at an early stage of CRF have a specific gene expression profile of aortic tissue and suggest that genes implicated in collagen fibrillogenesis, and VSMCs migration and proliferation, particularly LUM and ODC1, may play a role.

Calcification of arteries is a major risk factor for cardiovascular mortality in humans. Using genetic approaches, we demonstrate here that the transcriptional intermediary factor 1α (TIF1α), recently shown to function as a tumor suppressor in murine hepatocytes, also participates in a molecular cascade that prevents calcifications in arterioles and medium-sized arteries. We further provide genetic evidence that this function of TIF1α is not exerted in hepatocytes. The sites of ectopic calcifications in mutant mice lacking TIF1α resemble those seen in mice carrying an activating mutation of the calcium sensor receptor ( Casr ) gene and, in TIF1 α-deficient kidneys, Casr expression is increased together with that of many other vitamin D receptor (VDR) direct target genes, namely Car2 , Cyp24a1 , Trpv5 , Trpv6 , Calb1 , S100g , Pthlh , and Spp1 . Thus, our data indicate that TIF1α represses the VDR pathway in kidney and suggest that an up-regulation of Casr expression in this organ could account for ectopic calcifications generated upon TIF1 α deficiency. Interestingly, the calcifying arteriopathy of TIF1 α-null mutant mice shares features with the human age-related Mönckeberg's disease and, overall, the TIF1 α-null mutant pathological phenotype supports the hypothesis that aging is promoted by increased activity of the vitamin D signaling pathway.

“Nanobacteria” are nanometer-scale spherical and ovoid particles which have spurred one of the biggest controversies in modern microbiology. Their biological nature has been severely challenged by both geologists and microbiologists, with opinions ranging from considering them crystal structures to new life forms. Although the nature of these autonomously replicating particles is still under debate, their role in several calcification-related diseases has been reported. In order to gain better insights on this calciferous agent, we performed a large-scale project, including the analysis of “nanobacteria” susceptibility to physical and chemical compounds as well as the comprehensive nucleotide, biochemical, proteomic, and antigenic analysis of these particles. Our results definitively ruled out the existence of “nanobacteria” as living organisms and pointed out the paradoxical role of fetuin (an anti-mineralization protein) in the formation of these self-propagating mineral complexes which we propose to call “nanons.” The presence of fetuin within renal calculi was also evidenced, suggesting its role as a hydroxyapatite nucleating factor., Author Summary In the last decade, the exact nature of nanobacteria was one of the most controversial of scientific questions. An audacious theory proposed the existence of nanobacteria, initially discovered in Italian hot spring deposits, as a new life form responsible for a wide range of diseases in humans, thus qualifying them as new agents of emerging infectious diseases. The community of microbiologists remained therefore skeptical about the fact that such structures, 100 times smaller than bacteria and highly resistant to heat and other treatments that would normally kill the latter, could be living entities fully capable of self-replication. Other scientists wondered if they might be an unusual form of crystal rather than micro-organisms. The comprehensive characterization of nanobacteria was the focus of our study. Our results definitively ruled out the existence of nanobacteria as living entities and revealed that they correspond to self-propagating mineral-fetuin complexes that we called “nanons.”

International audience; We report the CT findings in a patient with a lateral neck mass histologically diagnosed as a laryngeal schwannoma but presenting some uncommon CT features. CT showed unusual calcified components, very rarely observed and potentially misleading for diagnosis. However, this imaging feature can be found in ancient schwannomas. Our case is, therefore, a very rare one and reviews the main differential diagnoses.

Context: Hyperostosis-hyperphosphatemia syndrome (HHS) is a rare metabolic disorder characterized by hyperphosphatemia and localized hyperostosis. HHS is caused by mutations in GALNT3, which encodes UDP-N-acetyl-α-d-galactosamine:polypeptide N- acetylgalactosaminyltransferase 3. Familial tumoral calcinosis (TC), characterized by ectopic calcifications and hyperphosphatemia, is caused by mutations in the GALNT3 or fibroblast growth factor 23 (FGF23) genes. Objective: Our objective was to identify mutations in FGF23 or GALNT3 and determine serum FGF23 levels in an HHS patient. Design: Mutation detection in FGF23 and GALNT3 was performed by DNA sequencing, and serum FGF23 concentrations were measured by ELISA. Patients or Other Participants: A 5-year-old French boy with HHS and his family members participated. Results: The patient presented with painful cortical lesions in his leg. Radiographs of the affected bone showed diaphyseal hyperostosis. The lesional tissue comprised trabeculae of immature, woven bone surrounded by fibrous tissue. Biochemistry revealed elevated phosphate, tubular maximum rate for phosphate reabsorption per deciliter of glomerular filtrate, and 1,25-dihydroxyvitamin D levels. The patient was a compound heterozygote for two novel GALNT3 mutations. His parents and brother were heterozygous for one of the mutations and had no biochemical abnormalities. Intact FGF23 level in the patient was low normal, whereas C-terminal FGF23 was elevated, a pattern similar to TC. Conclusion: The presence of GALNT3 mutations and elevated C-terminal, but low intact serum FGF23, levels in HHS resemble those seen in TC, suggesting that HHS and TC are different manifestations of the same disorder. The absence of biochemical abnormalities in the heterozygous individuals suggests that one normal allele is sufficient for secretion of intact FGF23.

Calcific aortic valve stenosis is by far the most common valve disease in developed countries.1 The first clinical symptoms usually appear in the late 60s. Prosthetic aortic valve replacement is the only effective treatment at present.2 The reasons for the occurrence of calcifications of the aortic cusps leading eventually after many years to aortic valve stenosis are unknown. Some risk factors, mainly those already recognised in vascular disease, have been found to be associated with aortic valve stenosis and are considered to cause the disease.3,4 However, these factors are totally non-specific and may be confounded with factors leading to other illnesses. Recently a genetic hypothesis has been proposed after observation of a few familial cases5 but remains largely challenged in the absence of gene determination. The aim of our study was to evaluate whether epidemiological data collected in a selected region of France could provide evidence in favour of this hypothesis. The list of all patients who had undergone aortic valve replacement for calcific aortic valve stenosis in the cardiac surgery department of the Brest University Hospital between January 1996 and June 2003 was obtained from the central computerised registration of medical diagnosis and surgical procedures of the hospital, coded according to the International classification of diseases , 10th revision. This list was compared, and if necessary completed, with the diary registries of all the surgical interventions performed in the cardiac surgery department. For each patient, the following data were collected: name, sex, date of surgery, date of birth, and social security number. The social security number is a 15 digit number allowing identification for sex, year and month of birth, and geographic origin (region and commune). France is administratively divided into 22 provinces, about 100 regions, and 36 000 communes. The commune is the …

International audience; The barotrauma induced by inflation of the balloon on an obstructive atherosclerotic plaque induces several distinct, complex effects. The object of this study was to describe these mechanisms based on endovascular echographic sections of coronary stenoses before and after balloon angioplasty. The 32 lesions analysed were richly cellular (81.2%) and associated with calcifications in 31% of cases. The remodelling index before angioplasty was used to individualize a majority of lesions with chronic arterial constriction (56.2%). The modelling of the plaque (dilatation or constriction) had no effect on the final luminal result. Global analysis of the endoluminal gain (4.38 +/- 2.28 mm2) showed that it was mainly due to reduction of plaque surface (78.2% of gain) without prejudging the mechanism, and less due to expansion of the global arterial surface (21.8% of the gain). The type of remodelling affected the mechanisms of action of balloon angioplasty. Dissection was present in 53.1% of cases. Fragmentation of the plaque with embolisation is a common phenomenon (28% of cases). The authors conclude that there are four mechanisms which coexist: 1) Reduction of plaque thickness cannot physically correspond to simple compression of tissue. The plaque is redistributed longitudinally. 2) Arterial expansion only plays a minor part in endoluminal gain. 3) Plaque rupture is directly related to the acute increase in wall stress often exceeding the thresholds of rupture of its components. Finally, 4) embolisation by parietal fragmentation, a mechanism often unknown or ignored which plays an essential part in the potentially deleterious effects.

International audience; BACKGROUND: A recent study reported an association between a large head circumference at birth and adult total IgE. However, no study has yet looked at the relation between head circumference and cord blood IgE. OBJECTIVES: To assess the relationship between child's cord blood total IgE and head circumference at birth taking parental allergy and smoking habits as well as placental calcifications into account. METHODS: Two samples of unselected newborns and their mothers with uncomplicated pregnancies were studied: 235 in study A with data on parental allergy and 99 in study B with data on placental calcifications. RESULTS: In both studies, cord blood IgE was significantly related to large head circumference at birth (0.07 vs 0.15 IU/mL for newborns < 37 cm vs >/= 37 cm, respectively, P = 0. 03 for study A and 0.09 vs 0.28 IU/mL, P = 0.04 for study B). Cord blood IgE was unrelated to parental smoking habits. Maternal IgE significantly increased in mothers exposed to both active and passive smoking during pregnancy compared with other pregnant women. High cord blood IgE were associated with high maternal IgE (r = 0. 38; P < 0.001). Multiple linear regression showed that large head circumference, maternal IgE and clinical manifestations of maternal, but not paternal, allergy were independently related to cord blood IgE (study A). Large head circumference and placental calcifications were independently related to a higher cord blood IgE level (study B). CONCLUSIONS: Besides the role of genetic factors, results on the preferential role of maternal vs paternal allergy and associations to large head circumference and placental calcifications support the hypothesis of the role of environmental factors during pregnancy on the level of cord blood IgE.

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