Genotipizzazione di marcatori di suscettibilità mediante studio caso-controllo nelle vasculiti anca-associate e nella fibrosi retroperitoneale idiopatica

Le vasculiti sono un gruppo eterogeneo di malattie autoimmuni che hanno in comune fenomeni flogistici e necrotici a carico delle pareti dei vasi, con conseguente ischemia e necrosi dei tessuti a valle. Possono essere primarie o secondarie e sistemiche o limitate ad un organo. Nel presente studio sono state considerate 3 vasculiti dei piccoli vasi, definite ANCA-associate (Antineutrophil Cytoplasmic Antibody), in quanto presentano anticorpi anticitoplasma del nucleo dei neutrofili : Granulomatosi di Wegener (WG), Sindrome di Churg-Strauss (CSS) e Poliangite microscopica (MPA). Oltre a queste tre è stata considerata anche la Fibrosi Retroperitoneale Idiopatica (IRF), patologia che per alcune caratteristiche è assimilabile alle vasculiti dei grandi vasi. I pazienti (tutti di origine Italiana) sono stati reclutati in gran parte dalla U.O. Nefrologia dell’Azienda Ospedaliero-Universitaria di Parma, e i restanti da altre Aziende Ospedaliere e strutture Universitarie che hanno collaborato nello studio. I progetti sono stati approvati dal Comitato Etico Unico per la provincia di Parma. La valutazione è stata basata sulle metodiche di discriminazione allelica mediante varie tecniche, fra le quali PCR Real-Time e sequenziamento del DNA. Le frequenze alleliche dei pazienti e dei controlli sono risultate essere tutte in equilibrio di Hardy-Weinberg. Gli studi caso-controllo sono stati analizzati mediante analisi statistica. Gli studi sono iniziati nel 2005 ed hanno portato all’identificazione di diversi marcatori genetici associati alle patologie indagate, pubblicati su riviste internazionali peer-review. Oltre a progetti nazionali, sono stati effettuati (e sono in corso tuttora) studi multicentrici europei volti ad indagare varianti di suscettibilità in tutto il genoma

A Decentralized Scheduler for On-line Self-test Routines in Multi-core Automotive System-on-Chips

Modern System-on-Chips (SoCs) deployed for safety-critical applications typically embed one or more processing cores along with a variable number of peripherals. The compliance of such designs with functional safety standards is achieved by a combination of different techniques based on hardware redundancy and in-field test mechanisms. Among these, Software Test Libraries (STLs) are rapidly becoming adopted for testing the CPU and peripherals modules. The STL is usually composed of two sets of self-test procedures: boot-time and run-time tests. The former set is typically executed during the boot or power-on phase of the SoC since it requires full access to the available hardware (e.g., these programs need to manipulate the Interrupt Vector Table and to access the system RAM). The latter set instead, is designed to coexist with the user application and can be executed without requiring special constraints. When the STL is intended for testing the different cores within a multi-core SoC, the concurrent execution of the boot-time self-tests becomes an issue since this could lead to a longer power-up phase and excessive utilization of system resources. The main intent of this work is to present the architecture of a decentralized software scheduler, conceived for the concurrent execution of the STL on the available cores. The proposed solution considers the typical constraints of an STL in a multi-core scenario when deployed in field, namely minimum system resources usage (i.e., code and data memory). The effectiveness of the proposed scheduler was experimentally evaluated on an industrial STL developed for a multi-core SoC manufactured by STMicroelectronics

TLR-4 and VEGF polymorphisms in chronic periaortitis

Chronic periaortitis (CP) is a rare disease that is characterised by fibro-inflammatory tissue surrounding the abdominal aorta and has both non-aneurysmal (idiopathic retroperitoneal fibrosis [IRF]) and aneurysmal forms (inflammatory abdominal aortic aneurysm [IAAA]). We investigated whether toll-like receptor 4 (TLR-4) and vascular endothelial growth factor (VEGF) polymorphisms were associated with susceptibility to, and the clinical features of CP

Giant elephantiasis neuromatosa in the setting of neurofibromatosis type 1: A case report

Elephantiasis neuromatosa (EN) can arise from a plexiform neurofibroma of the superficial and deep nerves developing from a hyperproliferation of the perineural connective tissue infiltrating adjacent fat and muscles. To date, the clinical association between EN and neurofibromatosis type 1 (NF1) has been poorly defined, particularly with regard to the role of lymphatic alterations and the consequent lymphedema. The present study reports the clinical and biomolecular features of EN in a NF1 patient with the clear clinical diagnostic criteria of multiple caf\ue8-au-lait macules, neurofibromas, EN, a positive family history and a novel NF1 germline c.1541_1542del mutation. Lymphoscintigraphy (LS) highlighted marked dermal backflow in the affected limb, hypertrophy of the ipsilateral inguinal and external iliac lymph nodes, and a bilateral lower limb lymph flow delay. These data support the hypothesis that an extensive hyperproliferative process involving perineural connective, limb soft tissues, bones and the lymphatic system can be responsible for EN in NF1 patients, on the basis of adipocyte metaplasia triggered by lymphostasis and lymphedema, and bone overgrowth and gigantism caused by chronic hyperemia. LS and magnetic resonance imaging can be efficacious tools in the diagnosis and clinical characterization of the early onset of the disease

Deterministic Cache-based Execution of On-line Self-Test Routines in Multi-core Automotive System-on-Chips

Traditionally, the usage of caches and deterministic execution of on-line self-test procedures have been considered two mutually exclusive concepts. At the same time, software executed in a multi-core context suffers of a limited timing predictability due to the higher system bus contention. When dealing with selftest procedures, this higher contention might lead to a fluctuating fault coverage or even the failure of some test programs. This paper presents a cache-based strategy for achieving both deterministic behaviour and stable fault coverage from the execution of self-test procedures in multi-core systems. The proposed strategy is applied to two representative modules negatively affected by a multi-core execution: synchronous imprecise interrupts logic and pipeline hazard detection unit. The experiments illustrate that it is possible to achieve a stable execution while also improving the state-of-the-art approaches for the on-line testing of embedded microprocessors. The effectiveness of the methodology was assessed on all the three cores of a multi-core industrial System- on-Chip intended for automotive ASIL D applications

RECURRENT RENAL CARCINOMA MIMICKING A GOITRE: A CASE REPORT

Although the thyroid is a high vascularised gland, it is not common terget of metastases from extraglandular cancer. We reported a case of a 70 year-old woman who underwnt total thyroidectomy for multinodular goitre. In the patient's clinical hystory a nephrectomy was carried out 2 years before due to unspecified causes. The histopathological examination of the thyiroid showed a pattern compatible with clear cell renal carcinoma metastasis. The patient's relatives revealed, when questioned again, that the nephrectomy was due to the presence of a clear renal cell carcinoma keep concealed to the patients. Thanks to a timely intervention, the mass was removed and a better survival was guaranted to the patient

NF1 truncating mutations associated to aggressive clinical phenotype with elephantiasis neuromatosa and solid malignancies

Background/aim: Von Recklinghausen disease is a syndrome characterized by a wide phenotypic variability giving rise to both, cutaneous and visceral benign and malignant neoplasms. The first include cutaneous neurofibromas, subcutaneous and plexiform neurofibromas. The latter can undergo malignant transformation and/or determine elephantiasis neuromatosa. Visceral tumors may include malignant peripheral nerve sheet tumors, gastrointestinal stromal tumors, cerebral gliomas and abdominal neurofibromas. In the present study, the authors discuss the clinical and biomolecular characterization of a cohort of 20 families with a diagnosis of type 1 neurofibromatosis. Patients and methods: Clinically, the cohort includes three probands with elephantiasis neuromatosa and a peculiarly high incidence of breast and gastrointestinal cancer. Results: Among the 14 NF1 mutations documented, 10 encoding for a truncated protein have been associated to particularly aggressive clinical phenotypes including elephantiasis neuromatosa, malignant peripheral nerve sheet tumors, breast cancer, gastrointestinal stromal tumors. Conclusion: This effect on protein synthesis, rather than the type of NF1 mutation, is the key to the explanation of the genotype-phenotype correlations in the context of neurofibromatosis type 1

A new MEFV gene mutation in an Iranian patient with familial Mediterranean fever.

Familial mediterranean fever (FMF) is an inherited autoinflammatory disorder characterized by recurrent episodes of fever and painful inflammation involving the intra-abdominal organs, the lungs and the joints, which is highly prevalent in specific ethnic groups including the Iranians. We report a 12-year-old boy from Iran, with a clinical history of recurrent fever. Based on the suggestive clinical data, mutational analysis revealed the presence of the novel c.1945C>T heterozygous variant in exon 10, which leads to a leucine to phenylalanine change at position 649 of the protein. The mutation was inherited from the mother. This novel mutation lies in exon 10 of the MEFV gene, which encodes for a domain called B30.2-SPRY, located in the C-terminal region of the pyrin protein and contains the most frequent mutations associated with FMF. The present report expands the spectrum of MEFV gene mutations associated with FMF. The uniqueness of this study, compared with other published case reports, consists in the new mutation found in the MEFV gene. In fact, new mutations in this gene are of high interest, in order to better understand the role of this gene in autoinflammation

Clinico-pathological and biomolecular findings in Italian patients with multiple cutaneous neurofibromas

<p>Abstract</p> <p>Background</p> <p>Neurofibroma occurs as isolated or multiple lesions frequently associated with neurofibromatosis type 1 (NF1), a common autosomal dominant disorder affecting 1 in 3500 individuals. It is caused by mutations in the <it>NF1 </it>gene, which comprises 60 exons and is located on chromosome 17q11.2. <it>NF1 </it>is a fully penetrant gene exhibiting a mutation rate some 10-fold higher compared with most other disease genes. As a consequence, a high number of cases (up to 50%) are sporadic. Mutation detection is complex due to the large size of the <it>NF1 </it>gene, the presence of pseudogenes and the great variety of lesions.</p> <p>Methods</p> <p>110 patients with at least two neurofibroma lesions recorded in the files of the Pathology Department of the University of Modena during the period 1999-2010, were included in this study. Through interviews and examination of clinical charts, pedigrees were drawn for all patients who were affected by at least two neurofibromas. We attempted to delineate the clinical features of NF1 and the mutational spectrum in the cohort of 11 NF1 families identified. For each proband, the whole coding sequence and all splice sites were studied for mutations, either by the protein truncation test (PTT), or, more frequently, by denaturing high performance liquid chromatography (DHPLC). Two GIST tumors of NF1 patients were tested for somatic NF1 mutations.</p> <p>Results</p> <p>NF1 germline mutations were identified in 7 (68%) patients. A novel mutation, c.3457_3460delCTCA in exon 20, was detected in two unrelated patients and was associated with different clinical features. No NF1 somatic mutations were detected in the GIST tumors. A wide phenotypic and genotypic variability was registered, both in the spectrum of skin lesions and visceral neoplasms, even among members of the same family who had different clinical manifestations. A proclivity to multiple tumors arising in the same subject, and a higher tumor burden per family were the most relevant findings observed in patients affected with the NF1 mutation.</p> <p>Conclusions</p> <p>We report a novel NF1 mutation and we contribute data for the refinement of the NF1 genotype-phenotype spectrum.</p

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+\u2009ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+\u2009ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA