PASSIVE ACCESSORY MOVEMENT AT THE ELBOW: A ROENTGENOGRAPHIC ANALYSIS

Longitudinal movement of the radius, in relation to the ulna, occurring during abduction and adduction of the elbow, and during radial and ulnar deviation of the wrist, was examined roet-genographically on five students. A fixation device was designed to stabilize the humerus while the passive movements were carried out, and all measurements were done with the arm in 0° extension. The average movement from full adduction to full abduction was 10.4° and, at the same time, the radius moved an average of 1.6 mm distally in relation to the ulna. When the wrist was moved from full radial deviation to full ulnar deviation the radius moved an average of 0.1 mm in relation to the ulna. The importance of assessing passive accessory movements at the elbow in the examination and treatment of elbow lesions is discussed

Caratterizzazione molecolare dei difetti genici associati a Colestasi intraepatica familiare progressiva mediante Next Generation Sequencing

Progressive Familial Intrahepatic Cholestasis (PFIC) is a group of autosomal recessive diseases that affects especially newborns and children, with progression to liver failure in the first decades of life. PFIC is classified into five types based on the genetic defect involved in bile transport. It is caused by homozygous or compound heterozygous mutations in ATP8B1, ABCB11, ABCB4, TJP2 and NR1H4 genes. Other benign late-onset phenotypes and non-progressive forms (BRIC, LPAC, DIC and ICP) are caused by heterozygous mutations in the same gene pattern. Other genes have been recently involved in both progressive and non-progressive forms. The aim of the project is to develop and validate a broad, reliable, rapid and cost-saving NGS genetic test for PFIC patients. 96 patients were tested for the first described genes and 80 patients were sequenced with the latest discovered candidate genes for PFIC and other related benign phenotypes. Bioinformatic and statistic pipelines were applied. A total of 184 different variants has been identified in our cohort: 18 pathogenic, 46 VUS, 44 likely benign and 76 benign. P/LP mutations were found in 12% of patients: 2 in ATP8B1, 3 in ABCB11, ABCB4 and TJP2 each, one in ABCC2, JAG1, NOTCH2. Many patients had multiple variants in several genes. Patients had from 7 to 35 variants each and some SNPs were significantly associated with biochemical parameters and phenotypic features (e.g. liver fibrosis) that could better explain clinics and accelerate the progression to liver failure. Our detection rate is according to other studies proposing multi-gene panels. Our analysis may be useful for the molecular diagnostics of PFIC and a better characterization and understanding of the linking between molecular defects and different subtypes of the disease. The high SNPs prevalence let us to hypothesize a synergistic haplotype effect in determining different multifactorial cholestasis phenotypes and overlapping features

Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature

The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and whole-exome sequencing have improved the diagnostic procedures of familial intrahepatic cholestasis (FIC), as well as the discovery of several genes responsible for FIC. Moreover, mutations in these genes, even in the heterozygous status, may be responsible for cryptogenic cholestasis in both young and adults. Mutations in FIC genes can influence serum and hepatic levels of bile acids. Experimental studies on the NR1H4 gene have shown that high bile acids concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all risk conditions for developing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). NR1H4 gene encodes farnesoid X-activated receptor having a pivotal role in bile salts synthesis. Moreover, HCC and CCA can emerge in patients with several FIC genes such as ABCB11, ABCB4 and TJP2. Herein, we reviewed the available data on FIC-related hepatobiliary cancers, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation

Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis

Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more than 50% of acute fulminant hepatic failure cases. In addition, approximately 30% of iDILI are cholestatic (drug-induced cholestasis (DIC)). The liver's metabolism and clearance of lipophilic drugs depend on their emission into the bile. Therefore, many medications cause cholestasis through their interaction with hepatic transporters. The main canalicular efflux transport proteins include: 1. the bile salt export pump (BSEP) protein (ABCB11); 2. the multidrug resistance protein-2 (MRP2, ABCC2) regulating the bile salts' independent flow by excretion of glutathione; 3. the multidrug resistance-1 protein (MDR1, ABCB1) that transports organic cations; 4. the multidrug resistance-3 protein (MDR3, ABCB4). Two of the most known proteins involved in bile acids' (BAs) metabolism and transport are BSEP and MDR3. BSEP inhibition by drugs leads to reduced BAs' secretion and their retention within hepatocytes, exiting in cholestasis, while mutations in the ABCB4 gene expose the biliary epithelium to the injurious detergent actions of BAs, thus increasing susceptibility to DIC. Herein, we review the leading molecular pathways behind the DIC, the links with the other clinical forms of familial intrahepatic cholestasis, and, finally, the main cholestasis-inducing drugs

Gene Panel Analysis in a Large Cohort of Patients With Autosomal Dominant Polycystic Kidney Disease Allows the Identification of 80 Potentially Causative Novel Variants and the Characterization of a Complex Genetic Architecture in a Subset of Families

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders in humans and the majority of patients carry a variant in either PKD1 or PKD2. Genetic testing is increasingly required for diagnosis, prognosis, and treatment decision, but it is challenging due to segmental duplications of PKD1, genetic and allelic heterogeneity, and the presence of many variants hypomorphic or of uncertain significance. We propose an NGS-based testing strategy for molecular analysis of ADPKD and its phenocopies, validated in a diagnostic setting. Materials and Methods: Our protocol is based on high-throughput simultaneous sequencing of PKD1 and PKD2 after long range PCR of coding regions, followed by a masked reference genome alignment, and MLPA analysis. A further screening of additional 14 cystogenes was performed in negative cases. We applied this strategy to analyze 212 patients with a clinical suspicion of ADPKD. Results and Discussion: We detected causative variants (interpreted as pathogenic/likely pathogenic) in 61.3% of our index patients, and variants of uncertain clinical significance in 12.5%. The majority (88%) of genetic variants was identified in PKD1, 12% in PKD2. Among 158 distinct variants, 80 (50.6%) were previously unreported, confirming broad allelic heterogeneity. Eleven patients showed more than one variant. Segregation analysis indicated biallelic disease in five patients, digenic in one, de novo variant with unknown phase in two. Furthermore, our NGS protocol allowed the identification of two patients with somatic mosaicism, which was undetectable with Sanger sequencing. Among patients without PKD1/PKD2 variants, we identified three with possible alternative diagnosis: a patient with biallelic mutations in PKHD1, confirming the overlap between recessive and dominant PKD, and two patients with variants in ALG8 and PRKCSH, respectively. Genotype-phenotype correlations showed that patients with PKD1 variants predicted to truncate (T) the protein experienced end-stage renal disease 9 years earlier than patients with PKD1 non-truncating (NT) mutations and >13 years earlier than patients with PKD2 mutations. ADPKD-PKD1T cases showed a disease onset significantly earlier than ADPKD-PKD1NT and ADPK-PKD2, as well as a significant earlier diagnosis. These data emphasize the need to combine clinical information with genetic data to achieve useful prognostic predictions

Neural correlates of socio-emotional perception in 22q11.2 deletion syndrome.

BACKGROUND: Social impairments are described as a common feature of the 22q11.2 deletion syndrome (22q11DS). However, the neural correlates underlying these impairments are largely unknown in this population. In this study, we investigated neural substrates of socio-emotional perception. METHODS: We used event-related functional magnetic resonance imaging (fMRI) to explore neural activity in individuals with 22q11DS and healthy controls during the visualization of stimuli varying in social (social or non-social) or emotional (positive or negative valence) content. RESULTS: Neural hyporesponsiveness in regions of the default mode network (inferior parietal lobule, precuneus, posterior and anterior cingulate cortex and frontal regions) in response to social versus non-social images was found in the 22q11DS population compared to controls. A similar pattern of activation for positive and negative emotional processing was observed in the two groups. No correlation between neural activation and social functioning was observed in patients with the 22q11DS. Finally, no social × valence interaction impairment was found in patients. CONCLUSIONS: Our results indicate atypical neural correlates of social perception in 22q11DS that appear to be independent of valence processing. Abnormalities in the social perception network may lead to social impairments observed in 22q11DS individuals