Synonymous Mutations in RNASEH2A Create Cryptic Splice Sites Impairing RNase H2 Enzyme Function in Aicardi–Goutières Syndrome

Aicardi–Goutières syndrome is an inflammatory disorder resulting from mutations in TREX1, RNASEH2A/2B/2C, SAMHD1, or ADAR1. Here, we provide molecular, biochemical, and cellular evidence for the pathogenicity of two synonymous variants in RNASEH2A. Firstly, the c.69G>A (p.Val23Val) mutation causes the formation of a splice donor site within exon 1, resulting in an out of frame deletion at the end of exon 1, leading to reduced RNase H2 protein levels. The second mutation, c.75C>T (p.Arg25Arg), also introduces a splice donor site within exon 1, and the internal deletion of 18 amino acids. The truncated protein still forms a heterotrimeric RNase H2 complex, but lacks catalytic activity. However, as a likely result of leaky splicing, a small amount of full‐length active protein is apparently produced in an individual homozygous for this mutation. Recognition of the disease causing status of these variants allows for diagnostic testing in relevant families.     

Hyperferritinemia is Associated with Serologic Antiphospholipid Syndrome in SLE Patients

Ferritin may play a direct role on the immune system. We sought to determine if elevated levels of ferritin in lupus patients correlate with disease activity and organ involvement in a large cohort. Ferritin levels (gender and age adjusted) were assessed in 274 lupus serum samples utilizing the LIASON Ferritin automated immunoassay method. Significant disease activity was determined if European Consensus Lupus Activity Index (ECLAM)?>?2 or Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)?>?4. Utilizing an EXCEL database, we compared elevated ferritin levels to manifestations grouped by organ involvement, serology, and previous therapy. The patients were predominantly female (89%), median age was 37 years old, and disease duration was 10.6?±?7.7 years. Hyperferritinemia was found in 18.6% of SLE patients. Compared to subjects with normal ferritin levels, a significantly greater proportion of patients with hyperferritinemia had thrombocytopenia (15.4% vs. 33.3%, p?=?0.003) and lupus anticoagulant (11.3% vs. 29.0%, p?=?0.01). Additionally, compared to normoferritinemic subjects, hyperferritinemic subjects had significantly higher total aCL (99.7?±?369 vs. 30.9?±?17.3 GPI, p?=?0.02) and aCL IgM antibody levels (75.3?±?357.4 vs. 9.3?±?10.3 GPI, p?=?0.02), and marginally lower aCL IgG antibody levels (9.2?±?4.9 vs. 9.7?±?3.9 GPI, p?=?0.096). While the ECLAM score significantly correlated with hyperferritinemia (p?=?0.04), the SLEDAI score was marginally associated with hyperferritinemia (p?=?0.1). Serositis was marginally associated with hyperferritinemia, but not with other manifestations. An association with serologic APS was encountered. Hyperferritinemia was associated with thrombocytopenia, lupus anticoagulant, and anti-cardiolipin antibodies suggest that it may be an early marker for secondary antiphospholipid syndrome in SLE patients.     

Liver cirrhosis in glycogen storage disease Ib

Glycogen storage disease Ib is an inborn error of carbohydrate metabolism leading to impaired glycogenolysis and gluconeogenesis. Cardinal symptoms include fasting hypoglycemia, lactic acidosis and hepatomegaly as well as neutropenia. We report for the first time on the development of liver cirrhosis in a nine-year-old boy in the course of glycogen storage disease Ib and discuss possible underlying pathomechanisms.     

Improved detection of synovial boundaries in ultrasound examination by using a cascade of active-contours

Rheumatoid arthritis (RA) is a chronic multisystemic autoimmune disease, with an unclear etiopathogenesis. Its early diagnosis and activity assessment are essential to adjust the proper therapy. Among the different imaging techniques, ultrasonography (US) allows direct visualization of early inflammatory joint changes as synovitis, being also rapidly performed and easily accepted by patients. We propose an algorithm to semi-automatically detect synovial boundaries on US images, requiring minimal user interaction. In order to identify the synovia-bone and the synovia-soft tissues interfaces, and to tackle the morphological variability of diseased joints, a cascade of two different active contours is developed, whose composition corresponds to the whole synovial boundary.The algorithm was tested on US images acquired from proximal interphalangeal (PIP) and metacarpophalangeal (MCP) finger joints of 34 subjects. The results have been compared with a consensus manual segmentation. We obtained an overall mean sensitivity of 85 ± 13%, and a mean Dice's similarity index of 80 ± 8%, with a mean Hausdorff distance from the manual segmentation of 28 ± 10 pixels (approximately 1.4 ± 0.5 mm), that are a better performance than those obtained by the raters with respect to the consensus.     

EGFR-Targeted Therapy for Non-Small Cell Lung Cancer: Focus on EGFR Oncogenic Mutation

The two essential requirements for pathologic specimens in the era of personalized therapies for non-small cell lung carcinoma (NSCLC) are accurate subtyping as adenocarcinoma (ADC) versus squamous cell carcinoma (SqCC) and suitability for EGFR molecular testing, as well as for testing of other oncogenes such as EML4-ALK and KRAS. Actually, the value of EGFR expressed in patients with NSCLC in predicting a benefit in terms of survival from treatment with an epidermal growth factor receptor targeted therapy is still in debate, while there is a convincing evidence on the predictive role of the EGFR mutational status with regard to the response to tyrosine kinase inhibitors (TKIs).This is a literature overview on the state-of-the-art of EGFR oncogenic mutation in NSCLC. It is designed to highlight the preclinical rationale driving the molecular footprint assessment, the progressive development of a specific pharmacological treatment and the best method to identify those NSCLC who would most likely benefit from treatment with EGFR-targeted therapy. This is supported by the belief that a rationale for the prioritization of specific regimens based on patient-tailored therapy could be closer than commonly expected.     

Social reasoning in Tourette syndrome

Introduction. Tourette syndrome (TS) is thought to be associated with striatal dysfunction. Changes within frontostriatal pathways in TS could lead to changes in abilities reliant on the frontal cortex. Such abilities include executive functions and aspects of social reasoning.

Methods. This study aimed to investigate executive functioning and Theory of Mind (ToM; the ability to reason about mental states, e.g., beliefs and emotions), in 18 patients with TS and 20 controls. A range of tasks involving ToM were used. These required participants to make judgements about mental states based on pictures of whole faces or the eyes alone, reason about humour in cartoons that featured sarcasm, irony or “slapstick” style humour, and make economic decisions. The executive measures assessed inhibition and verbal fluency.

Results. Patients with TS exhibited significantly poorer performance than controls on all four tasks involving ToM, even when patients with comorbid obsessive-compulsive disorder were excluded. These difficulties were despite no inhibitory deficits. Patients with TS exhibited impairment on the verbal fluency task but their performance on executive and ToM tasks was not related.

Conclusions. We propose that TS is associated with changes in ToM. The observed deficits could reflect dysfunction in frontostriatal pathways involving ventromedial prefrontal cortex.     

Furo[3,2-c]coumarins carrying carbon substituents at C-2 and/or C-3. Isolation,biological activity,synthesis and reaction mechanisms

The isolation, biological activity and synthesis of natural furo[3,2-c]coumarins are presented, covering mainly the developments in the last 35 years. The most relevant approaches toward the synthesis of 2-substituted, 3-substituted and 2,3-disubstituted heterocycles are also discussed, with emphasis on the efficiency of the processes and their mechanisms.

The isolation, synthesis and biological activity of naturally occurring furo[3,2-c] coumarins carrying carbon substituents at C-2 and/or C-3, is discussed. Synthetic approaches toward the properly functionalized heterocyclic motif are also presented.     

Chemoselective and metal-free reduction of α,β-unsaturated ketones by in situ produced benzeneselenol from O-(tert-butyl) Se-phenyl selenocarbonate

The carbon–carbon double bond of arylidene acetones and chalcones can be selectively reduced with benzeneselenol generated in situ by reacting O-(tert-butyl) Se-phenyl selenocarbonate with hydrochloric acid in ethanol. This mild, metal-free and experimentally simple reduction procedure displays considerable functional-group compatibility, products are obtained in good to excellent yields, and the use of toxic Se/CO mixture and NaSeH, or the smelly and air-sensitive benzeneselenol, is avoided.

The carbon–carbon double bond of arylidene acetones and chalcones can be selectively reduced with benzeneselenol generated in situ by reacting O-(tert-butyl) Se-phenyl selenocarbonate with hydrochloric acid in ethanol.