Common structural features characterize interstitial intrachromosomal Xp and 18q triplications

Rare intrachromosomal triplications producing partial tetrasomies have been reported for a number of chromosomes. A detailed molecular characterization, necessary to define the mechanism of their formation, has so far been lacking. We report on the detailed clinical, cytogenetic, and molecular characterization of two triplications, one de novo involving chromosome 18q, the other familial on chromosome Xp. The clinical phenotype of the patient with 18q triplication, very likely due to overexpression of one or more of the genes in the region, consists mainly of facial dysmorphisms and developmental delay. The familial Xp triplication does not cause an increase in the number of copies of any gene and is almost certainly a polymorphism. The rearrangements are actually complex duplications/triplications. In both patients, their proximal breakpoints are located within complex segmental duplications, one containing the VCX gene cluster on chromosome Xp, the other the TCEB3 genes on chromosome 18q. A proximal duplicated region is also present in both patients. All junctions we analyzed were formed by non-homologous end joining (NHEJ). The structural features shared between our patients suggest the involvement of a common mechanism in the genesis of interstitial intrachromosomal triplications.     

Renal function and severity of bright liver. Relationship with insulin resistance, intrarenal resistive index, and glomerular filtration rate

Aims  

Relationships of renal function and liver disease are described in acute and chronic liver failure. The aim of the study is to investigate which relationship, if any, is present between severity of non-alcoholic fatty liver disease (NAFLD), assessed by bright liver score (BLS) versus mild-moderate renal insufficiency assessed by glomerular filtration rate (GFR) and by ultrasound intra-renal arterial resistive index (RRI). Moreover, which difference, if any, can be found in NAFLD patients with normal versus increased transaminases.     

The amyloid-β₄₂ proxy, amyloid-β(25-35), induces normal human cerebral astrocytes to produce amyloid-β₄₂

Amyloid-β (Aβ) peptides in the brain of patients with Alzheimer's disease (AD) assemble into various aggregation forms that differ in size, structure, and functional properties. Previous studies have shown that Aβ binds to nicotinic acetylcholine receptors (nAChRs) and activates signaling cascades that result in the disruption of synaptic functions. These findings suggest a possible link between impaired cholinergic neurotransmitter function in AD and Aβ pathogenesis. However, it is not yet known how the different Aβ assemblies interact with specific nAChR subtypes. In the present study, we demonstrate that neurotoxicity in neuronal cells in culture induced by fibrillar Aβ(1-40) is prevented through an α7 nAChR-dependent mechanism. The α7 nAChR agonists varenicline and JN403 increased binding of the amyloid ligand [3H]PIB to fibrillar Aβ in AD frontal cortex autopsy tissue. This suggests that the presence of nAChR agonists may inhibit interaction of Aβ with α7 nAChRs and prevent the formation of Aβ/α7 nAChR complexes. This interaction was confirmed in binding assays with [12?I]Aβ(1-40) and α7 nAChRs in autopsy brain tissue homogenates from the frontal cortex. The functional effects of Aβ fibrils and oligomers on nAChRs were examined by measuring intracellular calcium ([Ca(2+)](i) levels. Oligomeric, but not fibrillar Aβ(1-40), increased [Ca(2+)](i) in neuronal cells, and this effect was attenuated by varenicline. Our findings demonstrate that fibrillar Aβ exerts neurotoxic effects mediated partly through a blockade of α7 nAChRs, whilst oligomeric Aβ may act as a ligand activating α7 nAChRs, thereby stimulating downstream signaling pathways.     

Elite controllers display higher activation on central memory CD8 T cells than HIV patients successfully on HAART

T cell activation plays an important role in driving CD4 depletion during the course of HIV infection. There is scarce information about activation of different T cell subsets in HIV(+) individuals experiencing distinct disease progression. The activation of different CD4(+) and CD8(+) T cell subsets and its contribution to total T cell activation were examined measuring CD38 expression by flow cytometry in 120 HIV-infected individuals and 9 uninfected healthy controls. HIV-infected patients were divided into four groups: 11 elite controllers (EC), 14 viremic controllers (VC), 61 antiretroviral-naive typical progressors (TP), and 34 progressors with viral suppression (VS) under antiretroviral therapy. EC displayed significantly greater activation levels than VS, with a higher contribution of central memory subsets to the activation of total CD8 T cells (p = 0.002). The activation of central memory CD8(+) T cells significantly correlated with viral load in TP regardless of CD4 counts. In contrast with VS, proviral load was undetectable in all EC. Compared to VS, EC display abnormal and higher activation levels of different CD8(+) T cell subsets. Factors other than the size of the viral reservoir should explain the high level of activation of central memory CD8(+) T cells characteristically seen in HIV(+) individuals with spontaneous control of viral replication.     

Tumor-induced osteomalacia

Tumor-induced osteomalacia (TIO) is a rare and fascinating paraneoplastic syndrome in which patients present with bone pain, fractures, and muscle weakness. The cause is high blood levels of the recently identified phosphate and vitamin D-regulating hormone, fibroblast growth factor 23 (FGF23). In TIO, FGF23 is secreted by mesenchymal tumors that are usually benign, but are typically very small and difficult to locate. FGF23 acts primarily at the renal tubule and impairs phosphate reabsorption and 1α-hydroxylation of 25-hydroxyvitamin D, leading to hypophosphatemia and low levels of 1,25-dihydroxy vitamin D. A step-wise approach utilizing functional imaging (F-18 fluorodeoxyglucose positron emission tomography and octreotide scintigraphy) followed by anatomical imaging (computed tomography and/or magnetic resonance imaging), and, if needed, selective venous sampling with measurement of FGF23 is usually successful in locating the tumors. For tumors that cannot be located, medical treatment with phosphate supplements and active vitamin D (calcitriol or alphacalcidiol) is usually successful; however, the medical regimen can be cumbersome and associated with complications. This review summarizes the current understanding of the pathophysiology of the disease and provides guidance in evaluating and treating these patients. Novel imaging modalities and medical treatments, which hold promise for the future, are also reviewed.