Secondary Amyloidosis Associated with Multiple Sclerosis

Background Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. Secondary amyloidosis can occur as a complication of chronic systemic inflammatory and infectious diseases. Until now there has been no report of secondary amyloidosis associated with MS. We report herein a case of renal biopsy-proven secondary amyloidosis in a patient with MS. Case Report A 41-year-old woman with MS was hospitalized due to aggravated quadriparesis and edema in both lower extremities. Laboratory findings showed nephrotic-range proteinuria and hypoalbuminemia. A percutaneous renal biopsy procedure was performed, the results of which revealed secondary amyloid-A-type amyloidosis associated with MS. Conclusions This is the first report of secondary amyloidosis associated with MS. J Clin Neurol 2009;5:146-14

A Case of Recurrent Infection Caused by a Pancreaticoduodenal Fistula Associated with a Pancreatic Arteriovenous Malformation

Although arteriovenous malformations (AVM) occur frequently in digestive organs, pancreatic AVM is rare. The clinical symptoms of pancreatic AVM are variable and include gastrointestinal bleeding, abdominal pain, jaundice, portal hypertension, pancreatitis, and duodenal ulcer. However, choledochoduodenal or pancreaticoduodenal fistulas complicated with ascending infection and pancreatitis is extremely rare. Herein, we report a case of pancreaticoduodenal fistula associated with a pancreatic AVM that induced recurrent anemia and ascending infection

The molecular basis of beta-thalassemia intermedia in southern China: genotypic heterogeneity and phenotypic diversity

<p>Abstract</p> <p>Background</p> <p>The clinical syndrome of thalassemia intermedia (TI) results from the β-globin genotypes in combination with factors to produce fetal haemoglobin (HbF) and/or co-inheritance of α-thalassemia. However, very little is currently known of the molecular basis of Chinese TI patients.</p> <p>Methods</p> <p>We systematically analyzed and characterized β-globin genotypes, α-thalassemia determinants, and known primary genetic modifiers linked to the production of HbF and the aggravation of α/β imbalance in 117 Chinese TI patients. Genotype-phenotype correlations were analyzed based on retrospective clinical observations.</p> <p>Results</p> <p>A total of 117 TI patients were divided into two major groups, namely heterozygous β-thalassemia (n = 20) in which 14 were characterized as having a mild TI with the Hb levels of 68-95 g/L except for five co-inherited ααα^anti-3.7triplication and one carried a dominant mutation; and β-thalassemia homozygotes or compound heterozygotes for β-thalassemia and other β-globin defects in which the β⁺-thalassemia mutation was the most common (49/97), hemoglobin E (HbE) variants was second (27/97), and deletional hereditary persistence of fetal hemoglobin (HPFH) or δβ-thalassemia was third (11/97). Two novel mutations, Term CD+32(A→C) and Cap+39(C→T), have been detected.</p> <p>Conclusions</p> <p>Chinese TI patients showed considerable heterogeneity, both phenotypically and genotypically. The clinical outcomes of our TI patients were mostly explained by the genotypes linked to the β- and α-globin gene cluster. However, for a group of 14 patients (13 β⁰/β^Nand 1 β⁺/β^N) with known heterozygous mutations of β-thalassemia and three with homozygous β-thalassemia (β⁰/β⁰), the existence of other causative genetic determinants is remaining to be molecularly defined.</p

Did Photosymbiont Bleaching Lead to the Demise of Planktic Foraminifer Morozovella at the Early Eocene Climatic Optimum?

The symbiont-bearing mixed-layer planktic foraminiferal genera Morozovella and Acarinina were among the most important calcifiers of early Paleogene tropical–subtropical oceans. A marked and permanent switch in the abundance of these genera is known to have occurred at low-latitude sites at the beginning of the Early Eocene Climatic Optimum(EECO), such that the relative abundance of Morozovella permanently and significantly decreased along with a progressive reduction in the number of species; concomitantly, the genus Acarinina almost doubled its abundance and diversified. Here we examine planktic foraminiferal assemblages and stable isotope compositions of their tests at Ocean Drilling Program Site 1051 (northwest Atlantic) to detail the timing of this biotic event, to document its details at the species level, and to test a potential cause: the loss of photosymbionts (bleaching). We also provide stable isotope measurements of bulk carbonate to refine the stratigraphy at Site 1051 and to determine when changes in Morozovella species composition and their test size occurred. We demonstrate that the switch in Morozovella and Acarinina abundance occurred rapidly and in coincidence with a negative carbon isotope excursion known as the J event (~53 Ma), which marks the start of the EECO.We provide evidence of photosymbiont loss after the J event from a size-restricted δ13C analysis. However, such inferred bleaching was transitory and also occurred in the acarininids. The geologically rapid switch in planktic foraminiferal genera during the early Eocene was a major evolutionary change within marine biota, but loss of photosymbionts was not the primary causal mechanism

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Hedgehog signalling in lung development and airway regeneration

Tumorigenesis is often caused by the dysregulation of developmental pathways that are activated during repair, a process that recapitulates development. The Hedgehog (Hh) pathway is a signalling pathway essential for cell patterning and identity during embryogenesis. Activation of Hh signalling has been reported in small cell lung cancer progression, but the role of the Hh receptor, Patched1 (Ptch1), remains poorly understood. Therefore, it is imperative that we understand how Ptch1 is involved in development and tissue repair in order to understand its roles in cancer. This project aimed to study the role of Ptch1 during the branching process of lung development and in the regeneration of airway epithelial cells. A conditional knockout approach was utilised to excise Ptch1 by crossing Ptch1 conditional mice with Dermo1-Cre mice (Dermo1Cre+/-;Ptch1lox/lox), thereby activating the Hh pathway in the mesenchyme, independent of ligand. Dermo1Cre+/-;Ptch1lox/lox embryos died at E12.0 and showed secondary lung branching arrest leading to lobe formation defects. Expression of Ptch1, Gli1 and Foxf1 were shown to be upregulated in both proximal and distal lung mesenchyme, indicating inappropriate pathway activation and disruption of the Hh gradient. Fgf10 expression was spatially reduced in Dermo1Cre+/-;Ptch1lox/lox lungs and the addition of Fgf10 to these lungs in culture showed partial restoration of branching, thus Hh signalling was shown to regulate branching via Fgf10. Due to the patterning defect associated with our in vivo model, we took an in vitro approach to delete Ptch1 in lung explants cultures. This also showed reduced branching and validated that mesenchymal proliferation was enhanced after Ptch1 deletion, consistent with the previously reported role of Hh signalling in mesenchymal cell survival. Small cell lung cancer originates in the proximal lung and has been linked to aberrant repair processes. Therefore, Hh signalling in proximal airway repair was investigated. Ptch1 expressing cells were detected in the bronchial epithelium and stroma during homeostasis. But these cells were not detected following polidocanol-induced injury in the murine nasal septum and lung. However during naphthalene-induced repair, Ptch1 expressing cells were detected in the regenerating bronchial epithelium, suggesting that Hh dependent progenitors respond specifically to naphthalene-induced damage and perhaps are pulmonary neuroendocrine or variant Clara cells. Therefore, this project has provided insight into how Ptch1 patterns lung branching and lobe specification during development and also highlights the importance of Ptch1 in pulmonary epithelial regeneration

Patched1 patterns fibroblast growth factor 10 and forkhead box F1 expression during pulmonary branch formation

Hedgehog (Hh) signalling, Fibroblast grovvth factor 10 (Fgr10) and Forkhead box Fl (Foxf1) are each individually important for directing pulmonary branch formation but theft interactions are not well understood. Here we demonstrate that Hh signalling is vital in regulating Foxf1 and Fgf10 expression during branching. The Hedgehog receptor Patched1 (Ptchl) was conditionally inactivated in the lung mesenchyme by Denno1-Cre in vivo or using a recombinant Cie recombinase protein (HNCre) in lung cultures resulting in cell autonomous activation of Hh signalling. Homozygous mesenchymal Ptchl deleted embryos (DertnolCre+/-; Ptch1(lox/lox)) showed secondary branching and lobe formation defects. Fgf 10 expression is spatially reduced in the distal tip of Derrno/Cre+/-; Ptch1(lox/lox) lungs and addition of Fgf10 recombinant protein to these lungs in culture has shown partial restoration of branching, indicating Ptchl function patterns Fgf10 to direct lung branching. Foxil expression is upregulatecl in Dermol Cre+/-; Ptch1(lox/lox) lungs, suggesting Foxf1 may mediate Hh signalling effects in the lung mesenchyme. In vitro HNCre-mecliated Ptchl deleted lung explants support the in vivo observations, with evidence of mesenchyme hyperproliferation and this is consistent with the previously reported role of Hh signalling in maintaining mesenchymal cell survival. Consequently it is concluded that during early pseudoglandular stage of lung development Ptchl patterns Fgf10 and regulates Foxf 1 expression in the lung mesenchyme to direct branch formation and this is essential for proper lobe formation and lung function. (C) 2017 Elsevier B.V. All rights reserved

The spindle-associated microcephaly protein, WDR62, is required for neurogenesis and development of the hippocampus

Primary microcephaly genes (MCPH) are required for the embryonic expansion of the mammalian cerebral cortex. However,\ua0MCPH\ua0mutations may spare growth in other regions of the developing forebrain which reinforces context-dependent functions for distinct\ua0MCPH\ua0genes in neurodevelopment. Mutations in the\ua0MCPH2\ua0gene,\ua0WD40-repeat protein 62\ua0(WDR62), are causative of primary microcephaly and cortical malformations in humans. WDR62 is a spindle microtubule-associated phosphoprotein that is required for timely and oriented cell divisions. Recent studies in rodent models confirm that WDR62 loss or mutation causes thinning of the neocortex and disrupted proliferation of apical progenitors reinforcing critical requirements in the maintenance of radial glia. However, potential contributions for WDR62 in hippocampal development had not been previously defined. Using CRISPR/Cas9 gene editing, we generated mouse models with patient-derived non-synonymous missense mutations (WDR62V66M\ua0and WDR62R439H) and a null mutation (herein referred to as WDR62Stop) for comparison. We find that WDR62 deletion or mutation resulted in a significant reduction in the thickness of the hippocampal ventricular zone and the area of the dentate gyrus (DG). This was associated with the mitotic arrest and depletion of radial glia and intermediate progenitors in the ammonic neuroepithelium. As a consequence, we find that the number of mitotic dentate precursors in the migratory stream and granule neurons in the DG was reduced with WDR62 mutation. These findings reveal that WDR62 is required for neurogenesis and the growth of the hippocampus during embryonic development