Thymic Hyperplasia Associated With Graves’ Disease in a 10-Year-Old Boy.

Thymic Hyperplasia Associated with Graves’ Disease in a 10-year-old Boy.

Clin Pediatr Endocrinol. 2011 Jul; 20(3): 61-4
Kawano A, Kohno H

Thymic hyperplasia associated with Graves’ disease is rarely reported in children, although it is not uncommon in adults. Occasionally, an enlarged thymus presents as an anterior mediastinal mass on a radiographic examination. Such patients often undergo invasive procedures such as a thymus biopsy or thymectomy because of suspected malignancy. However, an enlarged thymus with Graves’ disease is known to shrink after treatment with antithyroid drugs. Therefore, recognition of this benign course would avoid unnecessary surgical resection. This report presents the case of a 10-yr-old boy with Graves’ disease complicated with an anterior mediastinal mass. Computed tomography showed a homogenous mass with no invasion into the surrounding tissue. A gallium-67 scintigraphy showed no abnormal uptake. Shrinkage of the mass after treatment with an antithyroid drug (methyl-mercaptoimidazole) supported the diagnosis of thymic hyperplasia with Graves’ disease. This case report illustrates two important points. First, pediatricians should be aware that thymic hyperplasia can coexist with Graves’ disease, even in children. Second, close radiographic assessment would support a diagnosis of thymic hyperplasia and eliminate invasive diagnostic procedures. HubMed – drug

A Report of Three Girls with Antithyroid Drug-Induced Agranulocytosis; Retrospective Analysis of 18 Cases Aged 15 Years or Younger Reported between 1995 and 2009.

Clin Pediatr Endocrinol. 2011 Apr; 20(2): 39-46
Minamitani K, Oikawa J, Wataki K, Kashima K, Hoshi M, Inomata H, Ota S

Agranulocytosis is an extremely serious, although rare, adverse effect of antithyroid drugs (ATDs), including methimazole (MMI) and propylthiouracil (PTU), in children and adolescents. There are few reports about the characteristics of ATD-induced agranulocytosis in Japanese children and adolescents. This report presents the cases of three girls with ATD-induced agranulocytosis and a retrospective analysis of 18 patients with ATD-induced agranulocytosis, whose cases had been referred to the drug manufacturer, Chugai Pharmaceutical Co., Ltd. Our 3 patients, ranging in age from 12 to 14 yr, developed ATD-induced agranulocytosis between the 15th and 57th day of ATD treatment for hyperthyroidism. Fever and sore throat were the earliest symptoms of agranulocytosis. The patients were rescued by ceasing ATD therapy and administering antibiotics, potassium iodide, glucocorticoid, immunoglobulin and granulocyte colony-stimulating factor (G-CSF). We retrospectively analyzed 18 cases of ATD-induced agranulocytosis treated with MMI in 16 cases and PTU in 2 cases. Twelve patients were treated with 20-45 mg/d MMI. Agranulocytosis developed between the 15th and 1,344th day of therapy. In conclusion, considering the risk of ATD-induced agranulocytosis, we recommend low-dose MMI therapy for treatment of Graves’ disease. HubMed – drug

Dual Myxovirus Screen Identifies a Small-Molecule Agonist of the Host Antiviral Response.

J Virol. 2013 Aug 7;
Yan D, Krumm SA, Sun A, Steinhauer DA, Luo M, Moore ML, Plemper RK

Confronted with an increasing number of emerging and re-emerging viral pathogens, the identification of novel pathogen-specific and broad-spectrum antivirals has become a major developmental objective. Targeting host factors required for virus replication presents a tangible approach towards novel hits with broadened indication range. However, the identification of developable host-directed antiviral candidates remains challenging. We describe a novel screening protocol that interrogates the myxovirus host-pathogen interactome for broad-spectrum drug candidates and simultaneously probes for conventional, pathogen-directed hits. With resource-efficiency and pan-myxovirus activity as the central developmental parameters, we explored co-screening against two distinct, independently traceable myxoviruses in a single-well setting. Having identified a pair of unrelated pathogenic myxoviruses (influenza A virus and measles virus) with comparable replication kinetics, we observed unimpaired co-replication of both viruses, generated suitable firefly and renilla luciferase reporter constructs, respectively, and validated the protocol up to 384-well plate format. Combined with an independent counterscreen using a recombinant respiratory syncytial virus luciferase reporter, implementation of the protocol identified candidates with broadened anti-myxovirus profile in addition to pathogen-specific hits. Mechanistic characterization revealed a newly discovered broad-spectrum lead that does not block viral entry, but stimulates effector pathways of the innate cellular antiviral response. In summary, we provide proof-of-concept for the efficient discovery of broad-spectrum myxovirus inhibitors in parallel to para- and orthomyxovirus-specific hit candidates in a single screening campaign. The newly identified compound provides a basis for the development of a novel broad-spectrum small-molecule antiviral class. HubMed – drug

Antagonistic activities of the immunomodulator and PP2A-activating drug FTY720 (Fingolimod, Gilenya) in Jak2-driven hematologic malignancies.

Blood. 2013 Aug 7;
Oaks JJ, Santhanam R, Walker CJ, Roof S, Harb JG, Ferenchak G, Eisfeld AK, Van Brocklyn JR, Briesewitz R, Saddoughi SA, Nagata K, Bittman R, Caligiuri MA, Abdel-Wahab O, Levine R, Arlinghaus RB, Quintas-Cardama A, Goldman JM, Apperley J, Reid A, Milojkovic D, Ziolo MT, Marcucci G, Ogretmen B, Neviani P, Perrotti D

FTY720 (Fingolimod, Gilenya) is a sphingosine analog used as an immunosuppressant in multiple sclerosis patients. FTY720 is also a potent protein phosphatase 2A (PP2A)-activating drug (PAD). PP2A is a tumor suppressor found inactivated in different types of cancer. We show here that PP2A is inactive in Polycythemia Vera (PV) and other myeloproliferative neoplasms (MPNs) characterized by the expression of the transforming Jak2(V617F) oncogene. PP2A inactivation occurs in a Jak2(V617F) dose/kinase-dependent manner through the PI-3K?-PKC-induced phosphorylation of the PP2A inhibitor SET. Genetic and/or PAD-mediated PP2A reactivation induces Jak2(V617F) inactivation/downregulation and impairs clonogenic potential of Jak2(V617F) cell lines and PV but not normal CD34(+) progenitors. Likewise, FTY720 decreases leukemic allelic burden, reduces splenomegaly and significantly increases survival of Jak2(V617F) leukemic mice without adverse effects. Mechanistically, we show that in Jak2(V617F) cells, FTY720 anti-leukemic activity neither requires FTY720 phosphorylation (FTY720-P) nor SET dimerization or ceramide induction but depends on interaction with SET K209. Moreover, we showed that Jak2(V617F) also utilizes an alternative sphingosine kinase-1 (SPHK1)-mediated pathway to inhibit PP2A, and that FTY720-P, acting as a sphingosine-1-phosphate-receptor-1 (S1PR1) agonist, elicits signals leading to the Jak2-PI-3K?-PKC-SET-mediated PP2A inhibition. Thus, PADs (e.g. FTY720) represent suitable therapeutic alternatives for Jak2(V617F) MPNs. HubMed – drug