Ultrafast Magnetic Resonance Imaging for Iron Quantification in Thalassemia Participants in the Developing World The TIC-TOC Study (Thailand and UK International Collaboration in Thalassaemia Optimising Ultrafast CMR)

Thalassemia is the most common monogenetic disorder worldwide, with 60 000 infants with thalassemia major born annually.1 Survival often depends on regular blood transfusions to correct anemia and to reduce ineffective erythropoiesis, but these transfusions can result in iron overload and organ failure unless chelation therapy is undertaken. Serum ferritin levels continue to be used as a guide to chelation but are unreliable, and the availability of cardiovascular magnetic resonance (CMR) T2* imaging has transformed patient management by allowing organ-specific quantification of iron content. Countries with a high prevalence of thalassemia major have CMR, but magnet time is expensive and analytic expertise lacking. The aim of TIC-TOC (Thailand and UK International Collaboration in Thalassaemia Optimising Ultrafast CMR) was to investigate whether ultrafast CMR mapping could provide reliable immediate diagnoses of heart and liver iron content, eliminating the need for complex analysis, thus reducing costs to a level within local resources. The research received approval by the Institutional Review Board of the Faculty of Medicine at Chulalongkorn University. All participants provided written informed consent.</p

Nicotine exploits a COPI-mediated process for chaperone-mediated up-regulation of its receptors

Chronic exposure to nicotine up-regulates high sensitivity nicotinic acetylcholine receptors (nAChRs) in the brain. This up-regulation partially underlies addiction and may also contribute to protection against Parkinson’s disease. nAChRs containing the α6 subunit (α6* nAChRs) are expressed in neurons in several brain regions, but comparatively little is known about the effect of chronic nicotine on these nAChRs. We report here that nicotine up-regulates α6* nAChRs in several mouse brain regions (substantia nigra pars compacta, ventral tegmental area, medial habenula, and superior colliculus) and in neuroblastoma 2a cells. We present evidence that a coat protein complex I (COPI)-mediated process mediates this up-regulation of α6* or α4* nAChRs but does not participate in basal trafficking. We show that α6β2β3 nAChR up-regulation is prevented by mutating a putative COPI-binding motif in the β3 subunit or by inhibiting COPI. Similarly, a COPI-dependent process is required for up-regulation of α4β2 nAChRs by chronic nicotine but not for basal trafficking. Mutation of the putative COPI-binding motif or inhibition of COPI also results in reduced normalized Förster resonance energy transfer between α6β2β3 nAChRs and εCOP subunits. The discovery that nicotine exploits a COPI-dependent process to chaperone high sensitivity nAChRs is novel and suggests that this may be a common mechanism in the up-regulation of nAChRs in response to chronic nicotine

Supplementary Material for: Effect of Sodium Thiosulfate on Arterial Stiffness in End-Stage Renal Disease Patients Undergoing Chronic Hemodialysis (Sodium Thiosulfate-Hemodialysis Study): A Randomized Controlled Trial

<b><i>Background:</i></b> Arterial stiffness (AS) and vascular calcification are significantly related to a high cardiovascular mortality risk in hemodialysis (HD) patients. Intravenous sodium thiosulfate (IV STS) can prevent and delay the vascular calcification progression in uremic states; however, the STS effect on AS has not been assessed. This study aimed to evaluate the STS efficacy on vascular calcification and AS in HD patients. <b><i>Methods:</i></b> Fifty HD patients with abnormal AS, as measured via the cardio-ankle vascular index (CAVI ≥8), were prospectively randomized to open-label 12.5 g IV STS during the last HD hour twice weekly for 6 months (<i>n</i> = 24) or the usual care (control group; <i>n</i> = 26). Patients and treating physicians were not blinded. The CAVI, coronary artery calcification (CAC) score, hemodynamics, and biochemical parameters were measured at the baseline and at 3 and 6 months. <b><i>Results:</i></b> All the baseline parameters were comparable. The IV STS significantly reduced the CAVI when compared to the control group (mean CAVI difference = –0.53; 95% CI –1.00 to –0.06; <i>p</i> = 0.03). A significant CAVI improvement was seen in those patients without diabetes mellitus. The natural logarithm of the CAC volume score was significantly increased in the control group. The high sensitivity C-reactive protein level was slightly lowered in the IV STS group (not significant). <b><i>Conclusion:</i></b> The intradialytic STS treatment significantly reduced the AS, as measured by the CAVI, and stabilized the vascular calcification in the HD patients. STS may be a novel therapeutic strategy for delaying and treating the structural and functional vascular wall abnormalities in HD patients

Poly (I:C), an agonist of toll-like receptor-3, inhibits replication of the Chikungunya virus in BEAS-2B cells

<p>Abstract</p> <p>Background</p> <p>Double-stranded RNA (dsRNA) and its mimic, polyinosinic acid: polycytidylic acid [Poly (I:C)], are recognized by toll-like receptor 3 (TLR3) and induce interferon (IFN)-β in many cell types. Poly (I:C) is the most potent IFN inducer. In <it>in vivo</it> mouse studies, intraperitoneal injection of Poly (I:C) elicited IFN-α/β production and natural killer (NK) cells activation. The TLR3 pathway is suggested to contribute to innate immune responses against many viruses, including influenza virus, respiratory syncytial virus, herpes simplex virus 2, and murine cytomegalovirus. In Chikungunya virus (CHIKV) infection, the viruses are cleared within 7–10 days postinfection before adaptive immune responses emerge. The innate immune response is important for CHIKV clearance.</p> <p>Results</p> <p>The effects of Poly (I:C) on the replication of CHIKV in human bronchial epithelial cells, BEAS-2B, were studied. Poly (I:C) suppressed cytopathic effects (CPE) induced by CHIKV infection in BEAS-2B cells in the presence of Poly (I:C) and inhibited the replication of CHIKV in the cells. The virus titers of Poly (I:C)-treated cells were much lower compared with those of untreated cells. CHIKV infection and Poly (I:C) treatment of BEAS-2B cells induced the production of IFN-β and increased the expression of anti-viral genes, including IFN-α, IFN-β, MxA, and OAS. Both Poly (I:C) and CHIKV infection upregulate the expression of TLR3 in BEAS-2B cells.</p> <p>Conclusions</p> <p>CHIKV is sensitive to innate immune response induced by Poly (I:C). The inhibition of CHIKV replication by Poly (I:C) may be through the induction of TLR3, which triggers the production of IFNs and other anti-viral genes. The innate immune response is important to clear CHIKV in infected cells.</p