Localized AL amyloidosis: A suicidal neoplasm?

Abstract

Although AL amyloidosis usually is a systemic disease, strictly localized AL deposits are not exceptionally rare. Such case reports form a considerable body of published articles. Although both AL amyloidosis types are formed from an N-terminal segment of a monoclonal immunoglobulin light chain, a typical localized AL amyloid differs from the systemic counterpart by the morphological appearance of the amyloid, and presence of clonal plasma cells and of giant cells. In this article it is pointed out that localized AL amyloidosis (‘amyloidoma') represents a true plasma cell neoplasm and not a pseudotumor. The pathogenesis of localized AL amyloidosis may differ from that of the systemic type, a suggestion underlined by the fact that localized AL amyloidosis of kappa type is as common as that of lambda origin, in contrast to the systemic form where lambda chains constitute the overwhelming majority of cases. It is suggested that oligomeric assemblies of the produced immunoglobulin light chain are toxic to plasma cells, which in this way commit suicide.     

Role of sirtuin-1 (SIRT1) in hypoxic injury in pancreatic β-cells

Abstract

Islet transplantation (ITx) is being developed as a treatment for type 1 diabetes mellitus, but hypoxic damage to transplanted islet grafts is an important factor affecting successful transplantation. To investigate the role of sirtuin-1 (SIRT1) under hypoxic injury in INS-1 cells, one type of pancreatic β-cell lines, we used SRT1720 and GW4064 for SIRT1 activation. The small interfering RNA SIRT1 (si-SIRT1) was used to suppress SIRT1 gene expression. We measured cell viability, apoptosis, and the levels of inflammatory cytokines, including tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and reactive oxygen species (ROS), under hypoxic conditions. Real-time PCR and Western blot analysis were performed. Cell viability was significantly reduced to 71% and 40% after 4 and 6?h of hypoxic conditions, respectively. Apoptosis increased significantly 2.8-fold and 5.3-fold after 4 and 6?h of hypoxia, respectively. SIRT1 expression was significantly reduced at the mRNA and protein levels during hypoxia. Hypoxic damage significantly increased the TNF-α, IL-6 and ROS levels in INS-1 cells. However, the reduced cell viability and increased inflammatory cytokines from hypoxic damage were ameliorated by SIRT1 activation in INS-1 cells. These results suggest that SIRT1 is a potential target for the protection of pancreatic β-cells against hypoxic damage during ITx.     

Introduction and overview of the special issue “Brain imaging and aging”: The new era of neuroimaging in aging research

It is well known that the brain is one of the organs particularly affected by aging in terms of function, relative to the gastrointestinal tract and liver, which exhibit less functional decline. There is also a wide range of age-related neurological disorders such as stroke, Alzheimer’s disease, and Parkinson’s disease. Therefore, it is very important to understand the relationship between functional age-related change and neurological dysfunction. Neuroimaging techniques including magnetic resonance imaging and positron emission tomography have been significantly improved over recent years. Many physicians and researchers have investigated various mechanisms of age-related cerebral change and associated neurological disorders using neuroimaging techniques. In this special issue of Ageing Research Reviews, we focus on cerebral- and neuro-imaging, which are a range of tools used to visualize structure, functions, and pathogenic molecules in the nervous system. In addition, we summarize several review articles about the history, present values, and future perspectives of neuroimaging modalities.     

When astrocytes become harmful: Functional and inflammatory responses that contribute to Alzheimer's disease

A growing body of research suggests that astrocytes play roles as contributors to the pathophysiology of Alzheimer's disease (AD). Several lines of evidence propose that activated astrocytes produce and release proinflammatory molecules that may be critical for the generation of amyloid-β peptide (Aβ). However, accumulating evidence indicates that Aβ may activate astrocytes, which leads to an increase in cytokines that has been suggested to be a causative factor in the cognitive dysfunction of AD; thus, a vicious circle may be created. Intrinsic inflammatory mechanisms may provide a regulatory system that is capable of influencing the neuronal microenvironment that affects neuronal survival. In this article, we address the evidence surrounding the interactions of dysfunctional astrocytes with neighboring neurons that may initiate a cascade of events that culminates with neuronal injury and the expression of the hallmark lesions of AD. Comprehensive knowledge of the molecular mechanisms underlying the participation of astrocytes in neurodegeneration could aid the development of therapies to restore proper astrocyte function that can be used in AD patients to prevent or alleviate the progression of the disease in a more efficient and comprehensive manner.     

Sudden unexpected death owing to unilateral medial medullary infarction with early involvement of the respiratory center

A 64-year-old woman was found dead in her home. At autopsy, although relatively fresh bruises were found on her body, no lethal injury was observed in an internal observation. Mild edematous swelling of the right half of the medulla oblongata was observed. There was acute medial medullary infarction (MMI), which mainly involved the nucleus hypoglossi, medial lemniscus, hypoglossal root, inferior olivary nucleus, and pyramidal tract. Subacute infarction of the lower part of the cerebellum was also found, and severe atherosclerosis of the right vertebral artery containing thrombi was found as the culprit lesion. Immunohistochemistry using amyloid precursor protein (APP) was positive in neuronal tissue in the nucleus ambiguus, despite not showing coagulative necrosis in the nucleus. Therefore, acute ischemic necrosis of the nucleus ambiguus, which is considered to be a component of the dorsal respiratory group, may be a significant finding for her expected death. Immunohistochemistry of APP may be useful for confirming the precise extent of acute ischemia in brain stem infarction, such as unilateral MMI.     

针刀干预对颈椎病兔软骨终板整合素β1-FAK力学信号通路的影响

目的观察针刀干预对颈椎病兔软骨终板整合素β1-FAK力学信号通路相关因子整合素β1、磷酸化黏着斑激酶(p-FAK)mRNA和蛋白表达的影响,探讨针刀在延缓椎间盘退变恢复颈椎力学平衡过程中的可能作用机制。方法将40只新西兰雄性兔随机分为空白组、模型组、电针组及针刀组,每组10只,空白组不做干预处理,其余建立颈椎病动物模型,持续12周。造模成功后电针组于兔颈肌两侧"天柱""颈百劳""大杼"穴处行毫针干预,隔天治疗1次,每周3次,共3周;针刀组于兔颈肌硬结、条索以及棘突等处行针刀干预,每周1次,共3次。干预结束后1周,采用实时荧光定量PCR法检测椎间盘软骨终板整合素β1、p-FAK的mRNA表达水平,采用Western Blot技术检测椎间盘软骨终板整合素β1、p-FAK的蛋白含量。结果与空白组相比,模型组软骨终板整合素β1 mRNA和蛋白表达水平均明显降低(P<0.01),软骨终板p-FAK蛋白表达水平升高(P<0.05)。与模型组相比,电针组软骨终板整合素β1、p-FAK蛋白表达水平均升高(P<0.05)。针刀组软骨终板整合素β1、p-FAK mRNA和蛋白表达水平均明显升高(P<0.01)。与电针组相比,针刀组软骨终板p-FAK mRNA和蛋白表达水平升高(P<0.05)。结论针刀干预可调节软骨终板整合素β1、p-FAK mRNA和蛋白表达,这可能是针刀减缓椎间盘退变,重建颈椎力学平衡,治疗颈椎病的作用机制之一。     

Altered lipid composition in cortical lipid rafts occurs at early stages of sporadic Alzheimer's disease and facilitates APP/BACE1 interactions

The presence of lipid alterations in lipid rafts from the frontal cortex in late stages of Alzheimer's disease (AD) has been recently demonstrated. Here, we have isolated and analyzed the lipid composition of lipid rafts from different brain areas from control and AD subjects at initial neuropathologic stages. We have observed that frontal cortex lipid rafts are profoundly altered in AD brains from the earliest stages of AD, namely AD I/II. These changes in the lipid matrix of lipid rafts affected both lipid classes and fatty acids and were also detected in the entorhinal cortex, but not in the cerebellum from the same subjects. Paralleling these changes, lipid rafts from AD frontal and entorhinal cortices displayed higher anisotropy for environment-sensitive probes, indicating that lipid changes in AD lipid rafts increased membrane order and viscosity in these domains. The pathophysiological consequences of these alterations in the development and progression of AD were strengthened by the significant, and specific, accumulation of β-secretase within the lipid rafts of AD subjects even at the earliest stages. Our results provide a mechanistic connection between lipid alterations in these microdomains and amyloidogenic processing of amyloid precursor protein.     

Report on Patients with Non Transfusion-Dependent β-Thalassemia Major Being Treated with Hydroxyurea Attending the Thalassemia Research Center,Sari, Mazandaran Province,Islamic Republic of Iran in 2013

Hydroxyurea (HU) has been used to treat patients with non transfusion-dependent β-thalassemia major (β-TM) at the Thalassemia Research Center, Sari, Mazandaran Province, Islamic Republic of Iran since 1996. This study was performed to summarize and to share our experience. Medical records of all patients with β-thalassemia (β-thal) attending our center were reviewed in January 2013. Definition of β-TM was based on complete blood count (CBC), hemoglobin (Hb) electrophoresis, and for some patients, by the amplification refractory mutation system-restriction fragment length polymorphism (ARMS-RFLP) method. Patients who had not been transfused before, or had only occasionally had blood transfusions, were selected. Age at first blood transfusion, initial HU therapy and time of study was extracted from the records. The lowest Hb level before using HU and the last Hb value when on the HU regimen as well as the difference, were reported. Number of saved packed red cells was calculated according to duration of HU use and the usual needs of the patients. Hydroxyurea was discontinued before a planned pregnancy and during gestation and lactation periods. Hydroxyurea was discontinued for male patients willing to reproduce. A p value of <0.05 was considered statistically significant. It was consistent with 1856 patients/year, and 3542 units of blood were saved. We found HU to be effective and safe in treating patients with non transfusion-dependent β-TM. We strongly recommend HU therapy.