Status epilepticus (SE), a medical emergency that is typically terminated through antiepileptic drug treatment, leads to hippocampus dysfunction typified by neurodegeneration, inflammation, altered neurogenesis, as well as cognitive and memory deficits. Here, we examined the effects of intranasal (IN) administration of extracellular vesicles (EVs) secreted from human bone marrowderived mesenchymal stem cells (MSCs) on SE-induced adverse changes. The EVs used in this study are referred to as A1-exosomes because of their robust antiinflammatory properties. We subjected young mice to pilocarpine-induced SE for 2 h and then administered A1-exosomes or vehicle IN twice over 24 h. The A1-exosomes reached the hippocampus within 6 h of administration, and animals receiving them exhibited diminished loss of glutamatergic and GABAergic neurons and greatly reduced inflammation in the hippocampus. Moreover, the neuroprotective and antiinflammatory effects of A1-exosomes were coupled with long-term preservation of normal hippocampal neurogenesis and cognitive and memory function, in contrast to waned and abnormal neurogenesis, persistent inflammation, and functional deficits in animals receiving vehicle. These results provide evidence that IN administration of A1-exosomes is efficient for minimizing the adverse effects of SE in the hippocampus and preventing SE-induced cognitive and memory impairments.status epilepticus | memory dysfunction | neuroinflammation | exosomes | adult neurogenesis S tatus epilepticus (SE) is a grave medical crisis that requires swift remedy through all age groups (1, 2). It can produce substantial neurodegeneration, blood-brain barrier disruption, and inflammation in the hippocampus if not extinguished quickly by antiepileptic drug (AED) treatment (3-5). An episode of extended SE is sufficient to cause chronic hippocampus dysfunction, exemplified by persistent inflammation with activation of microglia and monocyte infiltration, loss of sizable fractions of several subclasses of inhibitory interneurons, aberrant and waned neurogenesis, hippocampus-dependent cognitive and memory impairments, and chronic epilepsy (5-12). Numerous situations such as head trauma, stroke, Alzheimer's disease, brain tumor, and encephalitis can engender SE. Although administration of AEDs leads to termination of SE in most instances, it does not thwart the evolution of SE into chronic epilepsy (13-16). A multitude of changes ensue in the hippocampus after an episode of SE, which evolve over a period of months, years, or even decades, and result in chronic epilepsy when they have reached certain thresholds (11,17,18). Hence, there is an urgent need to find an adjuvant therapy with AEDs that not only provides neuroprotection and suppression of inflammation in the early phase after SE but also maintains normal neurogenesis, preserves cognitive and memory function, and thwarts epilepsy development in the chronic phase after SE. The i.v. administration of bone marrow-derived mononuclear cells (MNCs) or mesenchymal stem cells (...

No potential conflict of interest relevant to this letter was reported. The authors reply: Campochiaro and Caruso are correct that mention of cardiovascular associations with ankylosing spondylitis and axial spondyloarthritis, including specific conductionsystem lesions and aortic-root lesions, was largely absent from our review of spondyloarthritis. These specific lesions are uncommon and tend to occur late in the disease course, as does the other more common but less specific cardiovascular illness mentioned in their letter. The focus of our article was on early diagnosis and clinical management of the axial disease, and this priority, along with space and citation limitations, precluded our describing specific cardiovascular manifestations. Rudwaleit M, van derRudwaleit and colleagues make the important point that diagnosis in clinical practice cannot be based solely on fulfillment of classification criteria. We tried to make this point in the article, but perhaps our wording conveyed some unintended ambiguity. In order to introduce the new concept of axial spondyloarthritis, we described the classification criteria for this entity proposed by the ASAS in 2009. In discussing this concept, including the critical role of MRI, we referred to this entity as a diagnosis, in the sense of its being a defined medical condition. We did not intend by this to imply that one can rely strictly on these criteria to establish a diagnosis in clinical practice. In fact, we stated explicitly, "These classification criteria have limited use outside the arena of clinical research," to introduce the algorithm (in Fig. 2 of our article) for use in clinical practice.The algorithm itself is a modification of one published by the correspondents and their colleagues, 1 but it was modified specifically to further emphasize the importance of weighing clinical data and post-test probabilities 2 and of applying clinical judgment to the diagnostic process. Moreover, the discussion of MRI findings includes mention of lesions that are not part of the classification criteria but that can be helpful in supporting a diagnosis in clinical practice. Finally, the Summary section in our article reemphasizes the potential difficulty in accurately establishing or ruling out a diagnosis of axial spondyloarthritis, with no mention of criteria. Viral Load Kinetics of MERS Coronavirus InfectionTo the Editor: The outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infection in South Korea involved 186 patients and resulted in 38 deaths, with four large hospital outbreaks accounting for 82% of the total cases. 1,2 Here, we report changes in viral load over time in patients with MERS.We included all patients who were admitted to three Seoul National University-affiliated hospitals; the institutional review boards of these hospitals approved this study and waived the need for written informed consent on public health grounds. The patients were categorized into a group with severe disease (severe group) or a group with mild disease (mild grou...

SummaryAccumulating evidence shows that extracellular vesicles (EVs) produced by mesenchymal stem/stromal cells (MSCs) exert their therapeutic effects in several disease models. We previously demonstrated that MSCs suppress autoimmunity in models of type 1 diabetes (T1D) and experimental autoimmune uveoretinitis (EAU). Therefore, here, we investigated the therapeutic potential of MSC-derived EVs using our established mouse models for autoimmune diseases affecting the pancreas and the eye: T1D and EAU. The data demonstrate that MSC-derived EVs effectively prevent the onset of disease in both T1D and EAU. In addition, the mixed lymphocyte reaction assay with MSC-derived EVs indicated that EVs inhibit activation of antigen-presenting cells and suppress development of T helper 1 (Th1) and Th17 cells. These results raise the possibility that MSC-derived EVs may be an alternative to cell therapy for autoimmune disease prevention.

IntroductionSevere hyperkalemia, with potassium (K+) levels ≥ 6.5 mEq/L, is a potentially life-threatening electrolyte imbalance. For prompt and effective treatment, it is important to know its risk factors, clinical manifestations, and predictors of mortality.MethodsAn observational cohort study was performed at 2 medical centers. A total of 923 consecutive Korean patients were analyzed. All were 19 years of age or older and were hospitalized with severe hyperkalemia between August 2007 and July 2010; the diagnosis of severe hyperkalemia was made either at the time of admission to the hospital or during the period of hospitalization. Demographic and baseline clinical characteristics at the time of hyperkalemia diagnosis were assessed, and clinical outcomes such as in-hospital mortality were reviewed, using the institutions' electronic medical record systems.ResultsChronic kidney disease (CKD) was the most common underlying medical condition, and the most common precipitating factor of hyperkalemia was metabolic acidosis. Emergent admission was indicated in 68.6% of patients, 36.7% had electrocardiogram findings typical of hyperkalemia, 24.5% had multi-organ failure (MOF) at the time of hyperkalemia diagnosis, and 20.3% were diagnosed with severe hyperkalemia at the time of cardiac arrest. The in-hospital mortality rate was 30.7%; the rate was strongly correlated with the difference between serum K+ levels at admission and at their highest point, and with severe medical conditions such as malignancy, infection, and bleeding. Furthermore, a higher in-hospital mortality rate was significantly associated with the presence of cardiac arrest and/or MOF at the time of diagnosis, emergent admission, and intensive care unit treatment during hospitalization. More importantly, acute kidney injury (AKI) in patients with normal baseline renal function was a strong predictor of mortality, compared with AKI superimposed on CKD.ConclusionsSevere hyperkalemia occurs in various medical conditions; the precipitating factors are similarly diverse. The mortality rate is especially high in patients with severe underlying disease, coexisting medical conditions, and those with normal baseline renal function.

IgAN was the most common primary GN, and MCD was the most common cause of nephrotic syndrome. In the 5-year quartile comparison, the relative frequency of IgAN increased, while the relative frequency of MCD and MPGN decreased significantly during the past 20 years.