Sphingosylphosphorylcholine inhibits plasma cell differentiation and ameliorates experimental autoimmune encephalomyelitis

IntroductionMultiple sclerosis (MS) is a potentially disabling disease that damages the brain and spinal cord, inducing paralysis of the body. While MS has been known as a T-cell mediated disease, recent attention has been drawn to the involvement of B cells in its pathogenesis. Autoantibodies from B cells are closely related with the damage lesion of central nervous system and worse prognosis. Therefore, regulating the activity of antibody secreting cell could be related with the severity of the MS symptoms.MethodsTotal mouse B cells were stimulated with LPS to induce their differentiation into plasma cells. The differentiation of plasma cells was subsequently analyzed using flow cytometry and quantitative PCR analysis. To establish an experimental autoimmune encephalomyelitis (EAE) mouse model, mice were immunized with MOG35–55/CFA emulsion.ResultsIn this study, we found that plasma cell differentiation was accompanied by upregulation of autotaxin, which converts sphingosylphosphorylcholine (SPC) to sphingosine 1-phosphate in response to LPS. We observed that SPC strongly blocked plasma cell differentiation from B cells and antibody production in vitro. SPC downregulated LPS-stimulated IRF4 and Blimp 1, which are required for the generation of plasma cells. SPC-induced inhibitory effects on plasma cell differentiation were specifically blocked by VPC23019 (S1PR1/3 antagonist) or TY52159 (S1PR3 antagonist), but not by W146 (S1PR1 antagonist) and JTE013 (S1PR2 antagonist), suggesting a crucial role of S1PR3 but not S1PR1/2 in the process. Administration of SPC against an EAE mouse model significantly attenuated the symptoms of disease, showing decreased demyelinated areas of the spinal cord and decreased numbers of cells infiltrated into the spinal cord. SPC markedly decreased plasma cell generation in the EAE model, and SPC-induced therapeutic effects against EAE were not observed in μMT mice.ConclusionCollectively, we demonstrate that SPC strongly inhibits plasma cell differentiation, which is mediated by S1PR3. SPC also elicits therapeutic outcomes against EAE, an experimental model of MS, suggesting SPC as a new material to control MS

A Case of Shwachman-Diamond Syndrome Confirmed with Genetic Analysis in a Korean Child

Shwachman-Diamond syndrome (SDS) is an autosomal recessive genetic disorder, consisting of exocrine pancreatic insufficiency, chronic neutropenia, neutrophil chemotaxis defects, metaphyseal dysostosis, short stature, dental caries, and multiple organ involvements. Although SDS is the second most common hereditary abnormality of exocrine pancreas following cystic fibrosis in the Western countries, it has rarely been reported in Asia. We diagnosed a case of SDS in a 42-month-old girl, and genetic analysis including the relatives of the patient confirmed the diagnosis for the first time in Korea. She had short stature, steatorrhea, dental caries, and recurrent prulent otitis media and pneumonias. Laboratory studies revealed cyclic neutropenia, and serum levels of trypsin, amylase, and lipase were decreased. Simple radiography revealed metaphyseal sclerotic changes at the distal femur. A CT scan demonstrated a fatty infiltration and atrophy of the pancreas. On direct sequencing analysis of Shwachman-Bodian-Diamond Syndrome gene exon 2 region, the patient was homozygous for the c.258+2T>C mutation and heterozygous for the c.183_184TA>CT mutation and c.201A>G single nucleotide polymorphism. Treatment with pancreatic enzyme replacement, multivitamin supplementation, and regular to high fat diet improved her weight gain and steatorrhea

Analysis On Runoff Characteristics Of Decentralized Rainwater Management System Using XP-SWMM Simulation

In recent years, impervious areas are increasing in residential zone as well as unsettled area with rapid urbanization and land use. Consequently, this phenomenon influences weak urban environmental compositions about climate change including urban flooding accidents. Therefore, a new paradigm on rainwater management is needed for sound and sustainable restoration of hydrological circulation. Recently, a novel rainwater management system has been developed and recommended for irrigation and flood control in Korea. Especially, P city is now planning a new rainwater management system adopting LID (Low Impact Development) techniques on a small scale development area. In this study, XP-SWMM was used to simulate effects on runoff characteristics by installation of 8 kinds of rainwater management facilities on small scale development area (4.2 ha) of P city in Korea. Also, flood control safety analysis under the condition of localized torrential downpour event was carried out and effects of rainwater recycling facility was evaluated to measure annual water resource amount and water cost reduction. Peak rate runoff was reduced 11.8% and 36.4% in restrict A and B, respectively. Total amount of annual water source substitution was estimated 3,000㎡/yr with LID adoption in land use planning. Acknowledgement : This research was supported by a grant (12-TI-C01) from Advanced Water Management Research Program funded by Ministry of Land , Infrastructure, and Transport of Korean government

Efficacy and safety of drug-eluting stents in elderly patients: A meta-analysis of randomized trials

Background: Current guidelines recommend newer generation drug-eluting stents (DES) over bare-metal stents (BMS) in patients with ischemic heart disease. However, there is no age-specific recommendation in elderly patients.Methods: Meta-analysis was performed of 6 randomized studies enrolling 5,042 elderly patients who underwent percutaneous coronary intervention (PCI) with stent implantation (DES, n = 2,579; BMS, n = 2,463).Results: Combined data indicated a significant reduction in major adverse cardiovascular events (MACEs) with use of DES (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.44–0.71, p < 0.001). Moreover, use of DES was associated with a significantly lower incidence of myocardial infarction (OR 0.54, 95% CI 0.36–0.81, p = 0.003) and repeat revascularization (OR 0.44, 95% CI 0.31–0.62, p < 0.001), was compared to that with the use of BMS. Stent thrombosis and bleeding complication rates were not significantly different between groups. In a subgroup meta-analysis, short duration (1 or 6 months) dual antiplatelet therapy (DAPT) was associated with a significantly lower MACE rate (OR 0.49, 95% CI 0.34–0.80; p = 0.003) in elderly patients who underwent PCI with everolimuseluting stent implantation, compared with that using long duration DAPT.Conclusions: This meta-analysis provides clinically relevant evidence that DES rather than BMS should be selected for elderly patients

Network-Level Structural Abnormalities of Cerebral Cortex in Type 1 Diabetes Mellitus

Type 1 diabetes mellitus (T1DM) usually begins in childhood and adolescence and causes lifelong damage to several major organs including the brain. Despite increasing evidence of T1DM-induced structural deficits in cortical regions implicated in higher cognitive and emotional functions, little is known whether and how the structural connectivity between these regions is altered in the T1DM brain. Using inter-regional covariance of cortical thickness measurements from high-resolution T1-weighted magnetic resonance data, we examined the topological organizations of cortical structural networks in 81 T1DM patients and 38 healthy subjects. We found a relative absence of hierarchically high-level hubs in the prefrontal lobe of T1DM patients, which suggests ineffective top-down control of the prefrontal cortex in T1DM. Furthermore, inter-network connections between the strategic/executive control system and systems subserving other cortical functions including language and mnemonic/emotional processing were also less integrated in T1DM patients than in healthy individuals. The current results provide structural evidence for T1DM-related dysfunctional cortical organization, which specifically underlie the top-down cognitive control of language, memory, and emotion. © 2013 Lyoo et al

A Case of Anaphylaxis to Chlorhexidine during Digital Rectal Examination

Chlorhexidine is widely used as an antiseptic and disinfectant in medical and non-medical environments. Although the sensitization rate seems to be low, its ubiquitous use raises the possibility of sensitization in many patients and medical care workers. We describe a patient with anaphylaxis during digital rectal examination with chlorhexidine jelly. Urticaria, angioedema, dyspnea, and hypotension developed within a few minutes of the rectal examination. The patient fully recovered after treatment with epinephrine and corticosteroids. Skin tests for chlorhexidine were undertaken 5 weeks later, showing positive prick and intradermal skin tests. Within 30 min of the skin test, the patient complained of febrile sensation, chest tightness, angioedema, and urticaria on the face and trunk. An enzyme allergosorbent test for latex was negative. We present this case to alert clinicians about hypersensitivity to chlorhexidine that could potentially be life-threatening. We suggest that chlorhexidine should be recognized as a causative agent of anaphylaxis during procedural interventions

A Cdo–Bnip-2–Cdc42 signaling pathway regulates p38α/β MAPK activity and myogenic differentiation

The p38α/β mitogen-activated protein kinase (MAPK) pathway promotes skeletal myogenesis, but the mechanisms by which it is activated during this process are unclear. During myoblast differentiation, the promyogenic cell surface receptor Cdo binds to the p38α/β pathway scaffold protein JLP and, via JLP, p38α/β itself. We report that Cdo also interacts with Bnip-2, a protein that binds the small guanosine triphosphatase (GTPase) Cdc42 and a negative regulator of Cdc42, Cdc42 GTPase-activating protein (GAP). Moreover, Bnip-2 and JLP are brought together through mutual interaction with Cdo. Gain- and loss-of-function experiments with myoblasts indicate that the Cdo–Bnip-2 interaction stimulates Cdc42 activity, which in turn promotes p38α/β activity and cell differentiation. These results reveal a previously unknown linkage between a cell surface receptor and downstream modulation of Cdc42 activity. Furthermore, interaction with multiple scaffold-type proteins is a distinctive mode of cell surface receptor signaling and provides one mechanism for specificity of p38α/β activation during cell differentiation