Therapeutic effect of and mechanisms underlying the effect of miR-195-5p on subarachnoid hemorrhage-induced vasospasm and brain injury in rats

Objectives There is much evidence suggesting that inflammation contributes majorly to subarachnoid hemorrhage (SAH)-induced cerebral vasospasm and brain injury. miRNAs have been found to modulate inflammation in several neurological disorders. This study investigated the effect of miR-195-5p on SAH-induced vasospasm and early brain injury in experimental rats. Methods Ninety-six Sprague-Dawley male rats were randomly and evenly divided into a control group (no SAH, sham surgery), a SAH only group, a SAH + NC-mimic group, and a SAH + miR-195-5p group. SAH was induced using a single injection of blood into the cisterna magna. Suspensions containing NC-mimic and miR-195-5p were intravenously injected into rat tail 30 mins after SAH was induced. We determined degree of vasospasm by averaging areas of cross-sections the basilar artery 24h after SAH. We measured basilar artery endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κ B), phosphorylated NF-κ B (p-NF-κ B), inhibitor of NF-κ B (Iκ Bα) and phosphorylated-Iκ Bα (p-Iκ Bα). Cell death assay was used to quantify the DNA fragmentation, an indicator of apoptotic cell death, in the cortex, hippocampus, and dentate gyrus. Tumor necrosis factor alpha (TNF-α) levels were measured using sample protein obtained from the cerebral cortex, hippocampus and dentate gyrus. Results Prior to fixation by perfusion, there were no significant physiological differences among the control and treatment groups. SAH successfully induced vasospasm and early brain injury. MiR-195-5p attenuated vasospasam-induced changes in morphology, reversed SAH-induced elevation of iNOS, p-NF-κ B, NF-κ B, and p-Iκ Bα and reversed SAH-induced suppression of eNOS in the basilar artery. Cell death assay revealed that MiR-195-5p significantly decreased SAH-induced DNA fragmentation (apoptosis) and restored TNF-α level in the dentate gyrus. Conclusion In conclusion, MiRNA-195-5p attenuated SAH-induced vasospasm by up-regulating eNOS, down-regulating iNOS and inhibiting the NF-κ B signaling pathway. It also protected neurons by decreasing SAH-induced apoptosis-related cytokine TNF-α expression in the dentate gyrus. Further study is needed to elucidate the detail mechanism underlying miR-195-5p effect on SAH-induced vasospasm and cerebral injury. We believe that MiR-195-5p can potentially be used to manage SAH-induced cerebral vasospasm and brain injury

Variability in Estimated Glomerular Filtration Rate by Area under the Curve Predicts Renal Outcomes in Chronic Kidney Disease

Greater variability in renal function is associated with mortality in patients with chronic kidney disease (CKD). However, few studies have demonstrated the predictive value of renal function variability in relation to renal outcomes. This study investigates the predictive ability of different methods of determining estimated glomerular filtration rate (eGFR) variability for progression to renal replacement therapy (RRT) in CKD patients. This was a prospective observational study, which enrolled 1,862 CKD patients. The renal end point was defined as commencement of RRT. The variability in eGFR was measured by the area under the eGFR curve (AUC)%. A significant improvement in model prediction was based on the −2 log likelihood ratio statistic. During a median 28.7-month follow-up, there were 564 (30.3%) patients receiving RRT. In an adjusted Cox model, a smaller initial eGFR AUC%_12M (P<0.001), a smaller peak eGFR AUC%_12M (P<0.001), and a larger negative eGFR slope_12M (P<0.001) were associated with a higher risk of renal end point. Two calculated formulas: initial eGFR AUC%_12M and eGFR slope_12M were the best predictors. Our results demonstrate that the greater eGFR variability by AUC% is associated with the higher risk of progression to RRT

Variability in Estimated Glomerular Filtration Rate by Area under the Curve Predicts Renal Outcomes in Chronic Kidney Disease

Greater variability in renal function is associated with mortality in patients with chronic kidney disease (CKD). However, few studies have demonstrated the predictive value of renal function variability in relation to renal outcomes. This study investigates the predictive ability of different methods of determining estimated glomerular filtration rate (eGFR) variability for progression to renal replacement therapy (RRT) in CKD patients. This was a prospective observational study, which enrolled 1,862 CKD patients. The renal end point was defined as commencement of RRT. The variability in eGFR was measured by the area under the eGFR curve (AUC)%. A significant improvement in model prediction was based on the −2 log likelihood ratio statistic. During a median 28.7-month follow-up, there were 564 (30.3%) patients receiving RRT. In an adjusted Cox model, a smaller initial eGFR AUC% 12M ( &lt; 0.001), a smaller peak eGFR AUC% 12M ( &lt; 0.001), and a larger negative eGFR slope 12M ( &lt; 0.001) were associated with a higher risk of renal end point. Two calculated formulas: initial eGFR AUC% 12M and eGFR slope 12M were the best predictors. Our results demonstrate that the greater eGFR variability by AUC% is associated with the higher risk of progression to RRT

Chronic Kidney Disease Stage Is a Modulator on the Association between High-Sensitivity C-Reactive Protein and Coronary Vasospastic Angina

The prevalence of coronary vasospasm and also the factors associated with coronary vasospasm in CKD is still unclear. In this cross-sectional study of 859 consecutive CKD patients with angina pectoris received coronary catheterization, we evaluated the factors associated with coronary vasospasm. Patients with vasospasm were older and had higher peripheral blood white cell counts, higher peripheral blood monocyte cell counts, higher haemoglobin levels, higher hs-CRP levels, and lower levels of serum creatinine than patients without vasospasm. The results of multivariate logistic regression analysis revealed that peripheral blood monocyte count and hs-CRP level were independently associated with coronary vasospasm in patients with stage 1 CKD. Only peripheral blood monocyte count but not hs-CRP was independently associated with coronary vasospasm in patients with stages 2 and 3 of CKD. In conclusion, peripheral blood monocyte count is independently associated with coronary vasospasm in patients with stage 1–3 CKD, whereas hs-CRP is only independently associated with coronary vasospasm in patients with stage 1 CKD

Molecular Diagnosis of Hereditary Myotonic Disorders

肌強直症(Myotonic disorders)是一種肌肉收縮後不易放鬆的現象，患者的骨骼肌會出現自發性收縮現象，也常常在自主性收縮或是電刺激之後無法正常地馬上放鬆。依臨床表徵可分為失養性肌肉強直症(Myotonic dystrophies)與非失養性肌肉強直症(Nondystrophic myotonias)，其原因分別有遺傳性與後天性，通常來說，非失養性肌肉肌強直症患者在神經傳導檢查是正常的，肌肉組織切片檢查也極少有異常問題，僅能由肌電圖檢查發現異常。若要探究真正致病原因則必須倚靠分子診斷，SCN4A與CLCN-1突變是引發非失養性肌肉肌強直症機率較高的兩個基因，但其相關研究並不多，且SNC4A與CLCN-1基因突變所造成的表現型(phenotype)又非常多樣化，因此本研究計畫期望能以分子診斷的方法，鑑別出真正患有先天性肌肉強直症的病患，增加在台華人SNC4A與CLCN-1突變資料庫的內容、瞭解突變點位和臨床症狀的相關性，作為未來鑑別診斷和遺傳諮詢的參考依據。 本研究收集分別來自於七個家族的12個受試者進行分析，研究過程中為受試者進行家族史調查、生理檢查與基因分析。結果發現在臨床表現上，個案之間嚴重度差異很大，常規的神經學檢查只能在肌電圖中發現有肌強直現象；基因分析結果則發現七個家族中有兩個為CLCN1基因變異、有五個為SCN4A基因變異，其中CLCN1 Leu198Arg和SCN4A Ala1737Thr為新發現的胺基酸置換，屬於SNP或有病理意義的突變仍須進一步探討。CLCN1基因突變造成肌肉強直症的發生率約十萬分之一，然而SCN4A基因突變造成肌肉強直症的總和發生率略高，比對本研究結果，若依照目前的檢查流程，分子檢查應首先考慮進行SCN4A的基因分析。Myotonia is the delayed relaxation of skeletal muscle after voluntary contraction which might cause trouble in daily life. Myotonic disorders include the myotonic dys-trophies and nondystrophic myotonias (NDM). Mutations in the genes encoding chlo-ride (CLCN1) or sodium (SCN4A) channels result in muscle fiber hyperexcitability in patients with NDM. The phenotype of NDM is variable leading to difficulties in clinical diagnosis. The aim of the study is to identify the mutations in the two responsible genes from patients with NDM and to correlate the clinical phenotypes and genotypes. We have 12 volunteers from 7 Taiwanese families with the problem of NDM. Mu-tation screening identified 2 families with CLCN1 mutations and 5 with SCN4A muta-tions. Clinically, patients with CLCN1 mutations (L198R and A402V) demonstrated marked myotonia with hypertrophic muscles. The age of onset of the patients is early at the first decade. Five index patients harbor four individual SCN4A mutations (V445M, V781I, T1313M and A1737T) with variable clinical features such as potassi-um-aggravated myotonia, paramyotonia congenita, or hyperkalemic-periodic paralysis. The age of onset is also quite young, at 1st ~2nd decades of life. Two mutations, L198R in CLCN1 and A1737T in SCN4A genes are novel. In our experience, it seems that fre-quency of a SCN4A mutation is higher than that of the CLCN1 mutation in Taiwanese patients with NDM. Herein, the details of the phenotypes of each mutant genotype have been discussed

Factors affecting intentional bird poisoning on bean farms in Taiwan: seeding methods and the presence of adjoining duck farms matter

Intentional poisoning is a common practice to reduce bird damage to agricultural crops. Understanding the extent, distribution, and influencing factors of such incidents is key to reducing poisoning of farmland birds and scavengers which are threatened via secondary poisoning. We recruited volunteers to look for dead birds in red bean (Vigna angularis) farms during the seeding period in autumn 2016. A total of 5,441 fields were surveyed, and 51 bird poisoning incidents were identified. We recorded 1,995 dead birds during the survey (39.1 ± 29.7 per incident ± SD), mostly seed-eating birds. We tested two possible factors influencing the practice of intentional poisoning: seeding methods and whether the red bean farm was adjacent to duck farms. Among three seeding methods, broadcast seeding does not cover the seeds with soils and resulted in a significantly higher proportion of bird poisoning incidents when compared to the whole study area. However, when red bean farms were adjacent to the duck farms, there were no differences in the percentage of poisoning incidents among seeding methods but the number of dead birds was two times higher compared to incidents that were not adjacent to the duck farms. We suspect that birds congregating at duck farms resulted in neighboring farmers taking anti-bird measures, regardless of seeding methods. We map bird poisoning hot spots and provide evidence that changing seeding method and limiting the number of wild birds congregating near duck farms would help reduce bird damage and intentional bird poisoning on red bean farms. Finally, we demonstrated that citizen scientists can make a significant contribution to conservation

Biosynthesis of a 3,6-dideoxyhexose: crystallization and X-ray diffraction of CDP-6-deoxy-l-threo-d-­glycero-4-hexulose-3-dehydrase (E1) for ascarylose biosynthesis

E1 dehydrase, which is important in the biosynthesis of the 3,6-dideoxy sugar ascarylose and is the only known PMP-containing enzyme to carry out one-electron chemistry, has been crystallized and diffracted to 1.9 Å

Associations among Heavy Metals and Proteinuria and Chronic Kidney Disease

Background: The prevalence of chronic kidney disease (CKD) is increasing annually in Taiwan. In addition to traditional risk factors, heavy metals contribute to the development of CKD. The aim of this study was to investigate associations among heavy metals and proteinuria and CKD in the general population in Southern Taiwan. We also explored the interaction and synergetic effects among heavy metals on proteinuria. Methods: We conducted a health survey in the general population living in Southern Taiwan between June 2016 and September 2018. Seven heavy metals were measured: blood lead (Pb) and urine nickel (Ni), chromium (Cr), manganese (Mn), arsenic (As), copper (Cu), and cadmium (Cd). Proteinuria was measured using reagent strips. CKD was defined as an estimated glomerular filtration rate (eGFR) of &lt;60 mL/min/1.73 m2. Results: The mean age of the 2447 participants was 55.1 ± 13.2 years and included 977 males and 1470 females. Participants with high blood Pb and high urine Ni, Mn, Cu, and Cd were significantly associated with proteinuria. Interactions between blood Pb and urine Cr, and between urine Cd and Cu, had significant effects on proteinuria. The participants with high blood Pb and high urine Cu were significantly associated with an eGFR of &lt;60 mL/min/1.73 m2. Conclusion: High blood Pb and high urine Cu may be associated with proteinuria and an eGFR of &lt;60 mL/min/1.73 m2. High urine Ni, Mn, and Cd were significantly associated with proteinuria. Co-exposure to Cd and Cu, and Pb and Cr, may have synergistic effects on proteinuria

Mediastinal diffuse large B-cell lymphoma invading the left atrium mimicking coronary artery disease with a mural thrombus

A left atrial mass associated with coronary artery disease is often diagnosed as a mural thrombus rather than other possible etiologies such as benign primary cardiac tumor (myxoma, lipoma), a malignant primary cardiac tumor (sarcoma, lymphoma), or secondary involvement for extracardiac tumors. Malignant lymphoma initially presenting as intracardiac masses is very rare. Chest computed tomography with contrast enhancement and cardiac magnetic resonance may be the best methods for distinguishing primary cardiac tumors from direct extension from adjacent mediastinal structures. We report the case of a 59-year-old man with incidentally found mediastinal diffuse large B-cell lymphoma invading the left atrium, which presented with coronary artery disease and a left atrial mass. Improvement in cardiac ventricular function heart after coronary artery bypass grafting may provide the patient with a better chance of receiving an adequate dose of chemotherapy

Samarangenin B from Limonium sinense Suppresses Herpes Simplex Virus Type 1 Replication in Vero Cells by Regulation of Viral Macromolecular Synthesis

Inhibitory effects of ethanolic extracts from 10 Chinese herbs on herpes simplex virus type 1 (HSV-1) replication were investigated. By a bioassay-guided fractionation procedure, samarangenin B (Sam B) was isolated from Limonium sinense; Sam B significantly suppressed HSV-1 multiplication in Vero cells without apparent cytotoxicity. Time-of-addition experiments suggested that the inhibitory action of Sam B on HSV-1 replication was not due to the blocking of virus adsorption. In an attempt to further localize the point in the HSV-1 replication cycle where arrest occurred, a set of key regulatory events leading to viral multiplication was examined, including viral immediate-early (α), early (β), and late (γ) gene expression and DNA replication. Results indicated that levels of glycoprotein B (gB), gC, gD, gG, and infected-cell protein 5 (ICP5) expression and gB mRNA expression in Vero cells were impeded by Sam B. Data from PCR showed that replication of HSV-1 DNA in Vero cells was arrested by Sam B. Furthermore, Sam B decreased DNA polymerase, ICP0, and ICP4 gene expression in Vero cells. Results of an electrophoretic mobility shift assay demonstrated that Sam B interrupted the formation of an α-trans-induction factor/C1/Oct-1/GARAT multiprotein complex. The mechanisms of antiviral action of Sam B seem to be mediated, at least in part, by inhibiting HSV-1 α gene expression, including expression of the ICP0 and ICP4 genes, by blocking β transcripts such as DNA polymerase mRNA, and by arresting HSV-1 DNA synthesis and structural protein expression in Vero cells. These results show that Sam B is an antiviral agent against HSV-1 replication