Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Effects of Reinforcing Fiber and Microsilica on the Mechanical and Chloride Ion Penetration Properties of Latex-Modified Fiber-Reinforced Rapid-Set Cement Concrete for Pavement Repair

This study evaluated the influence of reinforcement fiber type and microsilica content on the performance of latex-modified fiber-reinforced roller-compacted rapid-hardening cement concrete (LMFRCRSC) for a concrete pavement emergency repair. Experimental variables were the microsilica substitution ratio (1, 2, 3, and 4%), and the reinforcement fiber (jute versus macrosynthetic fiber). In the tests, compressive, flexural, and splitting tensile strength; chloride ion penetration resistance; and abrasion resistance were assessed. From the compressive and flexural strength tests with microsilica substitution, the 4-hour curing strength decreased as the microsilica substitution ratio increased. From the chloride ion penetration test, as the microsilica substitution ratio increased, chloride ion penetration decreased. The abrasion resistances increased with the substitution ratio of microsilica increase. Based on these test results, microsilica at a substitution ratio of 3% or less and macrosynthetic fiber as the reinforcement improved the performance of LMFRCRSC for a concrete pavement emergency repair and satisfied all of the target strength requirements

Pressure Changes During Layer Cupping in a Skin Model

Background Cupping is widely used in Korean medicine, but there is a risk of bacterial infection if the suction pump (used for inducing negative pressure) and the patients’ skin are not separated. This study aimed to investigate the effect of layer cupping by comparing the pressure changes between layer cupping and conventional cupping. Methods To evaluate pressure changes the study was designed with 3 types of conditions applied to a skin model: (1) a Dongbang cup with a manual or motor suction pump (conventional cupping); (2) layer cupping with 2 Dongbang cups; and (3) layer cupping with a cup made by 3D printing and a Dongbang cup. Results When a manual suction pump was used (conventional cupping), the pressure did not decrease steadily, and in 1 section there was an increase in pressure. When layer cupping was used, the pressure in the lower cup (which would be directly applied to the patient’s skin), decreased steadily. Conclusion In the pressure change graph for layer cupping in this skin model, the pressure in the lower cup (which would be placed on the patient’s skin) steadily decreased, and reached equilibrium. Therefore, the layer cupping model may help to reduce the risks of bacterial infection

An Experimental Study on the Relationship Between Temperature and Pressure Inside the Cup During Cupping Procedures

Background Pressure changes related to temperature variation during cupping may lead to dropout. This study aimed to investigate pressure changes related to temperature variations in the cup during the cupping procedure. Methods Changes in temperature and pressure were measured for 15 minutes after the procedure was performed using the alcohol rub method with glass cups and with the addition of infrared irradiation. Changes in temperature and pressure were also measured for 15 minutes after pumping 3 times using the valve suction method, and with the addition of infrared irradiation. Results In a comparison between the alcohol rub method with glass cups and with the addition of infrared irradiation, the negative pressure increased over time in the absence of infrared irradiation, whereas it decreased when performed with infrared irradiation p = 0.094. However, in a comparison between pumping 3 times using the valve suction method, and with the addition of infrared irradiation, the negative pressure decreased in both cases, but this was more significant with infrared irradiation p = 0.172. There was a significantly higher temperature in the glass cups (p = 0.004) and the valve cups (p = 0.001) exposed to infrared radiation, compared with no infrared irradiation. Conclusion The reduction in negative pressure inside the cups exposed to infrared radiation was greater than without infrared irradiation. Temperature increases inside the cup can lead to the risk of dropout

Treatment of Lumbosacral Radiculopathy with Acupuncture and Medical Herbs: Four Case Reports

Lumbosacral radiculopathy (LR) is a musculoskeletal disorder or pain syndrome that is generally linked to the compression or irritation of the nerve root. There is a growing interest in the development of efficient acupuncture-based treatments for LR comparable to western medicine. Structured traditional Korean medical treatments including intensified acupuncture stimulus on the EX-B2 point using the G-shaped posture modified from the sitting posture were applied to four LR patients, and the outcomes were evaluated based on objective clinical endpoints including a numeric rating scale (NRS), the Oswestry disability index (ODI), the manual muscle test (MMT), neurological symptoms, and plantar photography. Patients showed improvements in NRS, ODI, MMT, and neurological symptoms without adverse effects during hospitalization and follow-up visits. Moreover, we observed substantial dissolvement of hyperkeratinization and parchedness of the soles of the feet, which was not reported previously. These four cases demonstrate the clinical usefulness of traditional medicine and the diagnostic applicability of plantar photography. However, further randomized controlled trials are required to confirm our findings

Threshold Voltage Control of Multilayered MoS2 Field-Effect Transistors via Octadecyltrichlorosilane and their Applications to Active Matrixed Quantum Dot Displays Driven by Enhancement-Mode Logic Gates

In recent past, for next-generation device opportunities such as sub-10 nm channel field-effect transistors (FETs), tunneling FETs, and high-end display backplanes, tremendous research on multilayered molybdenum disulfide (MoS2) among transition metal dichalcogenides has been actively performed. However, nonavailability on a matured threshold voltage control scheme, like a substitutional doping in Si technology, has been plagued for the prosperity of 2D materials in electronics. Herein, an adjustment scheme for threshold voltage of MoS2 FETs by using self-assembled monolayer treatment via octadecyltrichlorosilane is proposed and demonstrated to show MoS2 FETs in an enhancement mode with preservation of electrical parameters such as field-effect mobility, subthreshold swing, and current on-off ratio. Furthermore, the mechanisms for threshold voltage adjustment are systematically studied by using atomic force microscopy, Raman, temperature-dependent electrical characterization, etc. For validation of effects of threshold voltage engineering on MoS2 FETs, full swing inverters, comprising enhancement mode drivers and depletion mode loads are perfectly demonstrated with a maximum gain of 18.2 and a noise margin of approximate to 45% of 1/2 V-DD. More impressively, quantum dot light-emitting diodes, driven by enhancement mode MoS2 FETs, stably demonstrate 120 cd m(-2) at the gate-to-source voltage of 5 V, exhibiting promising opportunities for future display application

Distribution and Frequencie of SSR Motifs in the Chrysanthemum SSR-enrich Library through 454 Pyrosequencing Technology

Chrysanthemums, often called mums or chrysanths, belong to the genus Chrysanthemum, which includes about 30 species of perennial flowering plants in the family Asteraceae. We extracted DNA from Dendranthema grandiflorum (‘Smileball’) to construct a simple sequence repeat (SSR)- enriched library, using a modified biotin-streptavidin capture method. GS FLX (Genome Sequencer FLX System which provides the flexibility to perform the broad range of applications) sequencing (at the 1/8 run specification) resulted in 18.83 mega base pairs (Mbp) with an average read length of 280.06 bp. Sequence analyses of all SSR-containing clones revealed a predominance of di-nucleotide motifs (16,375, 61.5%) followed by tri-nucleotide motifs (6,616, 24.8%), tetra-nucleotide motifs (1,674, 6.3%), pentanucleotide motifs (1,283, 4.8%), and hexa-nucleotide motifs (693, 2.6%). Among the di-nucleotide motifs, the AC/CA class was the most frequently identified (93.5% of all di-nucleotide types), followed by the GA/AG class (6.1%), the AT/TA class (0.4%), and the CG/GC class (0.03%). When we analyzed the distribution of different repeat motifs and their respective numbers of repeats, regardless of the motif class, of 100 SSR markers, we found a higher number of di-nucleotide motifs with 70 to 80 repeats; we also found two di-nucleotide motifs with 83 and 89 repeats, respectively, but their product lengths were within optimum size (297 and 300 bp). In future work, we will screen for polymorphisms of possible primer pairs. The results will provide a useful tool for assessing molecular diversity and investigating the population structure among and within Chrysanthemum species

Effect of single nucleotide polymorphisms within the interleukin-4 promoter on aspirin intolerance in asthmatics and interleukin-4 promoter activity

Objective Aspirin affects interleukin-4 (IL-4) synthesis; however, the genetic role of IL-4 has not been evaluated in asthmatics with aspirin hypersensitivity. The objective of the study was to examine the influence of single nucleotide polymorphisms (SNPs) in IL-4 gene on aspirin hypersensitivity in asthmatics at the genetic and molecular levels. Methods Aspirin-intolerant (AIA, n = 103) and aspirintolerant asthmatics (n = 270) were genotyped and functional promoter assays were performed. Results Of 15 SNPs tested, seven (-589T>C (rs2243250) in promoter, -33T>C (rs2070874) in the 50-untranslated region, +4047A>G (rs2243266), +4144C>G (rs2243267), +4221C>A (rs2243268), +4367G>A (rs2243270), and +5090A>G (rs2243274) in introns) were significantly associated with AIA risk. The frequency of the rare allele (C) of -589T>C was higher in the AIA group than in the aspirin-tolerant asthmatic group (P(corr) = 0.016), and a gene dose-dependent decline in forced expiratory volume in 1 s was noted after an aspirin challenge (P = 0.0009). Aspirin unregulated IL-4 mRNA production in Jurkat T and K562 leukemia cells. A reporter plasmid assay revealed that aspirin augmented IL-4 promoter transactivation with the -589T>C C and -33T>C C alleles, compared with that bearing the -589T>C T and -33T>C T alleles. Further, electrophoretic mobility shift assay showed the formation of nuclear complexes with -33T>C and -589T>C allele-containing probes; this was augmented by aspirin. The complexes formed with the -33T>C and -589T>C probes were shifted by treatment with anti-CCAAT-enhancer-binding proteins beta and anti-nuclear factor of activated T-cells antibodies, respectively, indicating the inclusion of these transcription factors. Conclusion Aspirin may regulate IL4 expression in an allele-specific manner by altering the availability of transcription factors to the key regulatory elements in the IL4 promoter, leading to aspirin hypersensitivity. Pharmacogenetics and Genomics 20:748-758 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.This study was supported by the BK21, Korea Research Foundation to B.S.K. and J.H.K., partially; and the Korea Health 21 R&D Project, Ministry of Health, Welfare and Family Affairs, Republic of Korea [A010249].Kim TH, 2008, CLIN EXP ALLERGY, V38, P1727, DOI 10.1111/j.1365-2222.2008.03082.xGuo LY, 2008, J IMMUNOL, V181, P3984Hebenstreit D, 2008, J BIOL CHEM, V283, P22490, DOI 10.1074/jbc.M804096200Cormican LJ, 2005, CLIN EXP ALLERGY, V35, P717, DOI 10.1111/j.1365-2222.2005.02261.xCieslik KA, 2005, J BIOL CHEM, V280, P18411, DOI 10.1074/jbc.M410017200Szefler SJ, 2005, J ALLERGY CLIN IMMUN, V115, P233, DOI 10.1016/j.jaci.2004.11.014Adjers K, 2005, INT ARCH ALLERGY IMM, V138, P251, DOI 10.1159/000088726Basehore MJ, 2004, J ALLERGY CLIN IMMUN, V114, P80, DOI 10.1016/j.jaci.2004.05.035Pagani F, 2004, NAT REV GENET, V5, P389, DOI 10.1038/nrg1327Nyholt DR, 2004, AM J HUM GENET, V74, P765Mifflin RC, 2004, MOL PHARMACOL, V65, P470Cohn L, 2004, ANNU REV IMMUNOL, V22, P789, DOI 10.1146/annurev.immunol.22.012703.104716Li-Weber M, 2003, NAT REV IMMUNOL, V3, P534, DOI 10.1038/nri1128Szczeklik A, 2003, J ALLERGY CLIN IMMUN, V111, P913, DOI 10.1067/mai.2003.1487Sousa AR, 2002, NEW ENGL J MED, V347, P1493Nakashima H, 2002, GENES IMMUN, V3, P107, DOI 10.1038/sj/gene/6363820Dahlen SE, 2002, AM J RESP CRIT CARE, V165, P9OLIPHANT A, 2002, BIOTECHNIQUES S, V32, P56*GINA, 2002, GLOB STRAT ASTHM MANPEREZ GM, 2002, J IMMUNOL, V168, P1428Tegeder I, 2001, FASEB J, V15, P2057Stevenson DD, 2001, ANN ALLERG ASTHMA IM, V87, P177Stephens M, 2001, AM J HUM GENET, V68, P978Cianferoni A, 2001, BLOOD, V97, P1742Leff AR, 2001, ANNU REV MED, V52, P1Suzuki I, 2000, CLIN EXP ALLERGY, V30, P1746Berberich-Siebelt F, 2000, EUR J IMMUNOL, V30, P2576Kauffmann F, 1999, CLIN EXP ALLERGY, V29, P17Wiesch DG, 1999, J ALLERGY CLIN IMMUN, V104, P895Varga EM, 1999, EUR RESPIR J, V14, P610Burchard EG, 1999, AM J RESP CRIT CARE, V160, P919Schwenger P, 1999, J CELL PHYSIOL, V179, P109Drazen JM, 1999, NEW ENGL J MED, V340, P197Gerli R, 1998, BLOOD, V92, P2389Noguchi E, 1998, CLIN EXP ALLERGY, V28, P449Dong ZG, 1997, J BIOL CHEM, V272, P9962Marsh DG, 1997, NAT GENET, V15, P389Walley AJ, 1996, J MED GENET, V33, P689Klein SC, 1996, CELL IMMUNOL, V167, P259DAVYDOV IV, 1995, J IMMUNOL, V155, P5273ROSENWASSER LJ, 1995, CLIN EXP ALLERGY, V25, P74*AM THOR SOC, 1995, AM J RESP CRIT CARE, V152, P1107KOPP E, 1994, SCIENCE, V265, P956CRABTREE GR, 1994, ANNU REV BIOCHEM, V63, P1045FLESCHER E, 1991, J IMMUNOL, V146, P2553AKIRA S, 1990, EMBO J, V9, P1897SZCZEKLIK A, 1990, EUR RESPIR J, V3, P588*SENSORMEDICS, 1988, PULM UT OP MAN PREDHEDRICK PW, 1987, GENETICS, V117, P331MORRIS JF, 1976, WESTERN J MED, V125, P110SAMTER M, 1967, J ALLERGY, V40, P281

Appropriateness of a donor liver with respect to macrosteatosis: application of artificial neural networks to US images--initial experience

PURPOSE: To retrospectively compare performance of artificial neural networks (ANNs) applied to ultrasonographic (US) images with that of radiologists for prediction of appropriateness of a donor liver with respect to macrosteatosis before liver transplantation. MATERIALS AND METHODS: Institutional ethics committee approved study; written informed consent was obtained. ANNs, constructed with three-layered 15-neuron back-propagation algorithm, were trained to predict appropriateness of a donor liver with respect to macrosteatosis by using statistically significant laboratory and US parameters derived from univariate analyses, together with correct diagnosis. Input variables for ANNs were alkaline phosphatase, glutamic oxaloacetic transaminase, glutamic pyruvate transaminase, gamma-glutamyltransferase, hepatorenal ratio of echogenicity, and tail area ratio and tail length of portal vein wall echogenicity. Three radiologists graded US images in 94 potential donors (71 men and 23 women) on the basis of four degrees of hepatic steatosis. After training and testing of ANNs, performance of ANNs and radiologists in predicting appropriateness of potential donors was evaluated with receiver operating characteristic (ROC) analysis and compared by means of univariate z score test. RESULTS: Among 94 potential donor livers, 76 were normal or had mild steatosis, and 18 had moderate or severe macrosteatosis at histopathologic examination. Area under ROC curve (Az) of ANNs (Az=0.9673) was significantly greater than that of radiologists (faculty, Az=0.9106, P=.048; fellow, Az= 0.9038, P=.044; resident, Az=0.8931, P=.038). No statistically significant difference in sensitivity for predicting appropriateness as a liver donor with respect to macrosteatosis was found between ANNs (88.9%) and radiologists (P >.05). However, specificity of ANNs (96.1%) was significantly better than that of radiologists (P <.003). CONCLUSION: ANNs might be a useful tool to categorize whether a donor liver is appropriate for transplantation with respect to macrosteatosis on the basis of multiple variables related to laboratory and US features. Further study is needed