Bilirubin as a signaling molecule

For long time bilirubin was only considered as a potentially dangerous sign of liver diseases, but it now appears clear that it is also a powerful signaling molecule. Together with potent antioxidant activities that were only reported in the last few decades, many other biological effects have now been clearly described. These include especially profound inhibitory effects on almost all effectors of the immune system, with their clinical consequences in the bilirubin-mediated protection against autoimmune and inflammatory diseases. Separate from these, bilirubin activates various nuclear and cytoplasmic receptors, resembling the endocrine activities of actual hormonal substances. This is true for the “classical” hepatic nuclear receptors, including the aryl hydrocarbon receptor, or the constitutive androstane receptor; and also for some lesser-explored receptors such as peroxisome proliferator-activated receptors α and γ; Mas-related G protein-coupled receptor; or other signaling molecules including fatty acid binding protein 1, apolipoprotein D, or reactive oxygen species. All of these targets have broad metabolic effects, which in turn may offer protection against obesity, diabetes mellitus, and other metabolic diseases. The (mostly experimental) data are also supported by clinical evidence. In fact, data from the last three decades have convincingly demonstrated the protective effects of mildly elevated serum bilirubin concentrations against various “diseases of civilization.” Additionally, even tiny, micromolar changes of serum bilirubin concentrations have been associated with substantial alteration in the risks of these diseases. It is highly likely that all of the biological activities of bilirubin have yet to be exhaustively explored, and thus we can expect further clinical discoveries about this evolutionarily old molecule into the future.     

End-tidal estimates of arterial PCO2 for cardiac output measurement by CO2 rebreathing: A study in patients with cystic fibrosis and healthy controls

We set out to determine the effects of various estimates of arterial PCO₂ (PaCO₂) on calculation of cardiac output (Q) by the indirect Fick (CO₂) method in healthy children and children with cystic fibrosis (CF), and to develop a prediction equation for children for PaCO₂, based on end-tidal PCO₂ (PetCO₂). The study had 3 parts: 1) Twenty-three healthy children exercised lightly and moderately while arterialized capillary blood gases and PetCO₂ were measured simultaneously so that a prediction equation for PaCO₂ could be derived from PetCO₂. Cardiac output was measured by CO₂ rebreathing at each workload; different values for PaCO₂ (measured in arterialized capillary blood, end-tidal, and PaCO₂ derived from the Bohr equation assuming normal dead space) were used to calculate Q; 2) our equation PaCO₂ = 0.647 PetCO₂ + 12.4 was tested prospectively to measure Q in 9 healthy children; and 3) cardiac output based on arterialized capillary PaCO₂ was compared with that based on Jones-corrected PetCO₂ during light and moderate exercise in 16 CF patients whose forced expiratory volume in 1 second (FEV₁) range from normal to 37% predicted. Our results have shown that in health children end tidal based-estimates of PaCO₂ tended to overestimate Q, whereas PaCO₂ values derived by the Bohr equation and assuming normal dead space tended to underestimate Q, compared with Q calculated from directly measured PaCO₂. Our prediction equation resulted in good agreement compared with directly measured PaCO₂ when used to calculate Q (mean difference, +1.3%; range, +9% to −13%). CF patients with little or no airway obstruction had results similar to healthy controls, but those with severe airway obstruction had lower values for Q when PetCO₂ was used instead of directly measured PaCO₂. We conclude that estimates of PaCO₂ from PetCO₂ are not reliable in patients with moderately severe pulmonary disease due to CF. In healthy children, the prediction equation for PaCO₂ from PetCO₂ derived in the present study gives results superior to other bloodless methods currently in use for computation of Q by the indirect Fick (CO₂) method. Pediatr Pulmonol. 1996; 22:154–160. © 1996 Wiley-Liss, Inc.     

Analysis of naturally processed peptides eluted from HLA DRB1 *0402 and *0404

Understanding the structural features of naturally processed peptides found within the major histocompatibility complex (MHC) class II peptide binding groove from disease-associated MHC molecules may provide insights into the nature of potential disease-related antigens. Class II MHC/peptide complexes were purified by immunoaffinity from transformed B cell lines homozygous for DRB1*0404 (an allele associated with rheumatoid arthritis) and *0402 (a closely related allele not associated with this disease). Peptides were eluted at acidic pH, fractionated by reversed phase HPLC, and analyzed by capillary electrophoresis. Those fractions containing a single dominant peptide were sequenced by automated Edman degradation and tandem mass spectrometry. The predominant peptide species identified came from non-polymorphic regions of the HLA class I molecules expressed by each cell line. Peptides from DRB1*0404 were found to be nested clusters derived from positions 26–43 of the HLA-B and -C α-chain. DRB1*0402 contained as the predominant peptide species a nested cluster from positions 129–145 of the HLA-B α-chain. The primary structure of the class I derived peptides was consistent with that seen by peptides exhibiting promiscuous DR binding behavior. Processing of MHC-derived peptides by MHC class II molecules is a common occurrence in the transformed B cell lines analyzed. © 1996 Wiley-Liss, Inc.     

Increased Salt Intake Decreases Diet-Induced Thermogenesis in Healthy Volunteers: A Randomized Placebo-Controlled Study

High salt intake ranks among the most important risk factors for noncommunicable diseases. Western diets, which are typically high in salt, are associated with a high prevalence of obesity. High salt is thought to be a potential risk factor for obesity independent of energy intake, although the underlying mechanisms are insufficiently understood. A high salt diet could influence energy expenditure (EE), specifically diet-induced thermogenesis (DIT), which accounts for about 10% of total EE. We aimed to investigate the influence of high salt on DIT. In a randomized, double-blind, placebo-controlled, parallel-group study, 40 healthy subjects received either 6 g/d salt (NaCl) or placebo in capsules over 2 weeks. Before and after the intervention, resting EE, DIT, body composition, food intake, 24 h urine analysis, and blood pressure were obtained. EE was measured by indirect calorimetry after a 12 h overnight fast and a standardized 440 kcal meal. Thirty-eight subjects completed the study. Salt intake from foods was 6 g/d in both groups, resulting in a total salt intake of 12 g/d in the salt group and 6 g/d in the placebo group. Urine sodium increased by 2.29 g/d (p < 0.0001) in the salt group, indicating overall compliance. The change in DIT differed significantly between groups (placebo vs. salt, p = 0.023). DIT decreased by 1.3% in the salt group (p = 0.048), but increased by 0.6% in the placebo group (NS). Substrate oxidation indicated by respiratory exchange ratio, body composition, resting blood pressure, fluid intake, hydration, and urine volume did not change significantly in either group. A moderate short-term increase in salt intake decreased DIT after a standardized meal. This effect could at least partially contribute to the observed weight gain in populations consuming a Western diet high in salt.     

降黄散熏蒸联合捏脊、推拿治疗湿热蕴蒸型新生儿病理性黄疸临床研究

目的:观察降黄散熏蒸联合捏脊、推拿治疗湿热蕴蒸型新生儿病理性黄疸的临床疗效。方法:将92例湿热蕴蒸型病理性黄疸患儿按随机数字表法分为观察组和对照组各46例。对照组给予蓝光照射治疗,观察组在对照组基础上加降黄散熏蒸联合捏脊、推拿治疗,2组均治疗5 d。对比2组临床疗效和治疗前后的血清总胆红素水平、免疫球蛋白(Ig)及T细胞亚群的变化,记录黄疸消退时间。结果:观察组临床疗效优于对照组,差异有统计学意义(P<0.05)。治疗后,2组血清总胆红素水平均较治疗前下降(P<0.05),观察组血清总胆红素水平比对照组下降更明显(P<0.05);观察组黄疸消退时间短于对照组(P<0.05)。治疗后,2组血清IgA、IgG、IgM水平均较治疗前升高(P<0.05),观察组IgA、IgG、IgM水平均比对照组升高更明显(P<0.05)。治疗后,2组CD3^+、CD4^+、CD4^+/CD8^+值均较治疗前升高(P<0.05),观察组CD3^+、CD4^+、CD4^+/CD8^+值均比对照组升高更明显(P<0.05)。结论:降黄散熏蒸联合捏脊、推拿治疗湿热蕴蒸型新生儿病理性黄疸,可以有效降低患儿的血清总胆红素水平,缩短退黄时间,提高机体免疫功能。     

The effects of isotretinoin therapy on the biliary system

The aim of the present study was to investigate the potential effects of isotretinoin on the biliary system in patients with acne vulgaris receiving isotretinoin therapy. This was a preliminary retrospective study involving 40 patients with severe acne vulgaris who attended the dermatology clinic and were administered different doses (20 or 30 mg/day) of isotretinoin. Serum levels of AST, ALT, ALP, GGT, total bilirubin, direct bilirubin, and indirect bilirubin at the beginning and at the first month of therapy were scanned, recorded, and statistically analyzed. Total and indirect bilirubin levels at the first month of treatment in 30 patients, receiving isotretinoin at a dose of 20 mg/day, were significantly lower compared to the baseline values (p = .02 and p = .03, respectively), whereas AST and GGT serum levels were significantly higher (p = .003 and p = .006 respectively). No significant reduction in total and indirect bilirubin levels was detectable at the first month of treatment in 10 patients receiving isotretinoin at a dose of 30 mg/day; however, AST, ALP, and GGT levels were significantly elevated in these patients (p = .023; p = .004; and p = .001, respectively). To our knowledge, there is no previous study investigating the effects of isotretinoin on the biliary system, and, therefore, the present study is a preliminary one. Our findings implicate that low dose (20 mg/day) isotretinoin therapy can potentially reduce total and indirect bilirubin levels. Long‐term, large‐scale, prospective studies with patients receiving different doses of isotretinoin may provide more reliable information regarding the bilirubin lowering effects of isotretinoin and optimum dosing for achieving this clinical effect.     

Therapeutic effect of regulating autophagy in spinal cord injury: a network meta-analysis of direct and indirect comparisons

Objective:An increasing number of studies indicate that autophagy plays an important role in the pathogenesis of spinal cord injury,and that regulating autophagy can enhance recovery from spinal cord injury.However,the effect of regulating autophagy and whether autophagy is detrimental or beneficial after spinal cord injury remain unclear.Therefore,in this study we evaluated the effects of autophagy regulation on spinal cord injury in rats by direct and indirect comparison,in an effort to provide a basis for further research.Data source:Relevant literature published from inception to February 1,2018 were included by searching Wanfang,CNKI,Web of Science,MEDLINE(OvidSP),PubMed and Google Scholar in English and Chinese.The keywords included"autophagy","spinal cord injury",and"rat".Data selection:The literature included in vivo experimental studies on autophagy regulation in the treatment of spinal cord injury(including intervention pre-and post-spinal cord injury).Meta-analyses were conducted at different time points to compare the therapeutic effects of promoting or inhibiting autophagy,and subgroup analyses were also conducted.Outcome measure:Basso,Beattie,and Bresnahan scores.Results:Of the 622 studies,33 studies of median quality were included in the analyses.Basso,Beattie,and Bresnahan scores were higher at 1 day(MD=1.80,95%CI:0.81-2.79,P=0.0004),3 days(MD=0.92,95%CI:0.72-1.13,P<0.00001),1 week(MD=2.39,95%CI:1.85-2.92,P<0.00001),2 weeks(MD=3.26,95%CI:2.40-4.13,P<0.00001),3 weeks(MD=3.13,95%CI:2.51-3.75,P<0.00001)and 4 weeks(MD=3.18,95%CI:2.43-3.92,P<0.00001)after spinal cord injury with upregulation of autophagy compared with the control group(drug solvent control,such as saline group).Basso,Beattie,and Bresnahan scores were higher at 1 day(MD=6.48,95%CI:5.83-7.13,P<0.00001),2 weeks(MD=2.43,95%CI:0.79-4.07,P=0.004),3 weeks(MD=2.96,95%CI:0.09-5.84,P=0.04)and 4 weeks(MD=4.41,95%CI:1.08-7.75,P=0.01)after spinal cord injury with downregulation of autophagy compared with the control group.Indirect comparison of upregulation and downregulation of autophagy showed no differences in Basso,Beattie,and Bresnahan scores at 1 day(MD=-4.68,95%CI:-5.840 to-3.496,P=0.94644),3 days(MD=-0.28,95%CI:-2.231-1.671,P=0.99448),1 week(MD=1.83,95%CI:0.0076-3.584,P=0.94588),2 weeks(MD=0.81,95%CI:-0.850-2.470,P=0.93055),3 weeks(MD=0.17,95%Cl:-2.771-3.111,P=0.99546)or 4 weeks(MD=-1.23,95%Cl:-4.647-2.187,P=0.98264)compared with the control group.Conclusion:Regulation of autophagy improves neurological function,whether it is upregulated or downregulated.There was no difference between upregulation and downregulation of autophagy in the treatment of spinal cord injury.The variability in results among the studies may be associated with differences in research methods,the lack of clearly defined autophagy characteristics after spinal cord injury,and the limited autophagy monitoring techniques.Thus,methods should be standardized,and the dynamic regulation of autophagy should be examined in future studies.     

Eco-Friendly Incorporation of Crumb Rubber and Waste Bagasse Ash in Bituminous Concrete Mix

The consumption of waste materials in the construction sector is a sustainable approach that helps in reducing the environmental pollution and decreases the construction cost. The present research work emphasizes the mechanical properties of bituminous concrete mix prepared with crumb rubber (CR) and waste sugarcane bagasse ash (SCBA). For the preparation of bituminous concrete mix specimens with CR and SCBA, the effective bitumen content was determined using the Marshall Mix design method. A total of 15 bituminous concrete mix specimens with 4%, 4.5%, 5%, 5.5% and 6% of bitumen content were prepared, and the effective bitumen content turned out to be 4.7%. The effect of five different CR samples of 2%, 4%, 6%, 8% and 10% by weight of total mix and SCBA samples of 25%, 50%, 75% and 100% by weight of filler were investigated on the performance of bituminous concrete. A total of 180 samples with different percentages of CR and SCBA were tested for indirect tensile strength (ITS) and Marshall Stability, and the results were compared with conventional bituminous concrete mix. It was observed that the stability values rose with an increase in CR percentage up to 6%, while the flow values rose as the percentage of SCBA increased in the mix. Maximum ITS results were observed at 4% CR and 25% SCBA replacement levels. However, a decrease in stability and ITS result was observed as the percentages of CR and SCBA increased beyond 4% and 25%, respectively. We concluded that the optimum CR and SCBA content of 4% and 25%, respectively, can be effectively used as a sustainable alternative in bituminous concrete mix.     

间接减压经椎弓根植骨在胸腰椎爆裂骨折中的应用价值

目的比较在胸腰椎爆裂骨折中后路间接减压经椎弓根植骨与开放减压后外侧植骨2种手术方法的临床疗效。方法回顾性分析1998年4月—2008年3月所收治的胸腰椎爆裂骨折并经完整随访的患者56例,将其分为2组:间接减压组32例,于伤后早期(72 h内)经后路行短节段椎弓根钉棒系统复位固定、间接减压,经伤椎椎弓根植入自体松质骨浆;开放复位组24例,行半椎板或全椎板切除,短节段椎弓根螺钉系统内固定,半椎板、横突或关节突融合。观察2组手术中的情况及并发症,评价各组在脊柱的矫形、Cobb角的矫正及神经功能恢复情况。结果2组手术时间分别为1.81 h、2.23 h,出血量为360 mL、440 mL,2组比较均有显著性差异(P均<0.05),全部病例经9~24个月随访,平均15.2个月,2组患者术前、术后脊髓功能Frankel分级、椎体前缘压缩率、Cobb角均无显著性差异(P均>0.05),术前2组脊髓功能恢复、椎体畸形的矫正率、Cobb角的矫正率比较均无显著性差异(P均>0.05),而2组术后脊髓功能均有明显恢复,Frankel分级分别提高1~4级,4例脊髓完全损伤者神经功能Frankel分级提高1级、2级,椎体前缘压缩率、Cobb角的矫正均明显好转(P均<0.05),全部病例基本达解剖复位,术后无内固定物失败,内固定物取出后矫正丢失率分别为0.8%,8.6%。结论后路器械复位间接减压能有效提供神经修复空间,经椎弓根植骨可有效降低内植物的失败及矫正度的丢失,同时能够缩短手术时间,减少出血量,是治疗胸腰椎爆裂骨折的可靠有效方法。