Effect of replacement of soybean oil by Hermetia illucens fat on performance,digestibility,cecal microbiome,liver transcriptome and liver and plasma lipidomes of broilers

Background In contrast to protein-rich insect meal,the feed potential of insect fat is generally less explored and knowledge about the suitability of insect fat as a fat source specifically in broiler diets is still limited.In view of this,the present study aimed to comprehensively investigate the effect of partial(50%) and complete replacement of soybean oil with insect fat from Hermetia illucens(HI) larvae in broiler diets on performance,fat digestibility,cecal microbiome,liver transcriptome and liver and plasma lipidomes.Thus,100 male,1-day-old Cobb 500 broilers were randomly assigned to three groups and fed three different diets with either 0(group HI-0,n cens(HI) larvae fat for 35 d.= 30),2.5%(group HI-2.5,n %(HI-5.0,n = 35) or 5.0= 35) Hermetia illuResults Body weight gain,final body weight,feed intake,and feed:gain ratio during the whole period and apparent ileal digestibility coefficient for ether extract were not different between groups.Cecal microbial diversity did not differ between groups and taxonomic analysis revealed differences in the abundance of only four low-abundance bacterial taxa among groups;the abundances of phylum Actinobacteriota,class Coriobacteriia,order Coriobacteriales and family Eggerthellaceae were lower in group HI-5.0 compared to group HI-2.5(P < 0.05).Concentrations of total and individual short-chain fatty acids in the cecal digesta were not different between the three groups.Liver transcriptomics revealed a total of 55 and 25 transcripts to be differentially expressed between groups HI-5.0 vs.HI-0 and groups HI-2.5 vs.HI-0,respectively(P < 0.05).The concentrations of most lipid classes,with the exception of phosphatidylethanolamine,phosphatidylglycerol and lysophosphatidylcholine in the liver and cholesterylester and ceramide in plasma(P < 0.05),and of the sum of all lipid classes were not different between groups.Conclusions Partial and complete replacement of soybean oil with HI larvae fat in broiler diets had no effect on growth performance and only modest,but no adverse effects on the cecal microbiome and the metabolic health of broilers.This suggests that HI larvae fat can be used as an alternative fat source in broiler diets,thereby,making broiler production more sustainable.

Association of mineral and bone biomarkers with adverse cardiovascular outcomes and mortality in the German Chronic Kidney Disease(GCKD)cohort

Mineral and bone disorder(MBD)in chronic kidney disease(CKD)is tightly linked to cardiovascular disease(CVD).In this study,we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular(CV)outcomes and mortality.In 5217 participants of the German CKD(GCKD)study enrolled with an estimated glomerular filtration rate(eG FR)between 30–60 mL·min-1 per 1.73 m2 or overt proteinuria,serum osteoprotegerin(OPG),C-terminal fibroblast growth factor-23(FGF23),intact parathyroid hormone(iP TH),bone alkaline phosphatase(BAP),cross-linked C-telopeptide of type 1 collagen(CTX1),procollagen 1intact N-terminal propeptide(P1NP),phosphate,calcium,and 25-OH vitamin D were measured at baseline.Participants with missing values among these parameters(n=971)were excluded,leaving a total of 4246 participants for analysis.During a median follow-up of6.5 years,387 non-CV deaths,173 CV deaths,645 nonfatal major adverse CV events(MACEs)and 368 hospitalizations for congestive heart failure(CHF)were observed.OPG and FGF23 were associated with all outcomes,with the highest hazard ratios(HRs)for OPG.In the final Cox regression model,adjusted for CV risk factors,including kidney function and all other investigated biomarkers,each standard deviation increase in OPG was associated with non-CV death(HR 1.76,95%CI:1.35–2.30),CV death(HR 2.18,95%CI:1.50–3.16),MACE(HR 1.38,95%CI:1.12–1.71)and hospitalization for CHF(HR 2.05,95%CI:1.56–2.69).Out of the nine biomarkers examined,stratification based on serum OPG best identified the CKD patients who were at the highest risk for any adverse CV outcome and mortality.

Uncoupling protein 2 deficiency of non-cancerous tissues inhibits the progression of pancreatic cancer in mice

Background: Pancreatic ductal adenocarcinoma(PDAC) is a disease of the elderly mostly because its development from preneoplastic lesions depends on the accumulation of gene mutations and epigenetic alterations over time. How aging of non-cancerous tissues of the host affects tumor progression, however, remains largely unknown. Methods: We took advantage of a model of accelerated aging, uncoupling protein 2-deficient( Ucp2 knockout, Ucp2 KO) mice, to investigate the growth of orthotopically transplanted Ucp2 wild-type(WT) PDAC cells(cell lines Panc02 and 6606PDA) in vivo and to study strain-dependent differences of the PDAC microenvironment. Results: Measurements of tumor weights and quantification of proliferating cells indicated a significant growth advantage of Panc02 and 6606PDA cells in WT mice compared to Ucp2 KO mice. In tumors in the knockout strain, higher levels of interferon-γ m RNA despite similar numbers of tumor-infiltrating T cells were observed. 6606PDA cells triggered a stronger stromal reaction in Ucp2 KO mice than in WT animals. Accordingly, pancreatic stellate cells from Ucp2 KO mice proliferated at a higher rate than cells of the WT strain when they were incubated with conditioned media from PDAC cells. Conclusions: Ucp2 modulates PDAC microenvironment in a way that favors tumor progression and implicates an altered stromal response as one of the underlying mechanisms.

Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells

AIM: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of same epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferator-activated receptor γ (PPARγ), the mechanism by which TZD exert their anticancer effect is presently unclear. In this study, we analyzed the mechanism by which TZD inhibit growth of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma. METHODS: The effects of TZD in pancreatic cancer cells were assessed in anchorage-independent growth assay. Expression of PPARy was measured by reverse-transcription polymerase chain reaction and confirmed by Western blot analysis. PPARy activity was evaluated by transient reporter gene assay. Flow cytometry and DMA fragmentation,assay were used to determine the effect of TZD on cell cycle progression and apoptosis respectively. The effect of TZD on ductal differentiation markers was performed by Western blot. RESULTS: Exposure to TZD inhibited colony formation in a PPARγ-dependent manner. Growth inhibition was linked to G1 phase cell cycle arrest through induction of the ductal differentiation program without any increase of the apoptotic rate. CONCLUSION: TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth by a PPAR-dependent induction of pacreatic ductal differentiation.

Hepatic steatosis is associated with an increased risk of carotid atherosclerosis

AIM: Although an association between hepatic steatosis and vascular risk factors has been described, direct relationships between fatty liver and atherosclerosis have not yet been investigated. The aim of the present study has been to investigate those relationships. METHODS: The Study of Health in Pomerania examined a random population sample aged between 20 and 79 years. A study population of 4 222 subjects without hepatitis B and C infections and without liver cirrhosis was available for the present analysis. Hepatic steatosis was defined sonographically and intima-media thickness (IMT) as well as plaque prevalence were estimated by carotid ultrasound. RESULTS: The prevalence rate of hepatic steatosis was 29.9%. Among subjects aged ≥45 years, an association between hepatic steatosis and IMT of the carotid arteries was found in bivariate analysis, but not after adjustment for atherosclerotic risk factors. Individuals with fatty liver had more often carotid plaques than persons without fatty liver (plaque prevalence rate 76.8% vs 66.6%; P<0.001). This association persisted after adjustment for confounding factors and was predominantly present in subjects with no to mild alcohol consumption. CONCLUSION: There is an independent association between hepatic steatosis and carotid atherosclerotic plaques. Metabolic changes due to nonalcoholic fatty liver disease may explain this relationship.

Metabolic inflammation as an instigator of fibrosis during nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)is characterized by excessive storage of fatty acids in the form of triglycerides in hepatocytes.It is most prevalent in western countries and includes a wide range of clinical and histopathological findings,namely from simple steatosis to steatohepatitis and fibrosis,which may lead to cirrhosis and hepatocellular cancer.The key event for the transition from steatosis to fibrosis is the activation of quiescent hepatic stellate cells(qHSC)and their differentiation to myofibroblasts.Pattern recognition receptors(PRRs),expressed by a plethora of immune cells,serve as essential components of the innate immune system whose function is to stimulate phagocytosis and mediate inflammation upon binding to them of various molecules released from damaged,apoptotic and necrotic cells.The activation of PRRs on hepatocytes,Kupffer cells,the resident macrophages of the liver,and other immune cells results in the production of proinflammatory cytokines and chemokines,as well as profibrotic factors in the liver microenvironment leading to qHSC activation and subsequent fibrogenesis.Thus,elucidation of the inflammatory pathways associated with the pathogenesis and progression of NAFLD may lead to a better understanding of its pathophysiology and new therapeutic approaches.

The local mammalian target of rapamycin(mTOR) modulation:a promising strategy to counteract neurodegeneration

Alzheimer’s disease (AD) and the evolution of the “Amyloid Hypothesis”: The primary risk factor for dementia is aging, as the overwhelming majority of individuals who have the disease (~95%) are 65 years old or older, and the rate of development of AD doubles roughly every five years from that age, peaking at a nearly 50% population prevalence by the age of 85. The disease is progressive and irreversible, with an average time course of 8 to 10 years. Regardless of catastrophic forecasts for the next decades, its actual prevalence has huge family and social costs.

Lithocholic acid induction of the FGF19 promoter in intestinal cells is mediated by PXR

To study the effect of the toxic secondary bile acid lithocholic acid （LCA） on the expression of fibroblast growth factor 19 （FGF19） in intestinal cells and to characterize the pregnane-X-receptor （PXR） response of the FGF19 promoter region. METHODS： The intestinal cell line LS174T was stimulated with various concentrations of chenodeoxy- cholic acid and lithocholic acid for several time points. FGF19 mRNA levels were determined with quantitative realtime RT-PCR. FGF19 deletion promoter constructs were generated and the LCA response was analzyed in reporter assays. Co-transfections with PXR and RXR were carried out to study FGF19 regulation by these factors, RESULTS： LCA and CDCA strongly up-regulate FGF19 mRNA expression in LS174T cells in a time and dose dependent manner. Using reporter gene assays with several deletion constructs we found that the LCA responsive element in the human FGF19 promoter maps to the proximal regulatory region containing two poten- tial binding sites for PXR. Overexpression of PXR and its dimerization partner retinoid X receptor （RXR） and stimulation with LCA or the potent PXR ligand rifampicin leads to a significant induction of FGF19 promoter activ- ity in intestinal cells. CONCLUSION： LCA induced feedback inhibition of bile acid synthesis in the liver is likely to be regulated by PXR inducing intestinal FGF19 expression.

Protective effects of exogenous gangliosides on ROS-induced changes in human spermatozoa

This article summarizes the available evidence on the efficacy of gangliosides to reduce the degree of reactive oxygen species （ROS）-mediated damage. The antioxidative efficacy of exogenous gangliosides in protecting different cells encouraged us to examine their ability to protect human spermatozoa. Gangliosides are sialic acid-containing glycosphingolipids with strong amphiphilic character due to the bulky headgroup made of several sugar rings with sialic acid residues and the double-tailed hydrophobic lipid moiety. The amphiphilicity of gangliosides allows them to exist as micelles in aqueous media when they are present at a concentration above their critical micellar concentration. The protective effect of ganglioside micelles on spermatozoa is believed to stem from their ability to scavenge free radicals and prevent their damaging effects, In our study, we particularly focused our attention on the protective effect of ganglioside micelles on DNA in human spermatozoa exposed to cryopreservation. The results indicate that ganglioside micelles can modulate the hydrophobic properties of the sperm membrane to increase tolerance to DNA fragmentation, thus protecting the DNA from cryopreservation-induced damage. Further actions of ganglioside micelles, which were documented by biochemical and biophysical studies, included （i） the modulation of superoxide anion generation by increasing the diffusion barrier for membrane events responsible for signal translocation to the interior of the cell; （ii） the inhibition of iron-catalysed hydroxyl radical formation due to the iron chelation potential of gangliosides; and （iii） inhibition of hydrogen peroxide diffusion across the sperm membrane.

Comprehensive evaluation of the metabolic effects of insect meal from Tenebrio molitor L.in growing pigs by transcriptomics, metabolomics and lipidomics

Background:The hypothesis was tested that insect meal(IM)as protein source influences intermediary metabolism of growing pigs.To test this,30 male,5-week-old crossbred pigs were randomly assigned to 3 groups of 10 pigs each with similar body weights(BW)and fed isonitrogenous diets either without(CON)or with 5%IM(IM5)or 10%IM(IM10)from Tenebrio molitor L.for 4 weeks and key metabolic tissues(liver,muscle,plasma)were analyzed using omics-techniques.Results:Most performance parameters did not differ across the groups,whereas ileal digestibilities of most amino acids were 6.7 to 15.6%-units lower in IM10 than in CON(P<0.05).Transcriptomics of liver and skeletal muscle revealed a total of 166 and 198,respectively,transcripts differentially expressed between IM10 and CON(P<0.05).Plasma metabolomics revealed higher concentrations of alanine,citrulline,glutamate,proline,serine,tyrosine and valine and a lower concentration of asparagine in IM10 than in CON(P<0.05).Only one out of fourteen quantifiable amino acid metabolites,namely methionine sulfoxide(MetS),in plasma was elevated by 45%and 71%in IM5 and IM10,respectively,compared to CON(P<0.05).Plasma concentrations of both,major carnitine/acylcarnitine species and bile acids were not different across groups.Lipidomics of liver and plasma demonstrated no differences in the concentrations of triacylglycerols,cholesterol and the main phospholipids,lysophospholipids and sphingolipids between groups.The percentages of all individual phosphatidylcholine(PC)and phosphatidylethanolamine(PE)species in the liver showed no differences between groups,except those with 6 double bonds(PC 38:6,PC 40:6,PE 38:6,PE 40:6),which were markedly lower in IM10 than in CON(P<0.05).In line with this,the percentage of C22:6n-3 in hepatic total lipids was lower in IM10 than in the other groups(P<0.05).Conclusions:Comprehensive analyzes of the transcriptome,lipidome and metabolome of key metabolic tissues indicate that partial or complete replacement of a conventional protein source by IM in the diet has only a weak impact on the intermediary metabolism of growing pigs.Thus,it is concluded that IM from Tenebrio molitor L.can be used as a dietary source of protein in pigs without causing adverse effects on metabolism.

Serum bile acid profiling reflects enterohepatic detoxification state and intestinal barrier function in inflammatory bowel disease

AIM： To determine free and conjugated serum bile acid （BA） levels in inflammatory bowel disease （IBD） subgroups with defined clinical manifestations. METHODS： Comprehensive serum BA profiling was performed in 358 IBD patients and 310 healthy con- trols by liquid chromatography coupled to electrospray ionization tandem mass spectrometry. RESULTS： Serum levels of hyodeoxycholic acid, the CYP3A4-mediated detoxification product of the second- ary BA lithocholic acid （LCA）, was increased significantly in Crohn＇s disease （CD） and ulcerative colitis （UC）, while most other serum BA species were decreased signifi- cantly. Total BA, total BA conjugate, and total BA glyco- conjugate levels were decreased only in CD, whereas total unconjugated BA levels were decreased only in UC. In UC patients with hepatobiliary manifestations, the conjugated primary BAs glycocholic acid, taurocholic acid, and glycochenodeoxycholic acid were as signifi- cantly increased as the secondary BAs LCA, ursodeoxy- cholic acid, and tauroursodeoxycholic acid compared to UC patients without hepatobiliary manifestations. Finally, we found that in ileocecal resected CD patients, the unconjugated primary BAs, cholic acid and chenode- oxycholic acid, were increased significantly compared to controls and patients without surgical interventions. CONCLUSION： Serum BA profiling in IBD patients that indicates impaired intestinal barrier function and increased detoxification is suitable for advanced diag- nostic characterization and differentiation of IBD sub- groups with defined clinical manifestations.

Different effects of a CD14 gene polymorphism on disease outcome in patients with alcoholic liver disease and chronic hepatitis C infection

AIM： Clinical and experimental data suggest that gut-derived endotoxins are an important pathogenic factors for progression of chronic liver disease. Recently, a C-T （-159） polymorphism in the promoter region of the CD14 gene was detected and found to confer increased CD14 expression and to be associated with advanced alcoholic liver damage. Here, we investigated this polymorphism in patients with less advanced alcoholic liver disease （ALD） and chronic hepatitis C virus （HCV） infection. METHODS： CD14 genotyping was performed by PCR-RFLP analysis in （a） 121 HCV patients, （b） 62 patients with alcohol-associated cirrhosis （AIc-Ci）, （c） 118 individuals with heavy alcohol abuse without evidence of advanced liver damage （Alc-w/o Ci）, and （d） 247 healthy controls. Furthermore, serum levels of soluble CD14 （sCD14） and transaminases were determined. RESULTS： The TT genotype was significantly more frequent in Alc-Ci compared to Alc-w/o Ci or controls （40.3% vs 23.7% or 24.0%, respectively）. In Alc-w/o Ci, serum levels of transaminases did not differ significantly between patients with different CD14 genotypes. In HCV patients, TT-homozygotes had significantly higher sCD14 levels and sCD14 serum levels were significantly higher in patients with advanced fibrosis or cirrhosis. However, no association was found between CD14 genotypes and histological staging or grading. CONCLUSION： Considering serum transaminases as surrogate markers for alcoholic liver damage, the CD14 polymorphism seems to exhibit different effects during the course of ALD. Differences in genotype distribution between cirrhotic HCV patients and alcoholics and the known functional impact of this polymorphism on CD14 expression levels further indicate differences in the pathophysiological role of CD14 and CD14-mediated lipopolysaccharides signal transduction with regard to the stage as well as the type of the underlying liver disease.

Epo/EpoR signaling in osteoprogenitor cells is essential for bone homeostasis and Epo-induced bone loss

High erythropoietin(Epo)levels are detrimental to bone health in adult organisms.Adult mice receiving high doses of Epo lose bone mass due to suppressed bone formation and increased bone resorption.In humans,high serum Epo levels are linked to fractures in elderly men.Our earlier studies indicated that Epo modulates osteoblast activity;however,direct evidence that Epo acts via its receptor(EpoR)on osteoblasts in vivo is still missing.Here,we created mice lacking EpoR in osteoprogenitor cells to specifically address this gap.Deletion of EpoR in osteoprogenitors(EpoR:Osx-cre,cKO)starting at 5 weeks of age did not alter red blood cell parameters but increased vertebral bone volume by 25%in 12-week-old female mice.This was associated with low bone turnover.Histological(osteoblast number,bone formation rate)and serum(P1NP,osteocalcin)bone formation parameters were all reduced,as were the number of osteoclasts and TRAP serum level.Differentiation of osteoblast precursors isolated from cKO versus control mice resulted in lower expression of osteoblast marker genes including Runx2,Alp,and Col1a1 on day 21,whereas the mineralization capacity was similar.Moreover,the RANKL70PG ratio,which determines the osteoclast-supporting potential of osteoblasts,was substantially decreased by 50%.Similarly,coculturing cKO osteoblasts with control or cKO osteoclast precursors produced significantly fewer osteoclasts than coculture with control osteoblasts.Finally,exposing female mice to Epo pumps(10 U-d_1)for 4 weeks resulted in trabecular bone loss(-25%)and increased osteoclast numbers(1.7-fold)in control mice only,not in cKO mice.Our data show that EpoR in osteoprogenitors is essential in regulating osteoblast function and osteoblast-mediated osteoclastogenesis via the RANKI70PG axis.Thus,osteogenic Epo/EpoR signaling controls bone mass maintenance and contributes to Epo-induced bone loss.

Regulatory role of sphingosine kinase and sphingosine-1-phosphate receptor signaling in progenitor/stem cells

Balanced sphingolipid signaling is important for the maintenance of homeostasis. Sphingolipids were demonstrated to function as structural components, second messengers, and regulators of cell growth and survival in normal and disease-affected tissues. Particularly, sphingosine kinase 1 (SphK1) and its product sphingosine-1-phosphate (S1P) operate as mediators and facilitators of proliferation-linked signaling. Unlimited proliferation (selfrenewal) within the regulated environment is a hallmark of progenitor/stem cells that was recently associated with the S1P signaling network in vasculature, nervous,muscular, and immune systems. S1P was shown to regulate progenitor-related characteristics in normal and cancerstemcells(CSCs) viaG-protein coupled receptorsS1Pn(n=1 to 5). The SphK/S1P axis is crucially involved in the regulation of embryonic development of vasculature and the nervous system, hematopoietic stem cell migration, regeneration of skeletal muscle, and development of multiple sclerosis. The ratio of the S1P receptor expression, localization, and specific S1P receptoractivated downstream effectors influenced the rate of selfrenewal and should be further explored as regeneration related targets. Considering malignant transformation,it is essential to control the level of self-renewal capacity.Proliferation of the progenitor cell should be synchronized with differentiation to provide healthy lifelong function of blood, immune systems, and replacement of damaged ordead cells. The differentiation-related role of SphK/S1P remains poorly assessed. A few pioneering investigations exploredpharmacologicaltoolsthattargetsphingolipid signaling and can potentially confine and direct self-renewal towards normal differentiation. Further investigation is required to test the role of the SphK/S1P axis in regulation of self-renewal and differentiation.

Hepatitis E in hemodialysis and kidney transplant patients in south-east Italy

AIM:To investigate the serovirological prevalence and clinical features of hepatitis E virus(HEV) infection in end-stage renal failure patients and in the healthy population.METHODS:HEV infection is a viral disease that can cause sporadic and epidemic hepatitis.Previous studies unexpectedly showed a high prevalence of HEV antibodies in immunosuppressed subjects,including hemodialysis(HD)patients and patients who had undergone kidney transplant.A cohort/case-control study was carried out from January 2012 to August 2013 in two hospitals in southern Italy(Foggia and S.Giovanni Rotondo,Apulia).The seroprevalence of HEV was determined in 801 subjects;231 HD patients,120 renal transplant recipients,and450 health individuals.All HD patients and the recipients of renal transplants were attending the Departments of Nephrology and Dialysis at two hospitals located in Southern Italy,and were included progressively in this study.Serum samples were tested for HEV antibodies(Ig G/Ig M);in the case of positivity they were confirmed by a Western blot assay and were also tested for HEV-RNA,and the HEV genotypes were determined.RESULTS:A total of 30/801(3.7%)patients were positive for anti-HEV Ig(Ig G and/or Ig M)and by Western blot.The healthy population presented with a prevalence of 2.7%,HD patients had a prevalence of 6.0%,and transplant recipients had a prevalence of 3.3%.The overall combined HEV-positive prevalence in the two groups with chronic renal failure was 5.1%.The rates of exposure to HEV(positivity of HEV-Ig G/M in the early samples)were lower in the healthy controls,but the difference among the three groups was not statistically significant(P>0.05).Positivity for anti-HEV/Ig M was detected in 4/30(13.33%)anti-HEV Ig positive individuals,in 2/14 HD patients,in1/4 transplant individuals,and in 1/12 of the healthy population.The relative risk of being HEV-Ig M-positive was significantly higher among transplant recipients compared to the other two groups(OR=65.4,95%CI:7.2-592.7,P<0.001),but the subjects with HEV-Ig M positivity were numerically too few to calculate a significant difference.No patient presented with chronic hepatitis from HEV infection alone.CONCLUSION:This study indicated a higher,but not significant,circulation of HEV in hemodialysis patients vs the healthy population.Chronic hepatitis due to the HEV virus was not observed.

Mitochondrial abnormalities drive cell death in Wolfram syndrome 2

Wolfram syndrome （WFS; MIM 222300） is an autosomal recessive disorder with highly variable clinical manifestations. It is characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness （thus, known as DIDMOAD syndrome） [ 1 ]. Other neurological and endocrine manifestations include dementia, psychiatric illnesses, renal-tract abnormalities, and bladder atony [2]. Gene linkage and positional cloning analysis reveal that a subset of Wolfram syndrome patients belonging to the WFS 1 group （MIM 606201） carry a loss-of-function mutation in the WFS1 gene, which encodes a transmembrane protein, Wolframin, localizing in the endoplasmic reticulm （ER） [3, 4]. Wolframin is thought to be involved in the regulation of ER stress and calcium ho- meostasis, and Wolframin deficiency in mice leads to progressive loss of β cells and impaired glucose tolerance, which is presumably caused by increased ER stress and apoptosis in the β cells.

神经精神药理学治疗药物监测共识指南:2017版

治疗药物监测(Therapeutic Drug Monitoring,TDM)通过定量测定和解释血药浓度以优化药物治疗。TDM着眼于药代动力学的个体差异,使个体化药物治疗成为可能。在精神病学和神经病学领域中,有可能明显获益于TDM的主要患者群体包括少年儿童、孕妇、老年患者、智障患者、药物滥用者、涉法精神病患者、已知或怀疑药代动力学异常的患者以及合并躯体疾病影响药代动力学的患者。常规剂量下治疗无效,用药依从性难以判断,药物耐受性不佳,以及可能存在药代动力学方面的药物-药物相互作用等情况都是治疗药物监测的典型指征。然而,只有将TDM充分整合到临床治疗过程中,才能发挥其优化药物治疗的潜在优势。为了向临床医生和实验室提供有效的TDM信息,神经精神药理学与药物精神病学协会(Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie,AGNP)的TDM专家组在2004年发表了第一版《精神科治疗药物监测指南》。2011年进行了更新之后,现在再次更新。遵循新版指南,可能会改善神经精神药物治疗的效果,加快很多患者的康复,并降低医疗费用。

神经精神药理学治疗药物监测共识指南:2017版

2.2剂量相关参考浓度范围对于TDM结果的解释,除了治疗参考浓度范围外还有另一个浓度范围,即所谓的剂量相关参考浓度范围。治疗参考浓度范围的应用是药效动力学问题,而剂量相关参考浓度范围的运用是药代动力学问题。后者比较的是测得的药物浓度与理论预期药物浓度范围。参照药代动力学研究,优先考虑没有合并用药或药物基因组异常的患者群(“正常”患者),在日维持剂量(Daily maintenance dose,D m)、给药间隔(Dosing interval,d i)、总清除率(Total clearance,CL)和生物利用度(Bioavailability,F)已知情况下,某种药物在某个“正常”患者体内的预期平均稳态浓度(Average steady-state concentration,C av)可通过下面的公式计算。

Sustained heavy ethanol drinking affects CD4⁺cell counts in HIV-infected patients on stavudine (d4T), lamivudine (3TC) and nevirapine (NVP) treatment regimen during 9 months follow-up period

Sustained heavy ethanol drinking is a common problem globally and ethanol is one of the most abused drugs among individuals of different socio-economic status including the HIV-infected patients on antiretroviral drugs. Ethanol is reward drug and a CNS depressant especially at high doses. The study determined the effect of sustained heavy ethanol drinking by HIV-infected patients on d4T/3TC/NVP regimen on CD4+ cell counts in Uganda using WHO AUDIT tool and chronic alcohol-use biomarkers. A case control study using repeated measures design with serial measurements model was used. The patients on stavudine (d4T) 30 mg, lamivudine (3TC) 150 mg and nevirapine (NVP) 200 mg and chronic alcohol use were recruited. A total of 41 patients (20 in alcohol group and 21 in control group) were screened for chronic alcohol use by WHO AUDIT tool and chronic alcohol use biomarkers. They were followed up for 9 months with blood sampling done at 3 months intervals. CD4+ cell count was determined using Facscalibur Flow Cytometer system. Results were then sorted by alcohol-use biomarkers (GGT, MCV and AST/ ALT ratio). Data were analysed using SAS 2003 version 9.1 statistical package with repeated measures fixed model and the means were compared using student t-test. The mean CD4+ cell counts in all the groups were lower than the reference ranges at baseline and gradually increased at 3, 6 and 9 months of follow-up. The mean CD4+ cell counts were higher in the control group as compared to the chronic alcohol use group in both WHO AUDIT tool group and chronic alcohol-use biomarkers group though there was no significant difference (p > 0.05). Chronic alcohol use slightly lowers CD4+ cell count in HIV-infected patients on d4T/3TC/NVP treatment regimen.

Chronic Alcohol Consumption Affects Serum Enzymes Levels in the HIV-Infected Patients on Stavudine (d4T)/Lamivudine (3TC)/Nevirapine (NVP) Treatment Regimen

Chronic alcohol use is a common problem globally among the HIV-infected patients on ARV treatment regimens, leading to severe liver damage and increase in serum enzymes. The study determined effect of chronic alcohol intake on serum enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyl transferase (GGT)) in HIV-infected patients on d4T/3TC/NVP treatment regimen in Uganda using the WHO alcohol use disorders’ identification test (AUDIT) tool and chronic alcohol use biomarkers (ALT, AST, GGT, AST/ALT ≥ 2.0 and mean corpuscular volume (MCV)). A case control study using repeated measure design with serial measurements model was used. Alcohol use biomarkers were used to standardize the gender differences in alcohol use. A total of 41 patients (21 alcohol group and 20 control group) were followed up for 9 months with blood sampling done at 3 month intervals. The serum enzymes’ levels were determined by using the Cobas Intergra 400 Plus analyzer system. The mean GGT levels were higher in chronic alcohol use group as compared to control group in both groups. The levels were above reference ranges during 6 month and three times higher during 9-month follow-up period for both chronic alcohol use self reporting WHO AUDIT tool and biomarkers’ groups. Generally, the mean AST, ALT and AST/ALT levels were slightly higher in alcohol use group as compared to control group and were slightly higher in both groups as compared to reference ranges during the 9 month follow-up period. Chronic alcohol consumption by HIV-infected patients on d4T/3TC/NVP drug regimen increased GGT and AST/ALT serum enzyme levels and hence was used as chronic alcohol use biomarkers.