Fatty Infiltration of Liver in Hyperlipidemic Patients

Hyperlipidemia is a known risk factor for fatty infiltration of the liver, a condition that can progress to cirrhosis and liver failure. The objectives of this study were to document the prevalence of fatty infiltration in the livers of hyperlipidemic patients and to identify the predictor variables associated with this condition. Over an 18-month recruitment period, clinical, biochemical, and radiologic assessments were performed in a cross-sectional manner in 95 adult patients referred to an urban hospital-based lipid clinic for evaluation and management of hyperlipidemia. The mean (±sd) age of the patients was 55 ± 13 years. Forty-eight (51%) were male. Fifty-two patients (55%) had hypercholesterolemia, 25 (26%) severe hypertriglyceridemia, 14 (15%) mixed hyperlipidemia, and 4 (4%) moderate hypertriglyceridemia. Obesity and diabetes were present in 36 (38%) and 12 (12%) of cases, respectively. A total of 61 (64%) patients had elevated liver enzyme tests. The most common enzyme abnormalities were an elevated serum ALT in 45 (47%) and GGT in 43 (45%) of patients. Ultrasound findings revealed diffuse fatty liver in 47 patients (50%), of which 21 cases (22%) were mild, 18 (19%) moderate, and 8 (9%) severe. The majority of patients with hypercholesterolemia [35/52 (67%)] had normal ultrasounds, whereas severe hypertriglyceridemia and mixed hyperlipidemia were frequently associated with radiologic evidence of fatty liver (odds ratios 5.9 and 5.1 respectively, P < 0.01). Independent predictors of fatty liver were; AST (P = 0.001), hyperglycemia (P = 0.02), and age (P = 0.04). In a model incorporating known risk factors for fatty liver, diabetes was the only risk factor other than hypertriglyceridemia that was significantly associated with fatty infiltration. No such effect was seen with age, gender, obesity, or alcohol consumption. In conclusions, the results of this study indicate that ultrasonographic evidence of fatty infiltration of the liver is evident in approximately 50% of patients with hyperlipidemia. Hypertriglyceridemia is the lipid profile most often associated with this condition. Serum AST values, hyperglycemia, and age independently predict the presence of fatty infiltration, while hypertriglyceridemia and diabetes are the only risk factors that significantly increase the risk of fatty infiltration in hyperlipidemic patients.     

Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells

Cluster of differentiation 1c (CD1c)-dependent self-reactive T cells are abundant in human blood, but self-antigens presented by CD1c to the T-cell receptors of these cells are poorly understood. Here we present a crystal structure of CD1c determined at 2.4 Å revealing an extended ligand binding potential of the antigen groove and a substantially different conformation compared with known CD1c structures. Computational simulations exploring different occupancy states of the groove reenacted these different CD1c conformations and suggested cholesteryl esters (CE) and acylated steryl glycosides (ASG) as new ligand classes for CD1c. Confirming this, we show that binding of CE and ASG to CD1c enables the binding of human CD1c self-reactive T-cell receptors. Hence, human CD1c adopts different conformations dependent on ligand occupancy of its groove, with CE and ASG stabilizing CD1c conformations that provide a footprint for binding of CD1c self-reactive T-cell receptors.Cluster of differentiation 1 (CD1) proteins are a family of MHC class I-like glycoproteins that present lipid antigens to T cells. CD1 restricted T cells are abundant in humans and play important roles in host defense and immune regulation. Human CD1 proteins comprise five CD1 isoforms, CD1a, CD1b, CD1c, CD1d, and CD1e, which exhibit different intracellular trafficking behaviors and ligand binding preferences (1). Structurally, the main differences between these CD1 isoforms lie in the architecture of their lipophilic ligand binding grooves. Whereas all CD1 isoforms share a highly conserved A′ channel (or pocket) for binding C18–C26 acyl chains, specialization is provided by further connecting channels (2–7). In CD1a, the A′ channel is “fused” to a wide and shallow F′ channel, enabling binding of lipopeptides such as mycobacterial didehydroxymycobactin (DDM) (8). CD1b features a unique T′ tunnel that connects A′ and F′, thereby forming a “superchannel” for accommodating very long acyl chains (e.g., mycobacterial mycolates) (2, 4). CD1d, the only isoform also conserved in rodents, exhibits a two-branched ligand binding groove with two linear channels A′ and F′ connected near the main portal into the groove, known as the F′ portal. A similar two-branched arrangement of A′ and F′ is seen in CD1e, the only CD1 isoform not expressed on the cell surface. Compared with CD1d, CD1a, and CD1b, the portal into the groove in CD1e is widely exposed, consistent with its known role in lipid transfer processes inside lysosomes (6).CD1c presents foreign- (9, 10) as well as self-lipid antigens to T cells (11). Two recent crystal structures of human CD1c revealed a two-branched design similar to that of CD1d and CD1e, with two channels A′ and F′ connecting near the groove portal. In these structures, a mycobacterial phosphomycoketide (PM) or mannosyl-β1-phosphomycoketide (MPM) occupied the A′ channel, whereas an undefined short ligand was present in the F′ channel (7, 12). The spatial arrangement of these ligands in the CD1c groove was very similar to and virtually overlapping in 3D comparisons with that of alpha-galactosylceramide (αGC) in human CD1d (Fig. S1 A and B). Because CD1c and CD1d are known to traffic to the same intracellular compartments for antigen sampling (13), these CD1c-PM and CD1c-MPM structures did not readily explain how CD1c and CD1d could functionally differentiate. Furthermore, the F′ channel in both CD1c-PM and CD1c-MPM was widely open to solvent, which was strikingly different from known structures of CD1a, CD1b, and CD1d and reminiscent of CD1e (7, 12). Based on these facts we hypothesized that human CD1c might undergo substantial conformational transformations in the F′ channel region upon binding of more optimal ligands, with relevance for T-cell receptor binding.Open in a separate windowFig. S1.Published CD1d-αGC and CD1c-MPM structures show a similar arrangement of their bound ligands in both the A′ and F′ channel. (A) Comparison of the configurations of bound ligands in CD1d-αGC (PDB ID code 1ZT4), CD1c-MPM (PDB ID code 3OV6), and CD1c-SL (PDB ID code 5C9J). (B) Ligands bound to CD1d (PDB ID code 1ZT4) (αGC; shown in yellow) and CD1c (PDB ID code 3OV6) (MPM; shown in blue, and spacer lipid shown in cyan) are superimposed and shown in two different orientations.     

A comparative study of the in vitro antioxidant activity of statins

Background: Treatment of hypercholesterolemia with statins is remarkably effective in cardiovascular prevention. This has led to the hypothesis that these drugs may act on the atherosclerotic plaque by mechanism(s) independent of the reduction of serum cholesterol levels. The aim of this study was to assess the total antioxidant activity of the most prescribed statins: fluvastatin, atorvastatin, pravastatin and simvastatin. Methods: We measured the in vitro antioxidant activity of statins as their ability to antagonize the oxidation of -keto-γ-methiolbutyric acid by both hydroxyl and peroxyl radicals. The results are expressed as Total Oxyradical Scavenging Capacity (TOSC) units. Uric acid and Trolox were used as the reference antioxidants. Results: The scavenging capacity towards hydroxyl radicals was highest for simvastatin (3375±112 U/mg), a value 270.2% higher (P<0.0001) compared to uric acid (reference antioxidant vs. hydroxyl radicals, 1249±71 U/mg). Among the tested statins, fluvastatin exhibited the highest anti-peroxyl radical antioxidant capacity (8755±187 U/mg) which appeared 50% lower (P<0.0001) compared to Trolox (reference antioxidant vs. peroxyl radicals, 17 460±379 U/mg). Conclusions: All the statins tested have intrinsic antioxidant activity with both anti-hydroxyl and peroxyl radical activity. Simvastatin was the most effective as an anti-hydroxyl radical antioxidant and fluvastatin as an anti-peroxyl radical antioxidant.     

长期有效控制血压改善高危高血压患者的肾功能

目的对《1999WHO/ISH高血压治疗指南》(《指南》)危险分层为高危和极高危组的患者单用或联合使用《指南》推荐的一线降压药,以血压<140/90mmHg作为目标血压,观察长期有效控制血压对高危高血压患者肾功能的影响。方法患者763例确定危险分层入选后,随机进入目标治疗组(n=382)和对照组(n=381)。目标治疗组在高血压专科门诊定期随访,按5步法治疗方案,直到达到或接近目标血压为止。对照组在普通门诊治疗。测定基线和治疗后的血清肌酐浓度并计算肾小球滤过率。结果两组患者的基线特征无明显差异。在平均4.4年随访期间,目标治疗组平均收缩压/舒张压为(133.8±6.6)/(79.7±5.5)mmHg,明显低于对照组[(151.7±12.7)/(87.7±8.0)mmHg,P<0.01]。尽管两组治疗强度不同,但两组间使用各类抗高血压药物的比例相似。共有526例患者复查血清肌酐1次以上。目标治疗组(n=304)血清肌酐由(90.9±29.1)降至(87.0±26.1)μmol/L,下降4.5%(P=0.006);对照组(n=222)则由(91.6±30.1)增至(96.4±46.4)μmol/L,增加5.2%(P=0.074),两组间治疗后比较,差异有非常显著意义(P<0.01)。目标治疗组血清肌酐清除率由(67.5±21.9)升至(70.0±22.3)mL/(min.1.73m2),升高4.5%(P=0.019);对照组则无明显变化[(66.9±24.2)vs(67.3±27.6)mL/(min.1.73m2),P=0.737]。结论与一般治疗相比,长期严格控制血压能降低高危高血压患者的血清肌酐,并提高血清肌酐清除率。     

心肌细胞膜脂流动性与超微结构研究

本研究应用荧光分光光度计偏振技术研究犬实验性急性心肌梗塞早期时心肌细胞膜流动性及超微结构改变的相关程度.结果表明,冠状动脉左前降支阻断后,心肌细胞膜脂流动性明显降低,阻断前为40.952±4.623,阻断1分钟为31.936±4.008.随着缺血时间延长,,心肌细胞膜脂流动性降低越明显,阻断15和120分钟时,膜脂流动性分别为27.164±4.204和26.572±3.126(与阻断前比较,P<0.05),阻断240分钟时膜脂流动性为23.374±2.604(P<0.01,与阻断前比较).而在电镜下则见心肌组织学损坏进行性加重,因此,心肌细胞膜脂流动性的降低程度与心肌缺血时间长短和损伤程度密切相关,并与心肌组织超微结构改变相一致,是反映心肌细胞缺血损伤的一个敏感指标.     

ELISA法检测人体血清中HIV-1+2型抗体结果不确定度评定

目的 对酶联免疫吸附试验(ELISA)法检测人体血清中艾滋病病毒(HIV)1 2型抗体结果的不确定度进行评定，降低初筛试验出现假阴性结果的风险。方法 按照JJF1059-1999《测量不确定度评定与表示》，对采用ELISA法、使用生物梅里埃中国有限公司提供的HIV-1 2型抗体检测诊断试剂盒，进行人体血清中HIV-1 2型抗体检测(初筛)结果所产生的不确定度进行评定。结果 通过对影响检测结果不确定度分量的分析和量化，求出被测量的标准不确定度[uc(△A)=0．005]和扩展不确定度(U=0．010，k=2)，给出各分量对检测结果不确定度的相对贡献，对检测结果进行了表述(△A=0．191-0．097-0．010，k=2)。结论 用包含有测量不确定度的结果对检测结果做完整表述，可为避免假阴性结果的出现提供科学依据。     

Evaluation of serum ferritin in screening for iron deficiency in tuberculosis

Serum ferritin (SF) values 10 µg/l are diagnostic of absent Bone Marrow Iron (BMI) stores and therefore of iron deficiency (ID). However, SF, which may be elevated as a part of acute phase reaction, is an unreliable indicator of BMI stores in the setting of chronic disorders, making it difficult to diagnose ID in these patients. Thus, in chronic disorders (CD) such as tuberculosis, bone marrow examination is the only reliable way to establish ID. This study was done in order to identify levels of SF that would be indicative of absent BMI stores and also to study a combination of hematological and biochemical parameters that would be helpful in raising the predictive power of SF in patients of tuberculosis. Fifty-five tuberculosis patients were studied and classified into Iron Deplete (ID) and Iron Replete (IR) based on BMI. Raising the cut-off values of SF from 10 µg/l to 30 µg/l diagnosed 88% of ID cases correctly, as compared with 61% when cut-off levels of 10 µg/l were used. At cut-off values higher than 30 µg/l, the sensitivity was markedly reduced. Therefore, raising cut-off levels of SF to 30 µg/l was most effective in predicting absent BMI, especially in a population where ID is highly prevalent. Combination of SF 30 µg/l with mean corpuscular volume (MCV), erythrocyte sedimentation rate (ESR) and total iron binding capacity (TIBC) did not improve the predictive power of SF further. Also, 89.5% cases could be correctly classified by logistic regression equations using SF with ESR and C- reactive protein (CRP).Abbreviations SF Serum ferritin - BMI Bone marrow iron - ID Iron deplete - IR Iron replete - CD Chronic disorders - MCV Mean corpuscular volume - TIBC Total iron binding capacity - ESR Erythrocyte sedimentation rate - ACD Anemia of chronic disorders - IDA Iron deficiency anemia - Hb Hemoglobin concentration - TLC Total leukocyte count - RBC Red blood cell - RDW Red cell distribution width - % TS Percent transferrin saturation - SI Serum iron     

13C labelled cholesteryl octanoate breath test for assessing pancreatic exocrine insufficiency

Background—A non-invasive test for assessment offat digestion has been developed based on the intraluminal hydrolysisof cholesteryl-[1-¹³C]octanoate by pancreatic esterase.
Aims—To determine the diagnostic performance ofthis breath test in the assessment of exocrine pancreatic function.
Methods—The test was performed in 20 healthycontrols, 22 patients with chronic pancreatic disease (CPD), four withbiliopancreatic diversion (BPD), and 32 with non-pancreaticdigestive diseases (NPD); results were compared with those of othertubeless tests (faecal chymotrypsin and fluorescein dilaurate test).
Results—Hourly recoveries of¹³CO₂ were significantly lower in CPD whencompared with healthy controls or NPD. In patients with CPD with mildto moderate insufficiency, the curve of ¹³CO₂recovery was similar to that of healthy controls, while in those withsevere insufficiency it was flat. In three patients with CPD withsevere steatorrhoea, a repeat test after pancreatic enzymesupplementation showed a significant rise in¹³CO₂ recovery. The four BPD patients had lowand delayed ¹³CO₂ recovery. Only eight of the32 patients with NPD had abnormal breath test results. There was asignificant correlation between the results of the breath test andthose of faecal chymotrypsin, the fluorescein dilaurate test, andfaecal fat measurements. For the diagnosis of pancreatic disease usingthe three hour cumulative ¹³CO₂ recovery test,the sensitivity was 68.2% and specificity 75.0%; values were similarto those of the other two tubeless pancreatic function tests. In sevenhealthy controls, nine patients with CPD, and nine with NPD a secondbreath test was performed using Na-[1-¹³C]octanoate and apancreatic function index was calculated as the ratio of¹³C recovery obtained in the two tests: at three hours thisindex was abnormal in eight patients with CPD and in three with NPD.
Conclusion—Thecholesteryl-[1-¹³C]octanoate breath test can beuseful for the diagnosis of fat malabsorption and exocrine pancreatic insufficiency.

     

Changes in biliary excretory mechanisms in bile duct-ligated rat

The effects of bile duct ligation on biliary excretion of bile acids, glutathione, and lipids were studied in the rat. The bile duct of the rat was ligated for three days. The biliary bile acid excretion after bile duct cannulation was higher at first, but after 90 min became lower than that in the control rat. The bile flow in the bile duct-ligated rat was higher after bile duct cannulation and gradually decreased to the same level as in the control rat. Biliary glutathione excretion, which has been suggested to be a driving force for the bile acid-independent canalicular bile flow, was markedly decreased in the bile duct-ligated rat. The mannitol clearance was increased and the bile ductules showed proliferation in the bile duct-ligated rat, suggesting an increase in the ductular bile flow. Biliary excretion of lithocholate glucuronide was more markedly impaired than that of taurocholate. When taurocholate was infused at higher rates, which increases bile flow and biliary excretion of bile acid and lipids in the control rat, biliary bile acid and lipid excretion remained constant in the bile duct-ligated rat. These findings indicate that, in the bile duct-ligated rat, the ductular bile flow was increased and bile acid-independent canalicular bile flow was decreased and that, although the biliary excretion of bile acids was not as impaired as that of organic anions, the capacity of bile acid and lipid excretion was markedly decreased.     

The association of total cholesterol with processing speed is moderated by age in mid- to late-age healthy adults

Objectives: To investigate the nature of the association of normal levels of total cholesterol with cognitive function and the contribution of age to this association.

Methods: A sample of 61 senior executives, who were summoned for an annual medical examination with approximately four measurements of total cholesterol during 4 years, were examined with a computerized cognitive battery assessing mental processing speed as a sensitive measure of cognitive decline. We examined the association of total cholesterol with processing speed and the moderating effect of age on this association.

Results: A multiple regression analysis yielded a significant interaction between cholesterol and age for processing speed (p = .045). In order to examine the source of the interaction, simple slope analysis was performed. A significant negative high correlation was found for young subjects (p = .021), while no significant correlation was observed at middle (p = .286) or older (p = .584) age. The difference in slopes was robust to adjustment for potential confounding factors, including body mass index, and fasting glucose.

Conclusions: Within the normal range, higher total cholesterol levels were associated with better processing speed in younger ages and this association diminished with increasing age. Our findings highlight the important role of brain cholesterol in good cognitive functioning.