经皮血管腔内成形术在布-加综合征中的应用

我们自1991年11月～1996年12月为32例布-加综合征患进行经皮血管腔内成形术治疗，其中膜型阻塞或狭窄21例，采用大球囊一次性扩张；段型11例，采用内支架植入术。其中28例随访2～60个月，疗效满意；管腔通畅，无严重并发症，无死亡。我们认为该技术安全，简单，对布-加氏综合征治疗有效，尤适合于肝段下腔静脉膜型阻塞的患。     

Metabolic Syndrome with Hyperglycemia and the Risk of Ischemic Stroke

Purpose

The association of ischemic stroke and metabolic syndrome (MetSyn) with or without diabetes mellitus (DM) is not clear. The present study aimed to identify the impact of diabetes or hyperglycemia on the risk of MetSyn-associated ischemic stroke.

Materials and Methods

This study comprised an Asian population of 576 patients with acute nonembolic cerebral infarction and 500 controls. MetSyn was defined according to the criteria of the International Diabetes Federation. MetSyn patients were further subgrouped according to their glucose levels: MetSyn with DM, MetSyn with impaired fasting glucose (IFG) and MetSyn with normal glucose tolerance (NGT). The impact of MetSyn on cerebral infarction was then evaluated.

Results

At baseline, the prevalence of MetSyn in patients with cerebral infarction was higher than that of the controls (57.29% vs. 10.00%, p<0.01). In the stroke group, the prevalences of MetSyn with DM, IFG, and NGT were 25.69%, 8.85% and 22.74%, respectively, all of which were higher than that of the controls (all p-values <0.05). By multiple logistic regression analysis, we discovered that MetSyn was associated with an increased risk of cerebral infarction (odds ratio: 5.73, p<0.01). After adjustment for all the components of MetSyn, the odds ratios of MetSyn with DM, IFG, and NGT were 5.70, 2.24 and 2.19 (all p-values <0.05), respectively.

Conclusion

In Asian population, patients with MetSyn accompanied by T2DM are at the greatest risk for acute non-embolic stroke. Additionally, IFG was not observed to be associated with an increased risk for MetSyn-related ischemic stroke.     

Metabolic Syndrome in Offspring of Parents with Metabolic Syndrome: A Meta-Analysis

BackgroundThe metabolic syndrome (MetS) represents a clustering of risk factors for cardiovascular diseases that includes abdominal obesity, hypertension, dyslipidemia, and insulin resistance.ObjectivesThe objective of this study was to reassess the parent-offspring association of MetS since the available findings are still controversial.MethodsThe Cochrane Library, PubMed, Embase, and Web of Science databases were searched to identify relevant articles. All studies comparing MetS status between the offspring of parents with MetS and offspring of parents without MetS were included in the analysis.ResultsA total of 9 studies met the inclusion criteria and they were analyzed. Offspring of at least 1 parent with MetS had a higher risk of MetS (OR 3.88, 95% CI 2.58–5.83, p < 0.001). Sons and daughters of fathers with MetS both had a higher risk of MetS (OR 2.31, 95% CI 1.70–3.12, p < 0.001, and OR 1.73, 95% CI 1.37–2.18, p < 0.001, respectively). Sons and daughters of mothers with MetS both had a higher risk of MetS (OR 1.95, 95% CI 1.37–2.76, p = 0.0002, and OR 1.91, 95% CI 1.54–2.35, p < 0.001, respectively).ConclusionThis meta-analysis showed that there is a higher risk of MetS in the offspring of parents with MetS. However, there was no differential association of MetS according to gender and/or age of the offspring.     

Sex Difference in the Associations among Obesity-Related Indices with Metabolic Syndrome in Patients with Type 2 Diabetes Mellitus

Background: The aim of this study was to investigate the associations among obesity-related indices and MetS in diabetic patients, and explore sex differences in these associations.Methods: Patients with type 2 DM were included from two hospitals in southern Taiwan. The Adult Treatment Panel III criteria for an Asian population were used to define MetS. In addition, the following obesity-related indices were evaluated: waist-to-height ratio, waist-hip ratio (WHR), conicity index (CI), body mass index (BMI), body roundness index, body adiposity index, lipid accumulation product (LAP), abdominal volume index, visceral adiposity index (VAI), abdominal volume index and triglyceride-glucose index.Results: A total of 1,872 patients with type 2 DM (mean age 64.0 ± 11.3 years, 808 males and 1,064 females) were enrolled. The prevalence rates of MetS were 59.8% and 76.4% in the males and female (p < 0.001), respectively. All of the obesity-related indices were associated with MetS in both sex (all p < 0.001). LAP and BMI had the greatest areas under the receiver operating characteristic curves in both sex. In addition, the interactions between BMI and sex (p = 0.036), WHR and sex (p = 0.016), and CI and sex (p = 0.026) on MetS were statistically significant.Conclusions: In conclusion, this study demonstrated significant relationships between obesity-related indices and MetS among patients with type 2 DM. LAP and VAI were powerful predictors in both sex. The associations of BMI, WHR and CI on MetS were more significant in the men than in the women.     

代谢综合征患者血清同型半胱氨酸与胱抑素C水平检测的临床意义

目的测定代谢综合征(MS)患者血清同型半胱氨酸(homocysteine,HCY)、胱抑素C(cystatin,CysC)的水平,探讨二者对代谢综合征患者的临床意义。方法随机收集代谢综合征患者血清30例,对照组血清32例。测定两组血清HCY、CysC的水平,并分析代谢综合征组HCY与CysC的相关性。结果代谢综合征组的血清HCY、CysC水平均较对照组升高且有统计学意义(P0.05),并且代谢综合征组血清CysC与HCY呈正相关(r=0.652,P0.01)。结论血清HCY和CysC水平均为可反映代谢综合征病情的较为敏感、准确、可靠的指标,两者联合检测对代谢综合征患者在诊断、治疗、病情监测上有一定的临床意义。     

代谢综合征患者血液流变特性分析

目的探讨代谢综合征患者血液流变特性。方法60例代谢综合征患者和28例年龄相匹配的正常对照者,按体重指数将代谢综合征患者分为肥胖组和非肥胖组,测定其身高、体重、腰围、臀围、血压、血糖、血脂及血液流变学指标,进行比较分析。结果代谢综合征组腰围、臀围、血压、血糖、血脂、全血粘度、血浆粘度、红细胞聚集指数等均显著高于对照组(P<0.01)。结论血液流变学指标的变化可作为代谢综合征的早期预警及治疗、监测指标之一。     

精神分裂症患者代谢综合征的患病率及相关因素

目的探索精神分裂症患者伴发代谢综合征的患病率及相关因素。方法对使用单一非典型精神病药物6月以上的精神分裂症患者做调查,测定其代谢指标,采用世界糖尿病联盟(IDF,2005)全球统一标准定义代谢综合征(MS),了解精神分裂症患者伴发代谢综合征的发生率,用Logistic回归分析影响发生的相关因素。结果共入组完成386例,MS患病率为35.8%,MS患病率随年龄、病程的增加而增加(P<0.001),同时与服药有关。Logistis回归分析结果显示,年龄、病程进入方程(P<0.01)。结论非典型抗精神病药引起代谢综合征发生率高于普通人群,可能的危险因素有高龄、长病程。     

Increased Inflammation, Reduced Plasma Phospholipid Eicosapentaenoic Acid and Reduced Antioxidant Potential of Treated Hypertensive Patients with Metabolic Syndrome

Purpose

In the present study, we tested whether the presence of metabolic syndrome (MetS) would worsen the features of inflammation, plasma omega 3 fatty acid levels and antioxidant potential in treated hypertensive patients.

Materials and Methods

Two groups were classified by the components of MetS: a reference group of treated hypertensive subjects: hypertension (HTN) group (n = 39) and with more than two additional MetS components: HTN with Mets group (n = 40). We further compared the parameters between HTN group and HTN with MetS group.

Results

The results showed that age (p < 0.001) and body mass index (BMI) (p < 0.001) were significantly different between HTN group and HTN with MetS group. Age- and BMI-adjusted total radical trapping antioxidant potential (TRAP) (p < 0.01) was significantly lower, whereas age- and BMI-adjusted CD (p < 0.05) and interleukin (IL) 6 (p < 0.05) were significantly higher in HTN with MetS group than in HTN group. Moreover, HTN with MetS group had significantly lower levels of age- and BMI-adjusted plasma phospholipid eicosapentaenoic acid (EPA) than HTN group (p < 0.05). On the other hand, the levels of age- and BMI-adjusted intracellular cell adhesion molecule-1 (ICAM-1), adiponectin and high molecular weight (HMW)-adiponectin were not significantly different between the groups.

Conclusion

In conclusion, our results showed increased inflammatory marker, reduced antioxidant potential and EPA levels in treated hypertensive patients in the presence of MetS, suggesting the importance of changes of therapeutic lifestyle to modify the features of MetS.     

齐拉西酮替代奥氮平对精神分裂症伴发代谢综合征患者的影响

目的探讨服用奥氮平伴发代谢综合征的精神分裂症患者换用齐拉西酮后代谢指标的变化及临床疗效。方法将108例服用奥氮平治疗,病情稳定(PANSS总分<60分),同时符合代谢综合征诊断标准的精神分裂症患者,随机分为换药组(研究组)与维持治疗组(对照组)各54例,研究组2周内将奥氮平换成齐拉西酮,并继续服用10周,对照组维持奥氮平治疗。分别于治疗前、6周后、12周后测量腰围、收缩压、舒张压、体重指数(BMI)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-c)、空腹血糖(FBG),同时采用阳性与阴性症状量表(PANSS)评定疗效、副反应量表(TESS)评定药物不良反应。结果治疗6周后,研究组腰围、收缩压、BMI、TG均显著低于对照组(P<0.05),12周后上述指标持续下降(P<0.001),FBG也出现下降,差异有显著性(P<0.05),两组PANSS及TESS评分6周、12周后均无显著差异(P>0.05)。结论用齐拉西酮替代奥氮平,是改善奥氮平伴发代谢综合征患者代谢指标的一个有效对策。     

齐拉西酮和喹硫平对女性精神分裂症患者代谢综合征患病率的影响

目的探讨和分析齐拉西酮与喹硫平对女性精神分裂症患者代谢综合征患病率的影响。方法将符合入组标准的68例女性精神分裂症患者随机分为两组,每组各34例。分别于治疗前、治疗后1个月和3个月测定体重指数(BMI)、腰围、血压、空腹血糖(FBS)、甘油三酯(TG)和高密度脂蛋白(HDL-C),并进行比较分析。结果齐拉西酮组和喹硫平组代谢综合征的发病率分别为5.88%和21.05%。结论齐拉西酮治疗女性精神分裂症患者,发生代谢综合征的风险低于喹硫平。     

Effect of Hedan Tablets on Body Weight and Insulin Resistance in Patients with Metabolic Syndrome

IntroductionApart from their recognized lipid-lowering effect, Hedan tablets, a mixture of Chinese herbal medicines, have demonstrated a certain weight-loss effect in clinical practice. The aim of this randomized, double-blind, placebo-controlled study was to verify the effect of Hedan tablets on body weight (BW) and insulin resistance (IR) in patients with metabolic syndrome (MetS).MethodsA total of 62 eligible patients with MetS were divided into two groups: the treatment group (Hedan tablets at 4.38 g/day tid) and the control group (placebo treatment). Both groups attended follow-ups at 8, 16, and 24 weeks during the process. The parameters of the assessment include lipid level, BW, triglyceride (TG) to high-density lipoprotein cholesterol (HDLc) ratio (TG/HDLc), homeostasis model assessment for IR (HOMA-IR) index, and adiponectin.ResultsPatients in the treatment group showed a significant decrease in BW compared to those in the control group (−4.47 vs. 0.06 kg) after 8 weeks of treatment. A significant decrease in body mass index (BMI) was also observed in the treatment group after 16 weeks of treatment (−1.79 vs. −0.03 kg/m²). In the treatment group, 20 out of 31 (64.5%) patients lost 5–10% BW and 4 out of 31 (12.9%) patients lost over 10% BW after 24 weeks of treatment. Although there were no significant changes in the patients'' HOMA-IR, the treatment group showed a significant reduction in TG/HDLc (−0.98 vs. −0.19) after 8 weeks of treatment and a significant increase in adiponectin (6.87 vs. −0.43) after 16 weeks of treatment.Discussion/ConclusionThe Hedan tablets significantly improve BW, BMI, TG/HDLc, and adiponectin in patients with MetS. Thus, Hedan tablets may be used as an adjunct to existing MetS management methods.     

上游转录因子1基因多态性与代谢综合征研究进展

上游转录因子基因位于染色体上代谢综合征和2型糖尿病连锁分析重现率最高的区域(1q21-q25)内.该基因编码的蛋白属于碱性螺旋-环-螺旋-亮氨酸拉链家族的成员,可参与控制和调节糖、脂代谢相关基因的表达,因而可作为代谢综合征和2型糖尿病的重要候选基因.本文就上游转录因子1基因的结构、生物学特性以及与代谢综合征相关性状关系的研究进展进行了综述.     

血浆YKL-40浓度对危重症患者并发腹腔间隙综合征的预测作用

目的:揭示危重症患者血浆YKL-40浓度的变化,探讨其对危重症患者并发腹腔间隙综合征的预测价值。方法:收集危重症患者和健康体检人群各98例。健康体检人群静脉血体检时获得,危重症患者静脉血在入院时获得。ELISA检测血浆YKL-40浓度。结果:危重症患者血浆YKL-40浓度(146.8±79.5)ng/ml显著高于健康体检者(39.4±12.5)ng/ml(t=8.749,P<0.01),与APACHEⅡ评分,呈显著正相关性(r=0.591,P<0.01)。28例(28.6%)并发腹腔间隙综合征。多因素分析显示,血浆YKL-40浓度(OR=1.492,95%CI=1.231～2.116,P<0.01)是危重症患者并发腹腔间隙综合征的独立危险因素。ROC曲线分析显示,血浆YKL-40浓度预测危重症患者并发腹腔间隙综合征有显著预测价值(曲线下面积=0.842,95%CI=0.791～0.914,P<0.001),且判定血浆YKL-40浓度>172.4 ng/ml,对预测并发腹腔间隙综合征有82.1%的灵敏度和78.6%的特异度。结论:危重症患者并发腹腔间隙综合征后,血浆YKL-40浓度显著升高,临床检测YKL-40作为有预报价值的标志物,有助于早期判断腹腔间隙综合征的发生。     

ACS患者血清学辅助诊断指标比较

目的：明确急性冠状动脉综合征（acute coronary syndrome,ACS）患者血清缺血修饰性白蛋白（ische-mia modified albumin,IMA）的临床诊断价值。方法：随机选择73例在胸痛3h内就诊的ACS患者,分别在就诊时（3h内组）和胸痛6h（6h组）抽血检测IMA,同时检测肌钙蛋白I（cTnI）和肌红蛋白（Mb）,与40例健康体检者（健康对照组）进行对照比较。结果：ACS患者3h内组血清IMA阳性率最高,与cTnI和Mb比较有统计学意义（87.67、10.96、17.81,χ2=110.788,P〈0.001）,ROC曲线显示IMA的ROC曲线下面积为0.958（95可信区间0.923～0.993）,IMA对ACS的临床诊断效能优于cTnI及Mb;6h组阳性率以Mb为最高,但IMA、cTnI及Mb三指标间无显著性差异（89.04、93.15、98.63,χ2=5.647,P〉0.05）,对ACS的临床诊断效能相近。结论：IMA是反映ACS心肌缺血早期诊断的灵敏指标,对于发病〈3h的ACS更有价值,结合cTnI和Mb有助于ACS的早期诊断和排除诊断。     

代谢综合征患者血管内皮损伤标志物、C反应蛋白与胰岛素抵抗的关系

目的:观察代谢综合征(MS)患者血管内皮损伤标志物血管性假性血友病因子抗原(vWF:Ag)、凝血酶调节蛋白(TM)及超敏C反应蛋白(Hs-CRP)的水平变化及其与胰岛素抵抗的关系。方法:测定67例MS患者(其中合并冠心病31例)及35例健康对照组TM、vWF:Ag、Hs-CRP、空腹胰岛素(Fins)水平,计算胰岛素抵抗指数(IR)。结果:单纯MS组(B组)TM、vWF:Ag、Hs-CRP水平明显高于对照组(A组),P<0.05;MS合并冠心病组(C组)TM、vWF:Ag、Hs-CRP水平均高于A组和B组,差异有显著性统计学意义(P<0.05)。单因素直线相关分析表明TM、vWF:Ag、Hs-CRP与IR显著正相关(r分别为0.32、0.36、0.38)。结论:MS患者血管内皮损伤标志物、CRP水平升高,且与IR抵抗有关。     

Optimal Waist Circumference Cutoff Value Reflecting Insulin Resistance as a Diagnostic Criterion of Metabolic Syndrome in a Nondiabetic Korean Population Aged 40 Years and Over: The Chungju Metabolic Disease Cohort (CMC) Study

Purpose

We aimed at determining the cutoff value of waist circumference with respect to its ability to reflect insulin resistance in a Korean population.

Materials and Methods

A total of 8,817 subjects aged 40 years and over were analyzed. Insulin resistant individuals were defined as those who had the highest quartile value of the homeostasis model assessment of insulin resistance (HOMA-IR) in a non-diabetic population. Receiver operating characteristic (ROC) curve analysis and multiple logistic regression analysis were applied.

Results

The cutoff value of waist circumference reflecting insulin resistance from the ROC analysis was 84.4 cm for men and 80.6 cm for women. Sensitivity and specificity were 70.0% and 54.2% in men and 71.1% and 59.3% in women, respectively. After being controlled for other covariates, the odds ratio for the risk of insulin resistance using < 70 cm of waist circumference as a reference increased significantly in the category of 85.0-89.9 cm for men and 80.0-84.9 cm for women. In addition, statistically significant associations were consistently observed over the category of 85.0-89.9 cm for men and 80.0-84.9 cm for women.

Conclusion

The optimal cutoff value for waist circumference reflecting insulin resistance is considered to be 85 cm for men and 80 cm for women, suggesting that the Asian criterion of abdominal obesity (90 cm for men and 80 cm for women) as a component of metabolic syndrome (MetS) might not be applicable for middle-aged to older men in Korea.     

二甲双胍缓释片治疗女性精神分裂症伴发代谢综合征的研究

目的观察二甲双胍缓释片对女性精神分裂症患者所伴发代谢综合征(MS)的疗效。方法将64例符合MS诊断的女性精神分裂症患者随机分为研究组和对照组各32例。研究组给予二甲双胍缓释片500mg/d,对照组给予同等片型的安慰剂,各治疗3个月,分别于治疗前、治疗1个月和治疗3个月时检测体重指数(BMI)、腰围、收缩压、舒张压、空腹血糖(FBS)、甘油三酯(TG)和高密度脂蛋白(HDL-C),并进行比较分析。结果治疗1个月后研究组收缩压、舒张压、TG、HDL-C这4项指标均低于治疗组,差异具有显著性(分别t=2.36,2.25,2.37,2.03;P<0.05);研究组FBS水平明显低于对照组,差异具有极显著性(t=12.34,P<0.01。治疗3个月后,两组间BMI、腰围相比无显著差异(P>0.05);研究组收缩压和舒张压仍低于对照组,具有显著差异(t=2.63,2.60;P<0.05);研究组的FBS、TG和HDL-C水平明显低于对照组,有极显著差异(t=13.65,10.36,2.77;P<0.01)。结论二甲双胍缓释片对于女性精神分裂症伴代谢综合征患者有较好疗效。     

Prognosis after Implantation of Cardioverter-Defibrillators in Korean Patients with Brugada Syndrome

Purpose

Our study aims to analyze prognosis after implantable cardioverter-defibrillator (ICD) implantation in Korean patients with Brugada syndrome (BrS).

Materials and Methods

This was a retrospective study of BrS patients implanted with an ICD at one of four centers in Korea between January 1998 and April 2012. Sixty-nine patients (68 males, 1 female) were implanted with an ICD based on aborted cardiac arrest (n=38, 55%), history of syncope (n=17, 25%), or induced ven tricular tachyarrhythmia on electrophysiologic study in asymptomatic patients (n=14, 20%). A family history of sudden cardiac death and a spontaneous type 1 electrocardiography (ECG) were noted in 13 patients (19%) and 44 patients (64%), respectively.

Results

During a mean follow-up of 59±46 months, 4.6±5.5 appropri ate shocks were delivered in 19 patients (28%). Fourteen patients (20%) experienced 5.2±8.0 inappropriate shocks caused by supraventricular arrhythmia, lead failure, or abnormal sensing. Six patients were admitted for cardiac causes during follow-up, but no cardiac deaths occurred. An episode of aborted cardiac arrest was a significant predictor of appropriate shock, and the composite of cardiac events in the Cox pro portional hazard model [hazard ratio (95% confidence interval) was 11.34 (1.31-97.94) and 4.78 (1.41-16.22), respectively]. However, a spontaneous type 1 ECG was not a predictor of cardiac events.

Conclusion

Appropriate shock (28%) and inappropriate shock (20%) were noted during a mean follow-up of 59±46 months in Korean BrS patients implanted with an ICD. An episode of aborted cardiac ar rest was the most powerful predictor of cardiac events.     

Dairy Product Intake Is Inversely Associated with Metabolic Syndrome in Korean Adults: Anseong and Ansan Cohort of the Korean Genome and Epidemiology Study

The objective of this study was to examine the relationship between dairy product intake and the incidence of metabolic syndrome (MetS) and its components among middle-aged Koreans. We examined 7,240 adults aged 40-69 yr without MetS at baseline over a 45.5-month follow-up period. They were taken from the Anseong and Ansan cohort of the Korean Genome and Epidemiology Study. Dairy product intake including milk, yogurt, and cheese was assessed with food frequency questionnaire. At the follow-up, the incidence of MetS was 17.1%. The incidences of MetS components were as follows: low HDL cholesterol (16.2%), abdominal obesity (14.0%), hypertriglyceridemia (13.8%), hyperglycemia (13.3%), and hypertension (13.1%). Adjusting for potential confounders, dairy product consumption frequency was inversely associated with the risk of MetS and abdominal obesity. Hazard ratio (HR) (95% confidence interval) for dairy product consumption more than 7 times/week compared to never was 0.75 (0.64-0.88, P for trend < 0.001) for MetS and 0.73 (0.61-0.88, P for trend < 0.001) for abdominal obesity. HR for milk intake was 0.79 for MetS and 0.82 for abdominal obesity. The results of this study suggest that daily intake of dairy products protects against the development of MetS, particularly abdominal obesity, in middle-aged Koreans.     

Short-Term Treatment with Metformin Improves the Cardiovascular Risk Profile in First-Degree Relatives of Subjects with Type 2 Diabetes Mellitus who have a Metabolic Syndrome and Normal Glucose Tolerance without Changes in C-Reactive Protein or Fibrinogen

OBJECTIVE:

To study if metformin, when administered to first-degree relatives of type 2 diabetes mellitus subjects who have metabolic syndrome and normal glucose tolerance, could improve the cardiovascular risk profile and reduce the levels of both C-reactive protein and fibrinogen.

INTRODUCTION:

Metabolic syndrome is associated with higher cardiovascular morbidity and mortality. Metformin has vasculo-protective effects even in normoglycemic subjects, and C-reactive protein and fibrinogen are considered markers of endothelial injury and inflammation.

METHODS:

Thirty-one non-diabetic first-degree relatives of type 2 diabetes mellitus subjects with metabolic syndrome were randomized (1:1) and double-blinded for placement in the placebo and metformin groups (850mg bid/±90days); 16 subjects were administered metformin (mean age 40.0 [33.5–50] years; 13 females) and 15 subjects were in the placebo group (mean age 37.0 [32–42] years; 9 females). Blood samples were collected at baseline and at the end of treatment for biochemical analyses, including an assessment of C-reactive protein and fibrinogen levels.

RESULTS:

Metformin improved the lipid profile and decreased fasting plasma glucose, systolic blood pressure, weight and body mass index without changing body composition. For those in the placebo we identified no changes in fibrinogen (282.2 [220.4–323.7] mg/L vs. 286.7 [249.6–295.1] mg/L; NS) or in C-reactive protein levels (0.68 [0.3–1.2] vs. 0.64 [0.3–1.0] mg/L; NS). The same was also observed for the levels of fibrinogen (303.9 [217.6–347.6] mg/L vs. 290.9 [251.5–301.9] mg/L; NS) and C-reactive proteins (0.78 [0.3–1.1] vs. 0.80 [0.4–0.9] mg/L; NS) in the metformin group.

CONCLUSIONS:

Metformin treatment in first-degree relatives of type 2 diabetes mellitus sufferers who have metabolic syndrome and normal glucose tolerance improved the cardiovascular risk profile without changing the levels of C-reactive protein and fibrinogen.