Nonconcordance between subclinical atherosclerosis and the calculated Framingham risk score in HIV‐infected patients: relationships with serum markers of oxidation and inflammation

Objectives

HIV‐infected patients show an increased cardiovascular disease (CVD) risk resulting, essentially, from metabolic disturbances related to chronic infection and antiretroviral treatments. The aims of this study were: (1) to evaluate the agreement between the CVD risk estimated using the Framingham risk score (FRS) and the observed presence of subclinical atherosclerosis in HIV‐infected patients; (2) to investigate the relationships between CVD and plasma biomarkers of oxidation and inflammation.

Methods

Atherosclerosis was evaluated in 187 HIV‐infected patients by measuring the carotid intima‐media thickness (CIMT). CVD risk was estimated using the FRS. We also measured the circulating levels of interleukin‐6, monocyte chemoattractant protein‐1 (MCP‐1) and oxidized low‐density lipoprotein (LDL), and paraoxonase‐1 activity and concentration.

Results

There was a weak, albeit statistically significant, agreement between FRS and CIMT (κ=0.229, P<0.001). A high proportion of patients with an estimated low risk had subclinical atherosclerosis (n=66; 56.4%). In a multivariate analysis, the presence of subclinical atherosclerosis in this subgroup of patients was associated with age [odds ratio (OR) 1.285; 95% confidence interval (CI) 1.084–1.524; P=0.004], body mass index (OR 0.799; 95% CI 0.642–0.994; P=0.044), MCP‐1 (OR 1.027; 95% CI 1.004–1.050; P=0.020) and oxidized LDL (OR 1.026; 95% CI 1.001–1.051; P=0.041).

Conclusion

FRS underestimated the presence of subclinical atherosclerosis in HIV‐infected patients. The increased CVD risk was related, in part, to the chronic oxidative stress and inflammatory status associated with this patient population.

     

雷公藤甲素通过IL-10/Th17细胞调节哮喘小鼠气道炎症

目的:探索雷公藤甲素对哮喘小鼠外周血白细胞介素-10(IL-10)、辅助性T17(Th17)细胞及气道炎症的影响。方法:32只雌性BALB/c小鼠随机分为对照组、哮喘组、雷公藤甲素组、地塞米松组,每组8只。对照组给予生理盐水致敏与激发,哮喘组给予卵清蛋白(OVA)致敏及激发,雷公藤甲素组在每次激发前给予40μg/(kg·d)雷公藤甲素腹腔注射干预,地塞米松组在每次激发前给予1 mg/(kg·d)地塞米松腹腔注射干预。最后一次激发24 h后收集各组小鼠肺泡灌洗液进行细胞分类计数,检测外周血细胞因子IL-10、外周血CD4+淋巴细胞中Th17细胞比例,对肺组织进行HE染色,评估小鼠气道炎症的变化。结果:哮喘组小鼠IL-10浓度明显低于对照组,Th17细胞比例明显高于对照组,且肺泡灌洗液细胞总数、嗜酸性粒细胞计数、中性粒细胞计数、气道周围炎症评分均明显高于对照组(均P 0. 01)。雷公藤甲素组及地塞米松组IL-10浓度较哮喘组明显升高,Th17细胞比例较哮喘组明显下降,且肺泡灌洗液细胞总数、嗜酸性粒细胞计数、中性粒细胞计数、气道周围炎症评分明显低于哮喘组(均P 0. 05),而雷公藤甲素组及地塞米松组之间上述指标比较差异无统计学意义(均P 0. 05)。结论:雷公藤甲素可能通过IL-10对Th17细胞的调节作用减轻气道周围炎症,为哮喘的临床治疗提供新的靶点。     

Lipoprotein (a) reduces platelet aggregation apo(a)-mediated decreases in production via thromboxane A 2

Agonist (collagen- or ADP-)-stimulated platelet aggregation and thromboxane B reduced in human whole blood (WB) and washed platelets (W P) that were co-incubated with lipoprotein (a) \[Lp(a)] at levels of 25, 50 and 100 mg% but not at 5 mg% relative to a baseline concentration of 1 mg% . Significant decreases in agonist-stimulated aggregation and T X B purified apo (a) that was co-incubated with W B and WP relative to a baseline concentration of 1 mg%. Purified Lp(a) that was free of apo(a) \[Lp(a)-], at concentrations of 5, 25, 50 and 100 mg%, that were co-incubated with WB and W P, had no impact on agonist-induced platelet aggregation and T X B level of 1 mg% . A monoclonal antibody (Mab) (3B1) against apo(a) blocked Lp(a)-mediated reduction in platelet aggregation and T X B concentrations in WB and W P that were stimulated by either agonist. Various Mabs 2 against apoB failed to affect an Lp(a)-induced reduction in WB and WP aggregation or T X B to either agonist. These results strongly suggest that Lp(a)-induced decreases in collagen or ADP stimulated platelet aggregation and T X B production are mediated by apo(a). 2 (T X B ) production was 2 2 levels were seen with 5, 25, 50 and 100 mg% 2 production relative to a baseline 2 levels in response 2     

Hypercoagulability,platelet function,inflammation and coronary artery disease acuity: Results of the Thrombotic RIsk Progression (TRIP) Study

The objective of the study was to determine the relation of platelet reactivity, hypercoagulability and inflammation in various stages of coronary artery disease acuity (CAD). Thrombin-induced platelet-fibrin clot strength (MA), time to initial platelet-fibrin clot formation (R), C-reactive protein (CRP), prothrombotic factors, activated GPIIb/IIIa receptor expression and other biomarkers were studied in patients with asymptomatic stable CAD (AS), in patients undergoing PCI for stable (SA) and unstable angina (UA). MA and R were measured by thrombelastography, GPIIb/IIIa expression by flow cytometry and all other markers by fluorokine multianalyte profiling assays. An overall increase in all measurements from a clinically stable to an unstable disease state was observed. There was a distinct stepwise increment in MA [AS vs. SA (p = 0.02), SA vs. UA (p = 0.02) and AS vs. UA (p < 0.001)]. MA exhibited the strongest correlation with other prothrombotic markers (p ≤ 0.02), with CRP (p < 0.001) at all levels of CAD acuity. A distinct pathophysiological state of heightened platelet function, hypercoagulability and inflammation marks the presence of unstable cardiovascular disease requiring intervention. Further studies are required to investigate the primary mechanisms linking the above processes associated with a prothrombotic state resulting in clinical destabilization of the disease.     

Impact of glycaemic control, hypertension and insulin treatment on general and cause-specific mortality: an Italian population-based cohort of Type II (non-insulin-dependent) diabetes mellitus

Summary The aims of this study were to assess the impact of diabetes and associated variables (fasting plasma glucose, blood pressure, antidiabetic treatment, body mass index) on general and cause-specific mortality in an Italian population-based cohort with Type II (non-insulin-dependent) diabetes mellitus, comprising mainly elderly patients. The patients (n = 1967) who had Type II diabetes were identified in 1988 with an 80 % estimated completeness of ascertainment. In 1995, a mortality follow-up (98 % completeness) of the cohort was done amounting to a total of 11 153 person-years. Observed and expected number of deaths were 577 and 428.7, respectively, giving a standardized mortality ratio (SMR) of 1.35 (95 % CI 1.24–1.46). The most common underlying causes of death were malignant neoplasm, ischaemic heart disease and cerebrovascular diseases, which accounted for 18 %, 17.8 % and 17.5 % of deaths, respectively. Cardiovascular disease as a whole (international classification of disease ICD-9 390–459) accounted for 260 of 577 deaths (SMR 1.21, 95 % CI 1.07–1.36). In internal analysis, the most important predictors of general mortality were insulin-treatment (relative risk [RR] 1.72, 95 % CI 1.19–2.49) and a fasting plasma glucose greater than 8.89 mmol/l ([RR] 1.29, 95 % CI 1.04–1.60), whereas the most important predictors of cardiovascular diseases were insulin-treatment and hypertension. In conclusion, this population-based study showed: 1) slight mortality excess of 35 % in Type II diabetes being associated with 2) a 30 % increased mortality in subjects with baseline fasting glucose greater than 8.89 mmol/l and 3) a 40 % increased risk of death from cardiovascular diseases in hypertensive patients. [Diabetologia (1999) 42: 297–301] Received: 27 July 1998 and in final revised form: 17 November 1998     

毛细支气管炎患儿血清25(OH)D水平与Th17/Treg平衡的关系

目的分析毛细支气管炎患儿血清25羟维生素D[25(OH)D]水平与辅助性T淋巴细胞17(Th17)/调节性T淋巴细胞(Treg)平衡的相关性。 方法选取2019年2月至2021年2月我院收治的毛细支气管炎患儿46例为观察组,选取同期门诊体检者39例为对照组,检测血清25(OH)D及Th17/Treg水平。比较两组一般资料及血清25(OH)D水平、Th17/Treg,采用Pearson分析血清25(OH)D水平与Th17/Treg的相关性,采用Logistic回归分析毛细支气管炎的影响因素。 结果两组性别、年龄、体质量、剖宫产、早产、监护人抽烟、家族史比较,差异无统计学意义(P>0.05);观察组过敏体质高于对照组,母乳喂养低于对照组(P<0.05);观察组血清25(OH)D水平(37.12±6.08)nmol/L、Th17/Treg水平(0.29±0.10);较对照组25(OH)D水平(45.69±7.52)nmol/L、Th17/Treg水平(0.17±0.05);观察组血清25(OH)D水平低于对照组,Th17/Treg高于对照组(P<0.05);Pearson相关性分析显示,观察组血清25(OH)D水平与Th17/Treg呈负相关(P<0.05);Logistic回归分析显示,过敏体质、Th17/Treg为毛细支气管炎的危险因素,母乳喂养、25(OH)D为毛细支气管炎的保护因素(P<0.05)。 结论毛细支气管炎患儿血清25(OH)D水平与Th17/Treg平衡具有明显关联性,二者是毛细支气管炎的影响因素。     

Morphometric analysis of Th(1) and Th(2) cytokine expression in human pulmonary tuberculosis

SETTING: Following infection with Mycobacterium tuberculosis, host cytokine responses influence disease manifestation. Differences in cytokine expression likely determine whether tuberculosis (TB) progresses, resolves, or becomes latent. In particular, the balance between Th(1) and Th(2) cytokine responses influences the expression of disease in individuals with pulmonary TB. OBJECTIVE AND DESIGN: Since the cytokine microenvironment in pulmonary TB remains suboptimally defined, we utilized quantitative immunohistochemistry to compare the expression of Th(1) cytokines [interferon-gamma (IFNgamma) and interleukin-12 (IL-12)] and Th(2) cytokines [IL-4, IL-10, transforming growth factor-beta (TGFbeta)] in surgically resected lungs of seven TB patients and four control subjects. We also quantified IFNgamma-inducible protein 10 (IP-10) expression, a CXC chemokine for macrophages and T cells. RESULTS: Morphometric analyses revealed increased IFNgamma, IL-12, IP-10, and TGFbeta in granulomas and in pneumonitis areas of TB lungs. In contrast, IL-10 and IL-4 expressions were globally reduced in TB lung tissues compared to controls. CONCLUSION: Th(1) cytokines and TGFbeta are increased while Th(2) cytokines are decreased in well-formed pulmonary granulomas of TB patients compared to controls.     

Rationale,design, and baseline characteristics of the Cardiovascular Prognostic COUPLING Study in Japan (the COUPLING Registry)

Vascular biomarkers, including the cardio‐ankle vascular index (CAVI), are increasingly being recognized as important indicators of cardiovascular risk. CAVI has been shown to have good discriminative ability for detecting new‐onset hypertension, but results of studies investigating cardiovascular risk prediction are inconsistent. Furthermore, there is a lack of data on the prognostic value of changes in CAVI over time. The Cardiovascular Prognostic Coupling study was designed to determine the impact of baseline CAVI and changes in CAVI on cardiovascular events in a Japanese cohort. The design of the ongoing, multicenter, prospective, observational registry and baseline characteristics of the enrolled population are reported. Eligible consecutive patients were aged ≥30 years, had ≥1 cardiovascular risk factor, and were being treated according to relevant Japanese guidelines. The primary outcome is time to onset of a major cardiovascular event (a composite of cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, stroke of unknown etiology, myocardial infarction, cardiovascular intervention for angina pectoris, and sudden death). Screening and enrollment occurred over a period of 3 years, followed by ≥7 years of follow‐up, with CAVI determined annually. A total of 5279 patients were registered, of whom 5109 had baseline data available and will be included in future analyses. Mean CAVI at baseline was 8.8 ± 1.4. The proportion of patients with CAVI of <8, 8‐10 or >10 was 25.3%, 57.0%, and 17.7%, respectively. Data from this registry should provide information on the significance of baseline CAVI and change in CAVI as indicators of cardiovascular prognosis in a representative patient population.     

A case control association study of ACE gene polymorphism (I/D) with hypertension in Punjabi population from Faisalabad,Pakistan

Angiotensin converting enzyme (ACE) is a key component of renin angiotensin aldosterone system. It converts angiotensin I to angiotensin II. Insertion/deletion (I/D) polymorphism of ACE gene is found associated with several complications. However, its association with hypertension and related metabolic diseases is still controversial. So, the aim of the present study was to check this association for Punjabi population from Faisalabad, Pakistan. For this purpose, blood samples (patients = 100, controls = 48) were collected and several biochemical parameters were measured. Genotyping for ACE (I/D) polymorphism was performed by polymerase chain reaction (PCR) assay.

ID genotype is found prevalent in the studied population as 41% in control subjects and 61% in patients. Furthermore, chi-square analysis showed significant (p = 0.005) difference for genotypic frequencies between both groups. One-way ANOVA for association of II, ID, and DD genotypes with anthropometric, clinical, and biochemical parameters showed that in patient group, DD genotype is significantly (p = 0.041) associated with systolic blood pressure (SBP). Moreover, ID genotype is found associated with the presence of cardiovascular diseases. This study concludes that DD genotype is strongly associated with higher SBP in hypertensive patients.     

老年2型糖尿病患者颈动脉粥样硬化与血清25-羟维生素D_3水平的关系

目的探讨血清25-羟维生素D3[25(OH)D3]与老年2型糖尿病患者颈动脉粥样硬化发生、发展的相关性。方法选择2型糖尿病患者174例,根据颈动脉内膜中层厚度(IMT)水平分为IMT正常组84例,IMT增厚组90例;又根据颈动脉有无狭窄分为颈动脉无狭窄组141例,颈动脉狭窄组33例。测量血压、身高、体重,计算体质量指数(BMI),并检测空腹血糖、血脂、糖化血红蛋白等指标,采用酶联免疫分析法测定血清25(OH)D3水平。超声检测及计算IMT及狭窄情况。结果 IMT增厚组血清25(OH)D3水平明显低于IMT正常组(P<0.05);颈动脉狭窄组血清25(OH)D3水平明显低于颈动脉无狭窄组,空腹血糖、尿酸水平明显高于颈动脉无狭窄组(P<0.05)。相关分析显示,颈动脉IMT最大值与老年2型糖尿病患者25(OH)D3呈负相关(P<0.05),与尿酸呈正相关(P<0.01)。logistic回归分析显示,颈动脉狭窄与25(OH)D3、尿酸独立相关。结论在老年2型糖尿病患者中,低水平血清25(OH)D3可能是颈动脉粥样硬化的独立危险因素。     

Dynamic role of hyaluronan (HYA) in connective tissue activation and inflammation

Gerdin B, Hällgren R (University Hospital, Uppsala, Sweden). Dynamic role of hyaluronan (HYA) in connective tissue activation and inflammation (Minisymposium: Hyaluronan). J Intern Med 1997; 242 : 49–55.
An increased tissue accumulation of HYA occurs in several human and experimental inflammatory conditions. Such is the case in sarcoidosis, idiopathic pulmonary fibrosis and farmer's lung in man, and experimental bleomycin-induced lung damage in rats. Graft rejection in man and rats, experimental myocarditis in mice and myocardial infarction in rats follow the same pattern. Increased amounts of HYA also appear in gut luminal perfusion fluid in human inflammatory bowel disease. A transient accumulation of HYA is seen in wound healing, which is more sustained in fetuses. An increased accumulation of water and presentation of ligands for receptors on inflammatory cells are two consequences of the HYA accumulation.     

Safety and reported adverse effects of coronavirus disease-2019 (COVID-19) vaccines in patients with rheumatic diseases

BackgroundCoronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Symptoms and severity of COVID19 are variable.Aim of the workTo evaluate the effectiveness and to identify side effects of the COVID-19 vaccines among Egyptian patients with autoimmune rheumatic diseases (RDs).Patients and methodsThe study included 126 patients with various RDs and 200 control. Detailed medical history was recorded with special concern regarding COVID-19 vaccination, types, doses, side effects, post-vaccination infection and treatment.ResultsIn patients, BBIBP-CorV (Sinopharm) was the most frequent vaccine 42.3 % (n = 52); CoronaVac (Sinovac) 22 % (n = 27); ChAdOx1 (AstraZeneca) 17.9 % (n = 22); BNT162 (Pfizer BioNTech) 14.6 % (n = 18); Sputnik V 1.6 % (n = 2) and Ad26.COV2-S (Johnson & Johnson) 1.6 % (n = 2). Regarding the control, 34.4 % (n = 62) received AstraZeneca; 26.1 % (n = 47) Sinopharm; 16.7 % (n = 30) Pfizer; 11.7 % (n = 21) Sinovac; 6.7 % (n = 12) Sputnik; 3.3 % (n = 6) Johnson & Johnson and 1.2 % (n = 2) mRNA1273 (Moderna). COVID-19 infection decreased after vaccination from 32 (25.4 %) to 7 (5.6 %), and from 162 (81.0 %) to 85 (42.7 %) in RD patients and the control respectively. ICU admission decreased from (6.3 %) among RD patients and from (1.3 %) in control to 0 % after vaccination in both groups. In RD patients, body ache was the commonest reported vaccine adverse effect (44.4 %). Pain at the injection site was the commonest among control (77 %). ChAdOx1 (AstraZeneca) had the highest incidence of side effects, mRNA1273 (Moderna) showed the lowest.ConclusionCOVID-19 vaccine was effective in decreasing infection and disease severity in RDs patients and control, with similar, mild adverse effects.     

Suppressive oligodeoxynucleotides inhibit atherosclerosis in ApoE(-/-) mice through modulation of Th1/Th2 balance

Atherosclerosis is a chronic inflammatory disease, which is positively and negatively regulated by T helper (Th) 1 and Th2 lymphocytes, respectively. Recent findings indicate that suppressive oligodeoxynucleotides (ODNs) expressing TTAGGG motifs selectively reduce Th1 cytokine production and have been proven effective at blocking the development of organ-specific autoimmune diseases. In the current research, we hypothesized that suppressive ODNs may alter the development of atherosclerosis. Eight-week-old homozygous ApoE^−/− male mice were injected with 300 μg ODNs A151 (TTAGGG) or nonspecific ODNs 1612. Atherosclerotic lesion sizes were dramatically reduced by ODNs A151, but not by nonspecific ODNs. MCP-1 and VCAM-1, which are the key inflammatory factors in atherogenesis, were significantly attenuated by the suppressive ODNs A151. In the splenic lymphocytes, FACS analysis showed ODNs A151 reduced the percentage of IFN-γ-producing Th1 cells and slightly increased the percentage of IL-4-producing Th2 cells, indicating that suppressive ODNs skewed the Th1/Th2 balance toward Th2 inflammation in vivo. Furthermore, ODNs A151 down-regulated the phosphorylation of STAT1 and STAT4 and suppressed up-regulation of T-bet, a signal modulator for Th1, and didn't impact GATA-3 and STAT6, which are associated with a Th2 phenotype. Consistent with this in vivo observation, ELISA analysis demonstrated that ODNs A151 suppressed Th1 cytokines IFN-γ and TNF-α, and augmented Th2 cytokines IL-4 and IL-10 in vitro. This study provides the first experimental evidence that suppressive ODNs inhibit the development of atherosclerosis through inhibition of the STAT1/4 and T-bet pathways, which further modulate the Th1/Th2 balance in vivo.     

Resistance to activated protein C (APCR) in children with venous or arterial thromboembolism

Resistance to activated protein C (APCR), in the majority of cases due to the point mutation Arg 506 Gln of the factor V gene, has emerged as the most important hereditary cause of venous thromboembolism. Using an activated thromboplastin time (aPTT) based method in the presence of APC together with a DNA technique based on the polymerase chain reaction, we investigated 37 children with venous (V: n = 19) or arterial (A: n = 18) thromboembolism and 196 age-matched healthy controls for the presence of this mutation. In the control group 10 children were detected to be heterozygous for the factor V Leiden mutation, indicating a prevalence of 5.1%. 10/19 children (52%) with venous thrombosis and 7/18 (38%) patients with arterial thromboembolism showed the common factor V gene mutation. Additional inherited coagulation disorders were found in 1/10 (V: 10%) and 2/7 (A: 28%) APC-resistant patients. Inherited coagulation disorders without APCR were diagnosed in 3/9 (V: 33%) and 2/11 (A: 18%) children. Furthermore, we diagnosed exogenous risk factors in 6/10 (V: 60%) and 2/7 (A: 28%) children with thrombosis and APCR. These data are evidence that APCR combined with exogenous reasons may play an important role in the early manifestation of thromboembolism during infancy and childhood.     

老年缺血性心脑血管疾病患者脂蛋白（a）的观察

本文测定１６２例老年住院患者和３８例健康老人血清脂蛋白（ａ）［Ｌｐ（ａ）］水平。分析结果显示老年冠心病（ＣＨＤ）、脑梗塞（ＣＭ）患者Ｌｐ（ａ）浓度明显高于健康组和其他疾病组（Ｐ＜０．０１或Ｐ＜０．０５）。高Ｌｐ（ａ）血症的检出率ＣＨＤ组、ＣＭ组亦分别高于健康组及其他疾病组（Ｐ＜０．０１或Ｐ＜０．０５）。Ｌｐ（ａ）水平不受饮食和降脂药物等影响。认为脂蛋白（ａ）是缺血性心脑血管疾病的独立危险因素之一。提出Ｌｐ（ａ）可作为临床缺血性心脑血管疾病的重要预测指标。