Reduction in circulating markers of endothelial dysfunction in HIV-infected patients during antiretroviral therapy

Objectives

Antiretroviral therapy (ART) in HIV‐infected patients is associated with increased cardiovascular risk. Circulating markers of endothelial dysfunction may be used to study early atherogenesis. The aim of our study was to investigate changes in such markers during initiation of ART.

Methods

In 115 HIV‐positive treatment‐naïve patients, plasma lipids, E‐selectin, soluble intercellular adhesion molecule 1 (sICAM‐1), soluble vascular cell adhesion molecule 1 (sVCAM‐1), tissue‐type plasminogen activator inhibitor 1 (tPAI‐1) and high‐sensitivity C‐reactive protein (hsCRP) were measured before and after 2 and 14 months of ART. A control group of 30 healthy subjects was included. Values are mean±standard error of the mean.

Results

Prior to treatment, HIV‐infected patients had elevated levels of sICAM‐1 (296±24 vs. 144±12 ng/mL), tPAI‐1 (18 473±1399 vs. 5490±576 pg/mL) and hsCRP (28 060±5530 vs. 6665±2063 ng/mL) compared with controls (P<0.001). In contrast, sVCAM‐1 and E‐selectin did not differ between the groups. Initiation of ART resulted in significantly lower levels of E‐selectin (15.1±0.8; P<0.01), sICAM‐1 (248±12 ng/mL; P<0.05), sVCAM‐1 (766±33 ng/mL; P<0.001) and hsCRP (14 708±2358 ng/mL; P<0.001) after 2 months, which remained reduced at 14 months. tPAI‐1 was not influenced by initiation of ART.

Conclusions

Markers of endothelial dysfunction were elevated in treatment‐naïve HIV‐infected patients and were related to HIV RNA viral load. Initiation of ART reduced the levels of the majority of these markers. The positive effect of ART initiation was dependent on the duration of HIV infection prior to treatment.     

Frequent red cell transfusions reduced vascular endothelial activation and thrombogenicity in children with sickle cell anemia and high stroke risk

Stroke is one of the most disabling complications of sickle cell anemia (SCA). The molecular mechanisms leading to stroke in SCA or by which packed red blood cell (PRBC) transfusion prevents strokes are not understood. We investigated the effects of PRBC transfusion on serum biomarkers in children with SCA who were at high‐risk for stroke. Serum samples from 80 subjects were analyzed, including baseline, study exit time point and 1 year after study exit. Forty of the 80 samples were from subjects randomized to standard care and 40 from transfusion arm. Samples were assayed for levels of BDNF, sVCAM‐1, sICAM‐1, MPO, Cathepsin‐D, PDGF‐AA, PDGF‐AB/BB, RANTES (CCL5), tPAI‐1, and NCAM‐1 using antibody immobilized bead assay. Significantly lower mean serum levels of sVCAM‐1 (2.2 × 10⁶ ± 0.8 × 10⁶ pg/mL vs. 3.1 × 10⁶ ± 0.9 × 10⁶ pg/mL, P < 0.0001), Cathepsin‐D (0.5 × 10⁶ ± 0.1 × 10⁶ pg/mL vs. 0.7 × 10⁶ ± 0.2 × 10⁶ pg/mL, P < 0.0001), PDGF‐AA (10556 ± 4033 pg/mL vs. 14173 ± 4631 pg/mL, P = 0.0008), RANTES (0.1 × 10⁶ ± 0.07 × 10⁶ pg/mL vs. 0.2 × 10⁶ ± 0.06 × 10⁶ pg/mL, P < 0.006), and NCAM‐1 (0.7 × 10⁶ ± 0.2 × 10⁶ pg/mL vs. 0.8 × 10⁶ ± 0.1 × 10⁶ pg/mL, P < 0.0006) were observed among participants who received PRBC transfusion, compared to those who received standard care. Twenty or more PRBC transfusion over 4 years was associated with lower serum levels of sVCAM‐1 (P < 0.001), PDGF‐AA (P = 0.025), and RANTES (P = 0.048). Low baseline level of BDNF (P = 0.025), sVCAM‐1 (P = 0.025), PDGF‐AA (P = 0.01), t‐PAI‐1 (P = 0.025) and sICAM‐1 (P = 0.022) was associated with higher probability of stroke free survival. Beyond improving hemoglobin levels, our results suggest that the protective effects of PRBC transfusion on reducing stroke in SCD may result from reduced thrombogenesis and vascular remodeling. Am. J. Hematol. 89:47–51, 2014. © 2013 Wiley Periodicals, Inc.     

Circulating blood markers and functional impairment in peripheral arterial disease

OBJECTIVES: To determine whether higher levels of inflammatory blood markers, D‐dimer, and homocysteine were associated with greater impairment in lower extremity functioning in persons with peripheral arterial disease (PAD). DESIGN: Cross‐sectional. SETTING: Three Chicago‐area medical centers. PARTICIPANTS: Four hundred twenty‐three persons with PAD (ankle–brachial index (ABI) <0.90). MEASUREMENTS: Lower extremity performance was assessed using the 6‐minute walk and with usual‐ and fast‐paced 4‐m walking speed. Blood markers were D‐dimer, C‐reactive protein (CRP), interleukin‐6 (IL‐6), soluble vascular cellular adhesion molecule‐1 (sVCAM‐1), soluble intracellular adhesion molecule‐1 (sICAM‐1), and homocysteine. Calf muscle area was measured using computed tomography. RESULTS: Adjusting for confounders, higher levels of D‐dimer (P<.001), IL‐6 (P<.001), sVCAM‐1 (P=.006), CRP (P=.01), homocysteine (P=.004), and sICAM‐1 (P=.046) were associated with poorer 6‐minute walk performance. Higher levels of D‐dimer (P<.001), IL‐6 (P=.003), sVCAM‐1 (P=.001), and homocysteine (P=.005) were associated with slower usual‐paced 4‐m walking speed. Higher levels of D‐dimer, sVCAM‐1, sICAM‐1, IL‐6, and homocysteine were associated with slower fast‐paced walking speed. Results were attenuated after additional adjustment for calf muscle area. CONCLUSION: Higher levels of inflammation and D‐dimer were associated with poorer lower extremity performance in participants with PAD, independent of confounders including ABI.     

Inflammatory cytokines,endothelial markers and adhesion molecules in rheumatoid arthritis: effect of intensive anti-inflammatory treatment

Tumour necrosis factor alpha (TNF-α) and interlekin-6 (IL-6) are key inflammatory cytokines in the pathogenesis of rheumatoid arthritis (RA), a disease also associated with endothelial perturbation and increased serum levels of adhesion molecules. As relationships between these processes and molecules are unclear, we tested the hypotheses (a) that TNF-α and IL-6 are linked to endothelial activation/damage and levels of soluble adhesion molecules, and (b) that intensive anti-inflammatory treatment improves levels of these indices. We recruited 66 patients with RA, 48 community controls (CC), and 25 disease controls (DC). Plasma TNF-α and IL-6 were compared to markers of vascular biology (vWF, sE-sel), soluble adhesion molecules (sICAM, sVCAM) and routine inflammatory markers (CRP and ESR). Blood was obtained at baseline and at 1 week and again 4 weeks after anti-inflammatory treatment in a subgroup of 29 patients with RA. With the exception of sE-selectin, RA patients had increased levels of all plasma markers compared to the HCs, whilst levels in the DCs were largely intermediate between RA and the CCs. Within the RA group, sEsel correlated with both CRP and ESR whilst TNF-α correlated with sVCAM (all r > 0.32, P < 0.01). After 1 week of combined anti-inflammatory therapy, only CRP, ESR, sEsel and sVCAM were significantly reduced (all P < 0.05). In RA, endothelial activation (as sEsel) correlates with classical markers of inflammation and is reduced by intensive anti-inflammatory medications.     

Serum levels of soluble vascular cell adhesion molecule are related to hyperdynamic circulation in patients with liver cirrhosis

Background: In patients with liver cirrhosis, serum levels of soluble vascular cell adhesion molecule‐1 (sVCAM‐1) have been associated with increasing fibrosis and are related to angiogenesis. Aim: To assess the possible correlation between sVCAM‐1 and splanchnic and systemic haemodynamic and clinical staging of cirrhotic patients. Methods: We assessed, using immunoassays, the serum levels of sVCAM‐1, in the peripheral and hepatic vein, in all consecutive patients with liver cirrhosis, who underwent a haemodynamic study as part of its routine clinical work‐up. Results: We studied 86 patients [61 M/25 F; age 51.1 (8.3) years] with alcoholic (31) or viral (HBV:6, HCV:49) cirrhosis, 10 of them with hepatocellular carcinoma (Milan criteria). The mean follow‐up was 391(187) days; 29 patients died or underwent transplantion during follow‐up. A strong correlation in serum levels of sVCAM‐1 was observed between the peripheral and the hepatic vein (r=0.8; P=0.0001). There was no correlation between levels of sVCAM‐1 and hepatic venous pressure gradient. At univariate analysis, sVCAM‐1 was inversely related with mean arterial pressure (r=?0.292; P=0.007), systemic vascular resistance (SVR) (r=?0.37; P=0.005) and serum sodium levels (r=?0.326; P=0.002). In multivariate linear regression only SVR remained as an independent variable associated to sVCAM‐1. A correlation of sVCAM‐1 with Child–Pugh scores, model for end‐stage liver disease (MELD) and the clinical stage proposed in the Baveno IV consensus conference was also observed. Finally, patients who died or underwent transplantion during follow‐up had significantly greater values of sVCAM‐1 at baseline than those who did not [3505(1329) vs. 2488(1208) P=0.001]. Conclusion: This study supports a potential role of sVCAM‐1 as a marker of hyperdynamic circulation, closely related to the different stage of liver cirrhosis.     

Traditional risk factor assessment does not capture the extent of cardiovascular risk in systemic lupus erythematosus

Background: Systemic lupus erythematosus (SLE) is associated with accelerated atherosclerosis. However, the degree of endothelial dysfunction and its relationship to traditional and novel cardiovascular risk factors have not been examined in SLE. Methods: In a case–control design, 35 patients with clinically stable SLE and 35 control subjects matched for age, sex, body mass index and smoking status were studied. Arterial elasticity, lipid profile, homocysteine, measures of inflammation and oxidative stress were determined. Results: Among traditional vascular risk factors, there was a nonsignificant trend towards lower blood pressure in the control subjects, whereas low‐density lipoprotein (LDL) cholesterol levels were significantly lower in the SLE group (2.5 vs 3.3 mmol/L, P < 0.001). Patients with SLE had significantly lower small artery elasticity (SAE; 4.9 vs 7.0 ml/mmHg × 100, P < 0.001) and higher plasma homocysteine (11.4 vs 8.3 mmol/L, P = 0.002) than control subjects. Levels of serum sVCAM‐1 (614 vs 494 ng/mL, P = 0.002), oxidized LDL (144 vs 97, P < 0.001) and CD40 ligand (4385 vs 1373 pg/ml, P = 0.001) were significantly higher in SLE. Oxidized LDL levels, older age at SLE diagnosis and higher disease damage scores correlated inversely with SAE but not traditional risk factors. Conclusion: Impaired endothelial function as shown by decreased SAE, and an adverse profile of novel proatherogenic and prothrombotic vascular disease risk factors were prevalent in clinically quiescent SLE. These findings show the vulnerability of patients with SLE for atherosclerosis, and emphasize that assessments based on traditional risk factors alone may be inadequate.     

Cholestasis enhances liver ischemia/reperfusion‐induced coagulation activation in rats

Aim: Cholestasis is associated with increased morbidity and mortality in patients undergoing major liver surgery. An additional risk is induced when vascular inflow occlusion is applied giving rise to liver ischemia/reperfusion (I/R) injury. The role of the coagulation system in this type of injury is elusive. The aim of the current study was to assess activation of coagulation following hepatic I/R injury in cholestatic rats. Methods: Male Wistar rats were randomized into two groups and subjected to bile duct ligation (BDL) or sham laparotomy. After 7 days, both groups underwent 30 min partial liver ischemia. Animals were sacrificed before ischemia or after 6 h, 24 h, and 48 h reperfusion. Results: Plasma AST and ALT levels were higher after I/R in cholestatic rats (P < 0.05). Hepatic necrosis, liver wet/dry ratio and neutrophil influx were increased in the BDL group up to 48 h reperfusion (P < 0.05). Liver synthetic function was decreased in the BDL group as reflected by prolonged prothrombin time after 6 h and 24 h reperfusion (P < 0.05). I/R in cholestatic rats resulted in a 12‐fold vs. 7‐fold (P < 0.01) increase in markers for thrombin generation and a 6‐fold vs. 2‐fold (P < 0.01) increase in fibrin degradation products (BDL vs. control, respectively). In addition, the cholestatic rats exhibited significantly decreased levels of antithrombin (AT) III and increased levels of the fibrinolytic inhibitor plasminogen activator inhibitor (PAI‐1) during reperfusion. Conclusions: Cholestasis significantly enhances I/R‐induced hepatic damage and inflammation that concurs with an increased activation of coagulation and fibrinolysis.     

Short‐Term Effect of Atorvastatin on Endothelial Function in Healthy Offspring of Parents with Type 2 Diabetes Mellitus

Endothelial function is impaired in healthy subjects at risk of type 2 diabetes mellitus (DM). We investigated whether endothelial dysfunction can be normalized by statin therapy in this potentially predisposed population. Flow‐mediated dilation (FMD) was measured in 56 first‐degree relatives (FDRs) (normotensive, normal glucose tolerance) and 20 age‐, sex‐, and BMI‐matched controls with no family history of DM. Other measurements included insulin resistance index using the homeostasis model of insulin resistance (HOMA_IR), plasma lipids, and markers of inflammation. The FDRs were then randomized and treated with atorvastatin (80 mg) or placebo daily in a 4‐week double‐blind, placebo‐controlled trial. The FDRs had significantly impaired FMD (4.4 ± 8.1% vs. 13.0 ± 4.2%; P < 0.001), higher HOMA_IR (1.72 ± 1.45 vs. 1.25 ± 0.43; P= 0.002), and elevated levels of plasma markers of inflammation—highly sensitive C‐reactive protein (hsCRP) (2.6 ± 3.8 mg/L vs. 0.7 ± 1.0 mg/L; P= 0.06), interleukin (IL)‐6 (0.07 ± 0.13 ng/mL vs. 0.03 ± 0.01 ng/mL; P < 0.001), and soluble intercellular adhesion molecule (sICAM) (267.7 ± 30.7 ng/mL vs. 238.2 ± 20.4 ng/mL; P < 0.001). FMD improved in the atorvastatin‐treated subjects when compared with the placebo‐treated subjects (atorvastatin, from 3.7 ± 8.5% to 9.8 ± 7.3%; placebo, from 3.9 ± 5.6% to 4.7 ± 4.2%; P= 0.001). There were also reductions in the levels of IL‐6 (0.08 ± 0.02 ng/mL vs. 0.04 ± 0.01 ng/mL; P < 0.001) and hsCRP (3.0 ± 3.9 mg/L vs. 1.0 ± 1.3 mg/L; P= 0.006). Our study suggests that treatment with atorvastatin may improve endothelial function and decrease levels of inflammatory markers in FDRs of type 2 DM patients.     

The acute phase inflammatory response to maximal exercise testing in children and young adults with sickle cell anaemia

Although individuals with sickle cell anaemia (SCA) have elevated baseline inflammation and endothelial activation, the acute phase response to maximal exercise has not been evaluated among children with SCA. We measured the acute phase response to maximal exercise testing for soluble vascular cell adhesion molecule (sVCAM) as well as interleukin 6 (IL6), total white blood cell (WBC) count, C‐reactive protein (CRP) and D‐dimer in a cohort of children with SCA and matched controls at baseline, immediately after, and 30, 60 and 120 min following exercise. Despite higher baseline levels of all biomarkers except CRP, the acute phase response from baseline to immediately after exercise was significantly greater in subjects versus controls for CRP (2·1 vs. 0·2 mg/l, P = 0·02) and D‐dimer (160 vs. 10 μg/l, P < 0·01) only. Similar between‐group trends were observed over time for all biomarkers, including sVCAM, IL6, total WBC, CRP and D‐dimer. Lower fitness, defined by peak oxygen consumption (VO₂), was independently associated with greater acute phase responses to exercise for sVCAM. Our results suggest maximal exercise may not be associated with any greater escalation of endothelial activation or inflammation in SCA and provide preliminary biomarker evidence for the safety of brief, high‐intensity physical exertion in children with SCA.     

The effect of anti‐inflammatory (aspirin and/or statin) therapy on body weight in Type 2 diabetic individuals: EAT,a retrospective study

Aims Obesity is associated with inflammation. Anti‐inflammatory interventions such as aspirin and statins (anti‐IFRx) might be a novel approach to the treatment of obesity and Type 2 diabetes mellitus (T2DM). The present study was designed to determine whether exposure to anti‐IFRx is associated with weight loss in T2DM patients. Methods Exposure to anti‐IFRx was compared between T2DM patients with a history of weight loss (n = 100) and those with no weight loss or with weight gain (n = 102) during a 1‐year follow‐up period. Logistic regression was used to develop odds ratios for weight loss status. Results Subjects who lost weight were more frequently exposed to anti‐IFRx (85.0 vs. 71.5%, P = 0.018) than subjects who maintained or gained weight during follow‐up. The 158 subjects exposed to anti‐IFRx were older (64.2 ± 9.4 vs. 60.6 ± 11.2 years, P = 0.04), had longer duration T2DM (14.5 ± 9.5 vs. 9.0 ± 9.4 years, P = 0.001), had greater prevalence of dyslipidaemia (72 vs. 19%, P < 0.0001) hypertension (57.3 vs. 38.1%, P = 0.03) and cardiovascular disease (37.7 vs. 9.5%, P < 0.0001) than subjects not exposed to anti‐IFRx. In a logistic regression model for weight change status, anti‐IFRx exposure was significantly associated with weight status (odds ratio = 2.3, 95% confidence interval 1.1–4.8, P = 0.02, an association that persisted), even after controlling for age, sex, baseline body mass index, years since diagnosis, OHA therapy and co‐morbidities. Conclusions Exposure to anti‐IFRx more than doubled the odds of weight loss in T2DM patients. Results of this study justify a randomized clinical trial to determine definitively the role of anti‐IFRx in weight loss in subjects with T2DM.     

[14C]aminopyrine breath test in chronic liver disease

The [¹⁴C]aminopyrine breath test (APBT) score, an estimate of hepatic mixed-oxidase function, was evaluated in 21 consecutive patients with active nonalcoholic chronic liver diseases. Ten had primary biliary cirrhosis (PBC) and 11 had chronic active hepatitis (CAH). The APBT score was normal or elevated in patients with PBC (P<0.001), and lower than normal in CAH patients (P<0.01); 10.5±1.6 and 3.5±1.86, respectively, vs control 7.65±1.15 (mean±sd). The 11 patients with CAH included two middle-aged women who displayed ambiguous severe intrahepatic cholestasis. There was no overlap between the APBT scores of the 10 PBC and 11 CAH patients. These initial data suggest that the APBT may be helpful in the differentiation of PBC and CAH, including misleading cholestatic forms of CAH.     

Simvastatin reduces vaso‐occlusive pain in sickle cell anaemia: a pilot efficacy trial

Sickle cell anaemia (SCA ) is a progressive vascular disease characterized by episodic vaso‐occlusive pain. Despite the broad impact of inflammation on acute and chronic clinical manifestations of SCA , no directed anti‐inflammatory therapies currently exist. Statins are cholesterol‐lowering agents shown to confer protection from vascular injury by suppressing inflammation. We previously documented a reduction in soluble biomarkers of inflammation in patients with sickle cell disease treated with simvastatin. To determine the potential clinical efficacy of simvastatin, we treated 19 SCA patients with single daily dose simvastatin for 3 months and assessed changes from baseline in the frequency and intensity of diary‐reported pain and levels of circulating nitric oxide metabolites (NO x), high sensitivity C‐reactive protein (hs‐CRP ), vascular cell adhesion molecule 1 (VCAM ‐1), intercellular adhesion molecule 1 (ICAM ‐1), ICAM ‐3, E‐selectin, and vascular endothelial growth factor (VEGF ). Treatment with simvastatin resulted in a significant reduction in the frequency of pain (P  =  0·0003), oral analgesic use (P  =  0·003) and circulating hs‐CRP (P  =  0·003), soluble (s)E‐selectin (P  =  0·01), sICAM ‐1 (P  =  0·02), sICAM ‐3 (P  =  0·02) and sVEGF (P  =  0·01). Simvastatin had no effect on pain intensity or levels of NO x, sP ‐selectin and sVCAM ‐1. The observed reductions in pain rate and markers of inflammation were greatest in subjects receiving hydroxycarbamide (HC ), suggesting a synergistic effect of simvastatin. These results provide preliminary clinical data to support a larger trial of simvastatin in SCA.     

Dialysate Vascular Endothelial Growth Factor Is an Independent Determinant of Serum Albumin Levels and Predicts Future Withdrawal From Peritoneal Dialysis in Uremic Patients

Peritoneal protein loss due to high peritoneal permeability may contribute to hypoalbuminemia and early withdrawal from peritoneal dialysis (PD) therapy in end stage renal disease (ESRD) patients. We have found that pigment epithelium‐derived factor (PEDF) has anti‐vasopermeability properties both in cell culture and animal models by counteracting the biological actions of vascular endothelial growth factor (VEGF). However, it remains unknown which clinical variables, including dialysate VEGF and PEDF, are associated with decreased serum albumin levels and could predict early withdrawal from the PD in ESRD patients. We address these issues. Twenty‐seven ESRD patients undergoing PD were enrolled. Clinical variables were measured at 6 months after commencing PD. We examined the independent correlates of serum albumin in PD patients and then prospectively investigated the predictors of withdrawal from the PD therapy over 4 years. Dialysate VEGF was associated with peritoneal solute transport rate (P = 0.002), serum albumin (inversely, P < 0.001) and dialysate PEDF levels (P < 0.001). In multiple stepwise regression analysis, age (P = 0.002) and dialysate VEGF levels (P < 0.001) were independent determinants of serum albumin levels. High VEGF (>27 pg/mL), low serum albumin (≤3.31 g/dL) and low hemoglobin (≤11.2 g/dL) were correlated with withdrawal from the PD therapy during the 4 years. The odds ratio of dialysate VEGF for early withdrawal from the PD was 6.310 (P = 0.035). The present study demonstrated that increased dialysate VEGF was associated with decreased serum albumin and early withdrawal from the PD therapy. Inhibition of peritoneal VEGF production may be a therapeutic target in PD patients.     

Angiopoietin Balance in Septic Shock Patients Treated by Direct Hemoperfusion With Polymyxin B‐immobilized Fiber

Capillary permeability is a tightly regulated feature of microcirculation in all organ beds; however, in sepsis this feature is fundamentally altered. We previously reported elevated levels of vascular endothelial growth factor and its receptor (fms‐like tyrosine kinase‐1) in patients with septic shock, then investigated two kinds of angiopoietins in those patients. An enzyme‐linked immunoassay was used to measure serum angiopoietin‐1 and ‐2 levels in 12 patients with septic shock who were treated by direct hemoperfusion with a polymyxin B‐immobilized fiber column (DHP‐PMX). The angiopoietin‐1 level was lower in patients with septic shock (7.01 ± 10.08 ng/mL) than in controls (28.24 ± 11.61 ng/mL, P < 0.001), but the angiopoietin‐2 level was higher in septic shock patients (40.83 ± 30.13 ng/mL vs. 2.47 ± 1.78 ng/mL, P < 0.001). Between seven survivors and five non‐survivors there was no significant difference in angiopoietin‐1 levels before DHP‐PMX therapy. During DHP‐PMX therapy, however, the angiopoietin‐2 level was significantly decreased in survivors (31.52 ± 26.15 ng/mL vs. 17.32 ± 22.46 ng/mL, P = 0.035). Moreover, at the end of the therapy, the angiopoietin‐1 level was significantly lower in non‐survivors (1.14 ± 1.30 ng/mL vs. 10.43 ± 13.56 ng/mL, P = 0.042), but the angiopoietin‐2 level in non‐survivors was significantly higher (70.79 ± 40.47 ng/mL vs. 17.32 ± 22.46 ng/mL, P = 0.019). The angiopoietin‐2 level may be associated with vascular permeability in septic patients, and angiopoietins may be suitable markers of disease severity and mortality.     

The oxidant–antioxidant balance in systemic sclerosis cases with interstitial lung involvement

We aimed to assess the plasma oxidant and antioxidant levels in systemic sclerosis (SS) patients with interstitial lung involvement. Twenty-seven female SS patients and 17 healthy female volunteers were included in the study. Plasma levels of oxidants and antioxidants levels were studied of two groups. The median oxidant and antioxidant levels in study and control groups were, MDA 5.2 ± 0.4/3.7 ± 0.5 nmol/ml (P < 0.001), NO 45.4 ± 3.7/34.2 ± 2.9 nmol/l (P < 0.001), SOD 25.6 ± 2.3/24.6 ± 2.0 U/ml (P > 0.05), catalase 99.9 ± 9.9/140.0 ± 10.0 U/ml (P < 0.001), vitamin E 20.5 ± 1.3/22.6 ± 2.0%mg (P < 0.001), vitamin C 70.6 ± 8.7/83.5 ± 7.3 mg/dl (P < 0.001), respectively. There was also no correlation between plasma levels of oxidants–antioxidants levels and disease duration, duration of pulmonary signs, pulmonary function test values, HRCT scores in SS patients (P > 0.05). In our study, the oxidant burden in SS patients with interstitial lung involvement was found to be increased; however no correlation was detected between the severity of lung involvement and oxidant–antioxidant levels.     

Hodgkin lymphoma post‐transplant lymphoproliferative disorder: A comparative analysis of clinical characteristics,prognosis, and survival

Hodgkin lymphoma post‐transplant lymphoproliferative disorder (HL‐PTLD) is an uncommon PTLD with unclear prognosis and differences between HL‐PTLD and immunocompetent HL are not well defined. Patient characteristics were compared among 192 patients with HL‐PTLD from the Scientific Registry of Transplant Recipients and 13,847 HL patients in SEER (HL‐SEER). Overall survival (OS) and disease‐specific survival (DSS) were compared after exact matching. Additionally, multivariable analyses were used to identify prognostic markers of survival and associations between treatment and survival. Median time from transplant to HL‐PTLD diagnosis was 88 months. When compared with HL‐SEER, patients with HL‐PTLD were older (median age, 52 vs. 36 years, P = 0.001), more likely male (73% vs. 54%, P < 0.001), Caucasian (81% vs. 70%, P = 0.02), and had extranodal disease (42% vs. 3%, P < 0.001). Five‐year OS for patients with HL‐PTLD was 57% versus 80% for HL‐SEER (P < 0.001); DSS was also inferior (P < 0.001). For patients with HL‐PTLD, the use of any chemotherapy was associated with decreased hazard of death (HR = 0.36, P < 0.001). Furthermore, patients who received no chemotherapy or nontraditional HL regimens had increased hazard of death (aHR = 2.94, P = 0.001 and 2.01, P = 0.04) versus HL‐specific chemotherapy regimens. In multivariable analysis, advanced age and elevated creatinine were associated with inferior OS (aHR = 1.26/decade P < 0.001 and 1.64/0.1 mg/dL increase P = 0.02). A prognostic score based on the number of these adverse factors (0, 1, 2) was associated with 10‐year OS rates of 79%, 53%, and 11%, respectively (P < 0.001). Altogether, HL‐PTLD patients have inferior survival when compared with HL‐SEER. Furthermore, treatment with HL‐specific chemotherapy was associated with improved OS, whereas age and creatinine identified patients with markedly divergent survival. Am. J. Hematol. 91:560–565, 2016. © 2016 Wiley Periodicals, Inc.     

Expression of breast cancer anti‐estrogen resistance 1 in relation to vascular endothelial growth factor,p53, and prognosis in esophageal squamous cell cancer

The purpose of this study was to clarify the role of breast cancer anti‐estrogen resistance 1 (BCAR1) expression in relation to vascular endothelial growth factor (VEGF), p53, and proliferation in esophageal squamous cell cancer (ESCC). Expression of BCAR1, VEGF, p53, and the ki‐67 proliferative index were examined by tissue microarray and immunohistochemistry in 106 specimens with ESCC and matched adjacent normal tissues. Among them, 40 cases were simultaneously examined by Western blot. Both Western blot and immunohistochemistry showed that BCAR1 expression was substantially higher in ESCC than in adjacent normal tissues (P < 0.001). BCAR1 expression was significantly connected with degree of tumor differentiation, with poorly differentiated tumors showing higher BCAR1 expression (P < 0.001). BCAR1 expression was significantly and positively correlated with VEGF and p53 expression levels (r= 0.541, P < 0.001; r= 0.374; P < 0.001) but not proliferative index (r= 0.44; P= 0.066). Additionally, a significant relationship was also observed between VEGF and p53 (r= 0.321; P= 0.001). Kaplan–Meier survival analysis revealed that patients with high BCAR1 expression had significantly shorter survival times than those with low BCAR1 expression levels (median survival 40 months vs. 27 months, P= 0.09). Multivariate analysis also revealed that levels of BCAR1 expression (hazard ratio 2.250, P= 0.015) was a significant and independent prognostic indicator. High expression of BCAR1 is associated with elevated VEGF and p53 expression levels, as well as poor prognosis in ESCC. Therefore, BCAR1 may be a potential candidate for predicting prognosis and a new therapy target for ESCC.     

Lack of concordance between plasma markers of cardiovascular risk and intima-media thickness in patients with type 2 diabetes

Aim: Endothelial dysfunction, oxidative stress and systemic inflammation play an important role in the enhanced cardiovascular risk in diabetes. Carotid intima‐media thickness (IMT), a widely accepted marker of subclinical atherosclerosis, is known to be increased in patients with type 2 diabetes. The relationships between plasma markers of cardiac risk and carotid IMT are not well known. We therefore studied a group of patients with type 2 diabetes to evaluate the relationships between plasma markers of cardiac risk and carotid IMT. Design and patients: We measured carotid IMT and the levels of soluble endothelial adhesion molecules [sE‐selectin, intercellular cell adhesion molecule‐1 (sICAM‐1) and vascular cell adhesion molecule‐1 (sVCAM‐1)], C‐reactive protein (CRP) and 8‐isoprostane in 40 patients with type 2 diabetes without clinical macrovascular complications (HbA_1c < 10%, duration of diabetes < 12 years) and 25 healthy subjects. We then examined the correlations between these plasma markers, carotid IMT and various clinical and biochemical parameters. Results: Diabetic patients had higher plasma sE‐selectin (p = 0.03), sICAM‐1 (p = 0.05), CRP (p = 0.047) and 8‐isoprostane (p = 0.001) concentrations than control subjects. Mean IMT values were identical (0.63 ± 0.02 mm) in diabetic (range, 0.40–0.92 mm) and healthy subjects (range, 0.45–0.85 mm). In diabetic patients, stepwise multivariate analysis showed that HbA_1c and plasma glucose were independent predictors of sE‐selectin (r² = 0.19 and r² = 0.17, p < 0.01, respectively), whereas waist circumference and body mass index (BMI) were predictors of sICAM‐1 (r² = 0.27, p = 0.001 and r² = 0.22, p = 0.002, respectively). Waist circumference was the only predictor of CRP (r² = 0.2, p < 0.01), and systolic blood pressure was the only predictor of 8‐isoprostane (r² = 0.19, p = 0.006). In control subjects, similar analysis showed that plasma glucose and waist circumference were predictors of sE‐selectin and sICAM‐1, respectively (r² = 0.2, p < 0.05). Conclusions: These results indicate that some well‐controlled type 2 diabetic patients free of clinical macrovascular complications have elevated plasma markers of cardiovascular risk without having increased IMT. The elevation of plasma markers of endothelial cell activation (sE‐selectin and s‐ICAM‐1) or inflammation (CRP) and oxidative stress (8‐isoprostane) in diabetics vs. controls is distinct from and cannot be explained simply by differences in the burden of atherosclerosis as assessed by carotid IMT.     

ALTERED LEVELS OF SOLUBLE ADHESION MOLECULES IN RHEUMATOID ARTHRITIS, VASCULITIS AND SYSTEMIC SCLEROSIS

We compared the levels of soluble adhesion molecules E-selectin(sE-selectin), intercellular adhesion molecule-1 (sICAM-1) andvascular cell adhesion molecule-1 (sVCAM-1) alongside von Willebrandfactor (vWf), CRP and rheumatoid factor in 40 patients withRA, 38 with systemic sclerosis (SSc), 35 with vasculitis andin 80 asymptomatic controls. Adhesion molecules were measuredin serum by ELISA, rheumatoid factor by sheep red blood cellagglutination and CRP by immunonephelometry. Compared to controls,increased sE-selectin was found in patients with RA (P = 0.0015),vasculitis (P = 0.0003) and SSc (P = 0.0126), whilst raisedsICAM-1 was found in RA (P < 0.0003), vasculitis (P <0.0003) and SSc (P < 0.0378). sVCAM was lower in RA thanin controls (P = 0.0102), but was unchanged in vasculitis orin SSc. vWf was raised in RA (P = 0.0102), vasculitis (P <0.0003) and SSc (P < 0.0003). In a Spearman's rank analysisof all the data, vWf correlated with sVCAM-1 and sICAM-1 (bothP < 0.001), sE-selectin with sICAM-1 (P < 0.001) and sVCAMwith sICAM-1 (P < 0.005). Levels of rheumatoid factor correlatedwith those of sE-selectin (P = 0.003) and sVCAM-1 (P < 0.012),but there were no correlations between any index and CRP. Thestrongest correlations within the RA group were between sICAMand sVCAM (P = 0.001), in vasculitis it was between sE-selectinand sICAM (P < 0.001), and in SSc it was between sE-selectinand sVCAM (P = 0.019). These data suggest that the differinglevels of vWf, sE-selectin and sICAM-1 in the inflammatory vasculitidesmay be useful in establishing a rolefor leucocyte/endothelialadhesion in these diseases. KEY WORDS: Vasculitis, Rheumatoid arthritis, Systemic sclerosis, von Willebrand factor, Soluble E-selectin, Soluble ICAM-1, Soluble VCAM-1     

Antibody levels correlate with creatine kinase levels and strength in anti–3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase–associated autoimmune myopathy

Objective

Autoantibodies recognizing 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) are found in patients with statin‐associated immune‐mediated necrotizing myopathy and, less commonly, in statin‐unexposed patients with autoimmune myopathy. The main objective of this study was to define the association of anti‐HMGCR antibody levels with disease activity.

Methods

Anti‐HMGCR levels, creatine kinase (CK) levels, and strength were assessed in anti‐HMGCR–positive patients. Associations of antibody level with CK level and strength at visit 1 were analyzed in 55 patients, 40 of whom were exposed to statins. In 12 statin‐exposed and 5 statin‐unexposed patients with serum from 5 serial visits, the evolution of antibody levels, CK levels, and strength was investigated.

Results

Antibody levels were associated with CK levels (P < 0.001), arm strength (P < 0.05), and leg strength (P < 0.05) at visit 1, but these associations were only significant among statin‐exposed patients in stratified analyses. With immunosuppressive treatment over 26.2 ± 12.6 months (mean ± SD), antibody levels declined (P < 0.05) and arm abduction strength improved (P < 0.05) in the 17 patients followed up longitudinally. The separate analysis showed that statin‐exposed patients developed decreased antibody levels (P < 0.01), decreased CK levels (P < 0.001), improved arm strength (P < 0.05), and improved hip flexion strength (P < 0.05) with treatment. Anti‐HMGCR antibody levels did not normalize in any patient.

Conclusion

In the entire cohort, initial anti‐HMGCR levels correlated with indicators of disease activity; with immunosuppressive treatment, antibody levels declined and arm strength improved. Statin‐exposed patients had significant improvements in CK levels and strength whereas statin‐unexposed patients did not, suggesting a phenotypic difference between statin‐exposed and statin‐unexposed anti‐HMGCR–positive patients.