Inflammation biomarkers and inflammatory genes expression in metabolically healthy obese patients.

BACKGROUND AND AIMS: Obesity without metabolic alterations (Metabolically Healthy Obesity, MHO) is a condition with a risk of death and cardiovascular disease lower than that of obesity associated with metabolic alterations (Metabolically Unhealthy Obesity, MUO) and similar to that of healthy non obese individuals. Inflammation is considered as a key risk factor mediating the adverse health outcomes in obesity. METHODS AND RESULTS: We compared circulating levels of thirteen major cytokines and adipokines and the expression profiles of fifteen pro-inflammatory and two anti-inflammatory genes in visceral and subcutaneous adipose tissue in a series of 16 MHO patients and in 32 MUO patients that underwent bariatric surgery. MHO was defined according to the most applied definition in current literature. Serum levels of a large set of major cytokines and adipokines did not differ between MHO and MUO patients (p ≥ 0.15). Analyses of the expression profile of pro-inflammatory and anti-inflammatory genes in subcutaneous and visceral adipose tissue failed to show differences between MHO and MUO patients (p ≥ 0.07). Sensitivity analyses applying two additional definitions of MHO confirmed the results of the primary analysis. CONCLUSION: In a series of metabolically healthy obese patients neither circulating levels of major cytokines and adipokines nor the gene expression profile of a large set of pro-inflammatory and anti-inflammatory genes in subcutaneous and visceral fat differed from those in metabolically unhealthy obese patients.

Mortality and prognostic factors in patients with bullous pemphigoid: a retrospective multicenter Italian study.

INTRODUCTION: Bullous pemphigoid is the most common autoimmune bullous dermatosis. In recent years several studies have tried to identify the main factors of the disease related with an increased risk of death. The aim of this multicenter Italian study was to assess the risk score of death considering epidemiologic, clinical, immunological, and therapeutic factors in a cohort of patients affected by bullous pemphigoid and try to identify the cumulative survival up to 120 months. METHODS: We retrospectively reviewed the medical records of patients with bullous pemphigoid who were diagnosed between 2005 and 2020 in the 12 Italian centers. Data collected included sex, age at the time of diagnosis, laboratory findings, severity of disease, time at death/censoring, treatment, and multimorbidity. RESULTS: A total of 572 patients were included in the study. The crude mortality rate was 20.6%, with an incidence mortality rate of 5.9 × 100 person/year. The mortality rate at 1, 3, 5, and 10 years was 3.2%, 18.2%, 27.4% and 51.9%, respectively. Multivariate model results showed that the risk of death was significantly higher in patients older than 78 years, in presence of multimorbidity, anti-BP180 autoantibodies >72 U/mL, or anti-BP230 > 3 U/mL at diagnosis. The variables jointly included provided an accuracy (Harrel's Index) of 77% for predicting mortality. CONCLUSION: This study represents the first nationwide Italian study to have retrospectively investigated the mortality rates and prognostic factors in patients with bullous pemphigoid. A novel finding emerged in our study is that a risk prediction rule based on simple risk factors (age, multimorbidity, steroid-sparing drugs, prednisone use, and disease severity) jointly considered with two biomarkers routinely measured in clinical practice (anti-BP230 and anti-BP180 autoantibodies) provided about 80% accuracy for predicting mortality in large series of patients with this disease.

Phenotyping congestion in patients with acutely decompensated heart failure with preserved and reduced ejection fraction: The Decongestion duRing therapY for acute decOmpensated heart failure in HFpEF vs HFrEF- DRY-OFF study.

AIMS: To evaluate pulmonary and intravascular congestion at admission and repeatedly during hospitalization for acute decompensated heart failure (ADHF) in HFrEF and HFpEF patients using lung (LUS) and inferior vena cava (IVC) ultrasound. METHODS AND RESULTS: Three-hundred-fourteen patients (82±9 years; HFpEF =172; HFrEF=142) admitted to Internal Medicine wards for ADHF were enrolled in a multi-center prospective study. At admission HFrEF presented higher indexes of pulmonary and intravascular congestion (LUS-score: 0.9 ±â€¯0.4 vs 0.7 ±â€¯0.4; p<0.01; IVC end-expiratory diameter: 21.6 ±â€¯5.1 mm vs 20±5.5 mm, p<0.01; IVC collapsibility index 24.4 ±â€¯17.4% vs 30.9 ±â€¯21.1% p<0.01) and higher Nt-proBNP values (8010 vs 3900 ng/l; p<0.001). At discharge, HFrEF still presented higher B-scores (0.4 ±â€¯4 vs 0.3 ±â€¯0.4; p = 0.023), while intravascular congestion improved to a greater extent, thus IVC measurements were similar in the two groups. No differences in diuretic doses, urine output, hemoconcentration, worsening renal function were found. At 90-days follow up HF readmission/death did not differ in HFpEF and HFrEF (28% vs 31%, p = 0,48). Residual congestion was associated with HF readmission/death considering the whole population; while intravascular congestion predicted readmission/death in the HFrEF, no association between sonographic indexes and the outcome was found in HFpEF. CONCLUSIONS: Serial assessment of pulmonary and intravascular congestion revealed a higher burden of fluid overload in HFrEF and, conversely, a greater reduction in intravascular venous congestion with diuretic treatment. Although other factors beyond EF could play a role in congestion/decongestion patterns, our data may be relevant for further phenotyping HF patients, considering the importance of decongestion optimization in the clinical approach.

Real-world effectiveness and safety of Guselkumab for the treatment of psoriasis: a 6-month prospective study in a series of psoriatic patients.

OBJECTIVE: Guselkumab is a fully human monoclonal IgG1 antibody which, by selectively binding to the p19 subunit of IL-23, prevents it from binding to the IL-23 receptor on the cell surfaces. To date, no prospective data are available on the efficacy and safety of this drug in everyday clinical practice in patients with psoriasis (PSO). MATERIALS AND METHODS: This is a longitudinal, single arm, real-world, prospective study to investigate the effect of Guselkumab on PSO and quality of life (DLQI) in 44 PSO patients. Outcomes were PASI, BSA, DLQI at 3 and 6 months. RESULTS: The longitudinal analysis showed that PASI improved from a median value of 24.1 at baseline to 2.0 at 6-months and this was also true for BSA (from 23.0 to 2.0) and DLQI (from 24.0 to 2.5) (all p<0.001). At 6-months, PASI75, PASI90 and PASI100 were 95.5%, 59.1% and 16%, respectively. The PSO improvement related with the increase of DLQI (∆PASI vs. ∆DLQI, r=0.77, p<0.001). No clinically relevant adverse events were observed. CONCLUSIONS: This study demonstrates the effectiveness and safety of Guselkumab on PSO in real world and shows that the reduction of PSO severity due to the drug is directly related with the improvement of quality of life in this patient population.

Novel markers of graft outcome in a cohort of kidney transplanted patients: a cohort observational study.

Renal biopsy (RBx) informs about kidney transplantation (KTx) prognosis. In our observational study the prevalence of histological anomalies and the prognostic role of CD45, vimentin (VIM) and periostin (POSTN) in KTx-RBx have been evaluated. One hundred forty-six KTx-RBx (2009-2012) were analysed for general histology and in immunohistochemistry for CD45, VIM and POSTN. Clinical data of the 146-KTx patients were collected at the RBx time (T0), 6 and 12 months before and after RBx. Follow-up time was 21 ± 14 months. Glomerulosclerosis was 20% glomeruli/biopsy. Tubular atrophy (TA), Interstitial infiltrate (I-Inf) and interstitial fibrosis (IF) were slight in 21-18% and 25%, moderate in 22-30% and 26% and severe in 30-18% and 28% of patients. Fifty-eight percent of patients had lesions compatible with IF-TA. CD45, VIM and POSTN correlated to each-other and to TA, I-Inf and IF. VIM and POSTN correlated to GS. CD45 and VIM correlated directly to renal function (RF) and 25(OH)VitD, while POSTN inversely to 25(OH)VitD. Thirty patients restarted dialysis (HD+). HD+ had lower T0-eGFR, and higher CD45, VIM and POSTN than HD-. POSTN resulted the strongest in discriminate for HD+ . CD45, VIM and POSTN correlate to each-other and predict graft outcome. POSTN was the strongest in discriminate for HD+. 25(OH)VitD might influence inflammation and fibrosis in KTx.

Insight into epileptic and physiological déjà vu: from a multicentric cohort study.

BACKGROUND AND PURPOSE: The presence of a continuum between physiological déjà vu (DV) and epileptic DV is still not known as well as epidemiological data in the Italian population. The aim was to identify the epidemiological distribution of DV in Italy, and secondly to look for specific features of DV able to discriminate between epileptic and non-epileptic DV. METHODS: In all, 1000 individuals, 543 healthy controls (C) (313 women; age 40 ± 15 years) and 457 patients with epilepsy (E) (260 women; age 39 ± 14 years), were prospectively recruited from 10 outpatient neurological clinics throughout Italy. All populations were screened using the Italian Inventory for Déjà Vu Experiences Assessment (I-IDEA) test and E and pairwise C underwent a comprehensive epilepsy interview. RESULTS: Of E, 69% stated that they experienced 'recognition' and 13.2% reported that this feeling occurred from a few times a month to at least weekly (versus 7.7% of the control group). Furthermore, a greater percentage of E (6.8% vs. 2.2%) reported that from a few times a month to at least weekly they felt that it seemed as though everything around was not real. In E, the feeling of recognition raised fright (22.3% vs. 13.2%) and a sense of oppression (19.4% vs. 9.4%). A fifth of E felt recognition during epileptic seizures. CONCLUSION: Only E regardless of aetiology firmly answered that they had the feeling of recognition during an epileptic seizure; thus question 14 of the I-IDEA test part 2 discriminated E from C. Paranormal activity, remembering dreams and travel frequency were mostly correlated to DV in E suggesting that the visual-memory network might be involved in epileptic DV.

Value of clinical features to differentiate refractory epilepsy from mimics: a prospective longitudinal cohort study.

BACKGROUND AND PURPOSE: Misdiagnosis of refractory epilepsy (rE) is common and such patients experience a long diagnostic delay. Our aim was to identify key clinical/laboratory factors in order to obtain an alternative diagnosis in patients referred for rE. METHODS: Between January 2010 and December 2015, 125 consecutive patients with a diagnosis of rE were prospectively enrolled. All patients underwent a comprehensive neurological, neuropsychiatric and cardiological evaluation, and had an observation time of at least 1 year after the study entry. RESULTS: Diagnosis of rE was confirmed in 104/125 (83.2%) patients (55 women, mean age 38.8 ± 14.3 years). Thirteen/125 patients (10.4%, seven women, mean age 50.8 ± 20.9) were diagnosed with syncope, which was cardiac/cardio inhibitory in 9/13 (69%). The remaining 8/125 patients (6.4%, six women, mean age 41.2 ± 14.6 years) were diagnosed with psychogenic non-epileptic seizures. Age at onset had a high accuracy in differentiating patients with syncope from others, with the best cut-off age at 35 years and above. Abnormal brain magnetic resonance imaging (MRI) had a significant yield of about 70% in rE. A diagnostic model including age at onset and brain MRI was highly accurate in differentiating patients with syncope from others. In patients with cardiac/cardio inhibitory syncope, the point score of historical features was ≥1 and falsely favoured the diagnosis of epileptic seizures. CONCLUSIONS: This prospective cohort study identifies rE mimics who are at high risk of morbidity and mortality. rE starting in adulthood should raise a high suspicion of cardiac syncope. Brain MRI is accurate in differentiating rE from other conditions.

Vitamin D receptor activation by paricalcitol and insulin resistance in CKD.

BACKGROUND AND AIMS: The nature of the link (causal vs non-causal) between low 1,25-OH vitamin D and insulin resistance (IR) in patients with chronic kidney disease (CKD) remains elusive. We have now made a post hoc analysis of the effect of vitamin D receptor activation by paricalcitol on IR in the complete dataset of a double-blind, randomized, placebo controlled trial, the Paricalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY). METHODS AND RESULTS: Eighty-eight patients with stage 3-4 CKD were randomized (1:1) to receive 2 µg/day paricalcitol or matching placebo for 12 weeks. IR was measured by five IR indices: the homeostasis model assessment of insulin resistance (HOMA-IR), the quantitative insulin sensitivity check index (QUICKI), the McAuley index, the HOMA corrected for adiponectin (HOMA-AD) and the Leptin-adiponectin ratio (LAR). As compared to placebo, paricalcitol produced the expected small rise in serum calcium (+0.07 mmol/L, P = 0.01) and phosphate (+0.08 mmol/L, P = 0.034) and the expected parathyroid hormone suppression (-96 pg/ml, P < 0.001). However, the drug largely failed to affect the five indices of IR which remained unchanged both in the active and the placebo arm (paricalcitol vs placebo, P ranging from 0.25 to 0.62) and no effect modification of paricalcitol on IR by vitamin D or other parameters was registered. CONCLUSION: Paricalcitol treatment for 12 weeks does not improve IR in patients with stage 3-4 CKD. Low vitamin D receptor activation is not a causal factor for IR in the CKD population.

Brand-to-generic levetiracetam switching: a 4-year prospective observational real-life study.

BACKGROUND AND PURPOSE: The purpose of this study was to determine whether switching from branded levetiracetam (Keppra® ) to a levetiracetam generic equivalent product (Matever® ) in an epilepsy cohort could provide adequate results in terms of seizure control and tolerability. METHODS: To be eligible for the study, patients had to have been taking Keppra® as monotherapy or polytherapy for at least 6 months. Between March 2013 and April 2017, patients were invited to switch to Matever® as part of their follow-up. We evaluated the number of seizures per month, drug-related adverse events and electroencephalography before the switch (T0, baseline) and 6 months after switching (T1). Furthermore, we reported the long-term follow-up of patients who continued to use Matever® after the end of the study, considering the most recent visit for each patient (T2). RESULTS: A total of 55 patients refused the switch. Among the remaining 125 patients, 59 (47%) were treated using Keppra® as monotherapy and 66 (53%) were on Keppra® as polytherapy. All 125 patients were subjected to switching from Keppra® to Matever® . Comparing patients before (T0) and after (T1) switching, we found no statistically significant differences in terms of seizure frequency and occurrence of adverse effects. There were no significant differences (number of seizures/month and drug-related adverse events) between patients treated with Matever® as monotherapy and patients who refused the switch and continued to use Keppra® as monotherapy for a long-term follow-up of 48 months. Electroencephalography findings were also unchanged. CONCLUSION: In our sample, brand-to-generic levetiracetam switching was effective and safe in both monotherapy and polytherapy regardless of the epilepsy syndrome.

Active vitamin D treatment in CKD patients raises serum sclerostin and this effect is modified by circulating pentosidine levels.

BACKGROUND AND AIMS: 1,25(OH)2Vitamin D increases the expression of the sclerostin gene. Whether vitamin D receptor activation (VDRA) influences serum sclerostin in CKD and whether compounds interfering with VDRA like Advanced Glycosylation End Products (AGEs) may alter the sclerostin response to VDRA is unknown. METHODS AND RESULTS: Eighty-eight stage G3-4 CKD patients randomly received 2 µg paricalcitol (PCT)/day (n = 44) or placebo (n = 44) for 12 weeks. Sclerostin, a major AGE compound like pentosidine, and bone mineral disorder biomarkers were measured at baseline, at 12 weeks and 2 weeks after stopping the treatments. At baseline, in the whole study population sclerostin correlated with male gender (P = 0.002), BMI (P < 0.001), waist circumference (P < 0.001), serum pentosidine (P = 0.002) and to a weaker extent, with diabetes (P = 0.04), 1,25(OH)2Vitamin D (r = 0.22, P = 0.04) and serum phosphate (r = -0.26, P = 0.01). Sclerostin increased during PCT treatment (average + 15.7 pg/ml, 95% CI: -3.0 to +34.3) but not during placebo (P = 0.03) and the PCT effect was abolished 2 weeks after stopping this drug. The increase in sclerostin levels induced by PCT was modified by prevailing pentosidine levels (P = 0.01) and was abolished by statistical adjustment for simultaneous changes in PTH but not by FGF23 changes. CONCLUSIONS: VDRA by paricalcitol causes a moderate increase in serum sclerostin in CKD patients. Such an effect is abolished by adjustment for PTH, suggesting that it may serve to counter PTH suppression. The sclerostin rise by PCT is attenuated by pentosidine, an observation in keeping with in vitro studies showing that AGEs alter the functioning of the VDRA.

A Genetic Biomarker of Oxidative Stress, the Paraoxonase-1 Q192R Gene Variant, Associates with Cardiomyopathy in CKD: A Longitudinal Study.

Background. Oxidative stress is a hallmark of CKD and this alteration is strongly implicated in LV hypertrophy and in LV dysfunction. Methods and Patients. We resorted to the strongest genetic biomarker of paraoxonase-1 (PON1) activity, the Q192R variant in the PON1 gene, to unbiasedly assess (Mendelian randomization) the cross-sectional and longitudinal association of this gene-variant with LV mass and function in 206 CKD patients with a 3-year follow-up. Results. The R allele of Q192R polymorphism associated with oxidative stress as assessed by plasma 8-isoPGF2α (P = 0.03) and was dose-dependently related in a direct fashion to LVMI (QQ: 131.4 ± 42.6 g/m(2); RQ: 147.7 ± 51.1 g/m(2); RR: 167.3 ± 41.9 g/m(2); P = 0.001) and in an inverse fashion to systolic function (LV Ejection Fraction) (QQ: 79 ± 12%; RQ: 69 ± 9%; RR: 65 ± 10% P = 0.002). On longitudinal observation, this gene variant associated with the evolution of the same echocardiographic indicators [LVMI: 13.40 g/m(2) per risk allele, P = 0.005; LVEF: -2.96% per risk allele, P = 0.001]. Multivariate analyses did not modify these associations. Conclusion. In CKD patients, the R allele of the Q192R variant in the PON1 gene is dose-dependently related to the severity of LVH and LV dysfunction and associates with the longitudinal evolution of these cardiac alterations. These results are compatible with the hypothesis that oxidative stress is implicated in cardiomyopathy in CKD patients.

Serum phosphorus levels are associated with endothelial dysfunction in hypertensive patients.

BACKGROUND AND AIMS: Recent data demonstrated that serum phosphorus, within the normal range, is an independent predictor of atherosclerotic cardiovascular disease, independently of renal function. Traditional cardiovascular risk factors are important mediators of endothelial dysfunction, the early step of atherosclerosis. We designed this study to evaluate a possible correlation between serum phosphorus and endothelium-dependent vasodilation, evaluated by the strain-gauge plethysmography, in naïve hypertensives. METHODS AND RESULTS: We investigated by strain-gauge plethysmography, the relationship between forearm blood flow (FBF) response to acetylcholine (ACh) and serum phosphorus in 500 patients with uncomplicated, never-treated, essential hypertension, divided by phosphorus tertiles. There were no significant differences among tertiles with the exclusion of forearm blood flow (FBF). Phosphorus (ß = -0.454; P = 0.0001), estimated-glomerular filtration rate (e-GFR, by CKD-EPI formula) (ß = 0.261; P = 0.0001), gender (ß = 0.215; P = 0.0001), BMI (ß = -0.086; P = 0.018), HDL-cholesterol (ß = 0.077; P = 0.036) were significantly related to endothelium-dependent vasodilation. In an additional analysis including serum high sensitivity C-reactive protein (hs-CRP) (measured in 400 patients) in the same model, the link between serum phosphorus and ACh-stimulated FBF did not change (ß = -0.422; P = 0.0001). Clinically relevant, 0.1 mg of phosphorus increase is associated with a reduction of 22% of ACh-stimulated FBF. On multiple logistic regression analysis, the risk of endothelial dysfunction was about twice higher in patients in the second (OR = 1.754, 95% CI = 1.055-2.915; P = 0.030) and three-fold higher in the third tertile (OR = 2.939, 95% CI = 1.598-5.408; P = 0.0001) in comparison with those in the first tertile of phosphorus. CONCLUSION: An impaired ACh-stimulated FBF is associated with serum phosphorus levels, within the normal range, in hypertensives.

Serum phosphate modifies the vascular response to vitamin D receptor activation in chronic kidney disease (CKD) patients.

BACKGROUND AND AIMS: Vitamin D receptor activation (VDRA) ameliorates endothelial dysfunction in CKD patients but also increases phosphate and FGF-23, which may attenuate the beneficial effect of VDRA on endothelial function. METHODS AND RESULTS: This is a pre-specified secondary analysis of the PENNY trial (NCT01680198) testing the effect of phosphate and FGF-23 on the flow mediated vasodilatory (FMD) response to paricalcitol (PCT, 2 µg/day) and placebo over a 12-weeks treatment period. Eighty-eight stage G3-4 CKD patients were randomized to PCT (n = 44) and Placebo (n = 44). Endothelial function was assessed by measuring endothelium dependent forearm blood flow (FBF) response to ischemia. The FMD response was by the 61% higher in PCT treated patients than in those on placebo (P = 0.01). Phosphate (+11%, P = 0.039), calcium (+3%, P = 0.01) and, particularly so, FGF23 (+164%, P < 0.001) increased in PCT treated patients. Changes in FMD by PCT associated inversely with phosphate (r = -0.37, P = 0.01) but were independent of FGF-23, calcium and PTH changes. The response to PCT was maximal in patients with no changes in phosphate (1st tertile), attenuated in those with mild-to-moderate rise in phosphate (2nd tertile) and abolished in those with the most pronounced phosphate increase (3rd tertile) (effect modification P = 0.009). No effect modification by FGF-23 and other variables was observed. CONCLUSIONS: The beneficial effect of PCT on endothelial function in CKD is maximal in patients with no or minimal changes in phosphate and it is abolished in patients with a pronounced phosphate rise. These findings generate the hypothesis that the endothelium protective effect by VDRA may be potentiated by phosphate lowering interventions.

A phase II, single-arm, prospective study of bendamustine plus melphalan conditioning for second autologous stem cell transplantation in de novo multiple myeloma patients through a tandem transplant strategy.

This phase II trial evaluates, for the first time, the safety and efficacy of bendamustine plus high-dose melphalan (HDM) as a conditioning regimen before the second autologous stem cell transplantation (ASCT) in previously untreated multiple myeloma (MM) patients. In total, 32 ASCT patients received HDM (200 mg/m(2)) as conditioning for the first ASCT. After 3-6 months from the first ASCT, responding patients underwent a second ASCT following bendamustine (200 mg/m(2)) and HDM (140 mg/m(2)). High-dose chemotherapy and ASCT were performed with complete neutrophil and platelet recovery in all patients. The median number of days to neutrophil and platelet engraftment was 11 (range 9-15) and 12 (range 10-19), respectively. Only one subject experienced grade 3 diarrhea; the rate of mucositis and vomiting was significantly lower with the bendamustine plus HDM regimen compared with the HDM-only regimen (81.2 vs 96.9%, P=0.025 and 78.1 vs 100%, P=0.008). Overall response rate (ORR) was 81.2% after the first transplant, and 90.6% after the second, while complete response rates were 46.8 and 62.5%, respectively (P=0.016). Actuarial 2-year PFS and OS were 79% (95% confidence interval (CI), 60-98) and 97% (95% CI, 91-100), respectively. Bendamustine+HDM is feasible as the conditioning regimen for second ASCT in MM patients. The present study may pave the way for phase III studies specifically aimed at further investigating this combination strategy. The role of this combination in MM for conditioning regimen in a first or single ASCT setting should be also investigated.

A genetic marker of hyperuricemia predicts cardiovascular events in a meta-analysis of three cohort studies in high risk patients.

INTRODUCTION: The strongest genetic marker of uric acid levels, the rs734553 SNP in the GLUT9 urate transporter gene, predicts progression to kidney failure in CKD patients and associates with systolic BP and carotid intima media thickness in family-based studies. METHODS: Since genes are transmitted randomly (Mendelian randomization) we used this gene polymorphism as an unconfounded research instrument to further explore the link between uric acid and cardiovascular disease (cardiovascular death, and non-fatal myocardial infarction and stroke) in a meta-analysis of three cohort studies formed by high risk patients (MAURO: 755 CKD patients; GHS: 353 type 2 diabetics and coronary artery disease and the TVAS: 119 patients with myocardial infarction). RESULTS: In separate analyses of the three cohorts, the incidence rate of CV events was higher in patients with the rs734553 risk (T) allele (TT/GT) than in those without (GG patients) and the HR in TT/GT patients in the three cohorts (range 1.72-2.14) coherently signaled an excessive cardiovascular risk with no heterogeneity (I2 = 0.01). The meta-analytical estimate (total number of patients, n = 1227; total CV events, n = 222) of the HR for the combined end-point in TT/GT patients was twice higher (pooled HR: 2.04, 95% CI: 1.11-3.75, P = 0.02) than in GG homozygotes. CONCLUSIONS: The T allele of the rs734553 polymorphism in the GLUT9 gene predicts a doubling in the risk for incident cardiovascular events in patients at high cardiovascular risk. Findings in this study are compatible with the hypothesis of a causal role of hyperuricemia in cardiovascular disease in high risk conditions.

Synergism between asymmetric dimethylarginine (ADMA) and a genetic marker of uric acid in CKD progression.

BACKGROUND & AIMS: We have recently reported that a polymorphism (rs734553) in a major urate transporter gene (GLUT9) is a strong predictor of incident renal events in stage 2-5 CKD patients implying that life-time exposure to high uric acid levels may be causally implicated in CKD progression. Since disturbed NO bioavailability is a major pathway whereby high uric may cause renal damage, we tested the interaction between the major endogenous inhibitor of NO synthase, asymmetric-dimethylargine (ADMA), and the rs734553 polymorphism for CKD progression in the same cohort. METHODS & RESULTS: Over a 29 ± 11 months follow-up the risk for incident renal events was higher in patients harboring the risk allele of the polymorphism (T) as compared to those without the risk allele (HR: 2.35, 95% CI: 1.25-4.42, P = 0.008) (p = 0.01). Similarly, patients with ADMA > median value had an increased risk for the same outcome (HR: 1.37, 95% CI: 1.06-1.76, P = 0.016). Interaction analysis showed a strong amplification by ADMA of the risk for renal events associated to the T allele because in adjusted (P = 0.016) and bootstrapping validated (P = 0.020) analyses the risk excess associated to this allele was progressively higher across increasing ADMA levels. CONCLUSIONS: The rs734553 polymorphism, the strongest genetic marker of uric acid levels discovered so far, interacts with ADMA in determining the risk for CKD progression in CKD patients. This synergic interaction conforms to biological knowledge indicating that disturbed NO bio-availability is a critical pathway whereby life time exposure to high uric acid may engender renal damage.

Pro- and anti-inflammatory cytokine gene expression in subcutaneous and visceral fat in severe obesity.

BACKGROUND AND AIMS: Pro-inflammatory molecules produced by adipose tissue have been implicated in the risk of cardiovascular (CV) disease in obesity. We investigated the expression profile of 19 pro-inflammatory and seven anti-inflammatory genes in subcutaneous adipose tissue (SAT) and in visceral adipose tissue (VAT) in 44 severely obese individuals who underwent bariatric surgery. METHODS AND RESULTS: SAT and VAT expressed an identical series of pro-inflammatory genes. Among these genes, 12 were significantly more expressed in SAT than in VAT while just one (IL18) was more expressed in VAT. The remaining genes were equally expressed. Among pro-inflammatory cytokines, both IL6 and IL8 were about 20 times more intensively expressed in SAT than in VAT. The expression of nine genes was highly associated in SAT and VAT. Only for three pro-inflammatory cytokines (IL8, IL18, SAA1) in SAT the gene expression in adipose tissue associated with the circulating levels of the corresponding gene products while no such an association was found as for VAT. CONCLUSIONS: The expression of critical pro-inflammatory genes is substantially higher in SAT than in VAT in individuals with morbid obesity. The variability in circulating levels of pro-inflammatory cytokines is, in small part and just for three pro-inflammatory cytokines, explained by underlying gene expression in SAT but not in VAT. These results point to a compartment-specific adipose tissue contribution to inflammation in obesity and indicate that abdominal SAT contributes more than VAT to the pro-inflammatory milieu associated with severe obesity.