Gout in the spotlight.

Understanding how uric acid crystals provoke inflammation is crucial to improving our management of acute gout. It is well known that urate crystals stimulate monocytes and macrophages to elaborate inflammatory cytokines, but the tissue response of the synovium is less well understood. Microarray analysis of mRNA expression by these lining cells may help to delineate the genes that are modulated. Employing a murine air-pouch model, a number of genes expressed by innate immune cells were found to be rapidly upregulated by monosodium urate crystals. These findings provide new research avenues to investigate the physiopathology of gouty inflammation, and may eventually lead to new therapeutic targets in acute gout.

Physiological changes in Biomphalaria glabrata say, 1818 (Pulmonata: Planorbidae) caused by sub-lethal concentrations of the latex of Euphorbia splendens var. hislopii N.E.B (Euphorbiaceae)

Molluscides have been used as one of the strategies to control schistosomiasis. Many plant extracts with molluscidal effects have been tested, but the action of the latex of Euphorbia splendens var. hislopii is considered the most promising because it meets the recommendations of the World Health Organization (WHO). The objective of this study was to determine the lethal dose and identify the effects of the different doses of latex of E. splendens var. hislopii on the physiology of Biomphalaria glabrata submitted to treatment for 24 h. The concentrations of glucose, uric acid and total proteins in the hemolymph and of glycogen in the digestive gland and cephalopodal mass were determined. The LD50 value was 1 mg/l. The highest escape index was found to be at a concentration of 0.6 mg/l. The results showed that the latex of E. splendens var. hislopii caused a sharp reduction in the reserves of glycogen in the digestive gland and elevation of the protein content in the hemolymph of B. glabrata.

The role of platelet and plasma markers of antioxidant status and oxidative stress in thrombocytopenia among patients with vivax malaria

Malaria remains an important health problem in tropical countries like Brazil. Thrombocytopenia is the most common hematological disturbance seen in malarial infection. Oxidative stress (OS) has been implicated as a possible mediator of thrombocytopenia in patients with malaria. This study aimed to investigate the role of OS in the thrombocytopenia of Plasmodium vivax malaria through the measurement of oxidant and antioxidant biochemical markers in plasma and in isolated platelets. Eighty-six patients with P. vivax malaria were enrolled. Blood samples were analyzed for total antioxidant and oxidant status, albumin, total protein, uric acid, zinc, magnesium, bilirubin, total thiols, glutathione peroxidase (GPx), malondialdehyde (MDA), antibodies against mildly oxidized low-density lipoproteins (LDL-/nLDL ratio) and nitrite/nitrate levels in blood plasma and GPx and MDA in isolated platelets. Plasma MDA levels were higher in thrombocytopenic (TCP) (median 3.47; range 1.55-12.90 µmol/L) compared with the non-thrombocytopenic (NTCP) patients (median 2.57; range 1.95-8.60 µmol/L). Moreover, the LDL-/nLDL autoantibody ratio was lower in TCP (median 3.0; range 1.5-14.8) than in NTCP patients (median 4.0; range 1.9-35.5). Finally, GPx and MDA were higher in the platelets of TPC patients. These results suggest that oxidative damage of platelets might be important in the pathogenesis of thrombocytopenia found in P. vivax malaria as indicated by alterations of GPx and MDA.

Oxidative stress is increased in critically ill patients according to antioxidant vitamins intake, independent of severity: a cohort study

Introduction. Critically ill patients suffer from oxidative stress caused by reactive oxygen species (ROS) and reactive nitrogen species (RNS). Although ROS/RNS are constantly produced under normal circumstances, critical illness can drastically increase their production. These patients have reduced plasma and intracellular levels of antioxidants and free electron scavengers or cofactors, and decreased activity of the enzymatic system involved in ROS detoxification. The pro-oxidant/antioxidant balance is of functional relevance during critical illness because it is involved in the pathogenesis of multiple organ failure. In this study the objective was to evaluate the relation between oxidative stress in critically ill patients and antioxidant vitamin intake and severity of illness. Methods. Spectrophotometry was used to measure in plasma the total antioxidant capacity and levels of lipid peroxide, carbonyl group, total protein, bilirubin and uric acid at two time points: at intensive care unit (ICU) admission and on day seven. Daily diet records were kept and compliance with recommended dietary allowance (RDA) of antioxidant vitamins (A, C and E) was assessed. Results. Between admission and day seven in the ICU, significant increases in lipid peroxide and carbonyl group were associated with decreased antioxidant capacity and greater deterioration in Sequential Organ Failure Assessment score. There was significantly greater worsening in oxidative stress parameters in patients who received antioxidant vitamins at below 66% of RDA than in those who received antioxidant vitamins at above 66% of RDA. An antioxidant vitamin intake from 66% to 100% of RDA reduced the risk for worsening oxidative stress by 94% (ods ratio 0.06, 95% confidence interval 0.010 to 0.39), regardless of change in severity of illness (Sequential Organ Failure Assessment score). Conclusion. The critical condition of patients admitted to the ICU is associated with worsening oxidative stress. Intake of antioxidant vitamins below 66% of RDA and alteration in endogenous levels of substances with antioxidant capacity are related to redox imbalance in critical ill patients. Therefore, intake of antioxidant vitamins should be carefully monitored so that it is as close as possible to RDA.

Determinants and burden of chronic kidney disease in the population-based CoLaus study: a cross-sectional analysis.

BACKGROUND: Chronic kidney disease (CKD) represents an increasing health burden. We present the population-based prevalence of CKD and compare the CKD Epidemiology collaboration (CKD-EPI) and modification of diet in renal disease (MDRD) equations to estimate the glomerular filtration rate, using the revised CKD classification with three albuminuria classes. We also explore factors associated with CKD. METHODS: The Swiss population-based, cross-sectional CoLaus study conducted in Lausanne (2003-2006) included 2810 men and 3111 women aged 35-75. CKD prevalence was assessed using CKD-EPI and MDRD equations and albuminuria estimated by the albumin-to-creatinine ratio in spot morning urine. Multivariate logistic regression was used to analyse determinants of CKD. RESULTS: Prevalence [95% confidence interval (CI)] of all stages CKD was 10.0% (9.2-10.8%) with CKD-EPI and 13.8% (12.9-14.6%) with MDRD. Using the revised CKD classification, the prevalence of low-, medium-, high- and very high-risk groups was 90.0, 8.46, 1.18 and 0.35% with CKD-EPI, respectively. With MDRD, the corresponding values were 86.24, 11.86, 1.55 and 0.35%. Using the revised classification, CKD-EPI systematically reclassified people in a lower risk category than MDRD. Age and obesity were more strongly associated with CKD in men [odds ratio (95% CI): 2.23(1.95; 2.56) per 10 years and 3.05(2.08;4.47), respectively] than in women [1.46 (1.29; 1.65) and 1.78 (1.30;2.44), respectively]. Hypertension, type 2 diabetes, serum homocysteine and uric acid were positively independently associated with CKD in men and women. CONCLUSIONS: One in 10 adults suffers from CKD in the population of Lausanne. CKD-EPI systematically reclassifies people in a lower CKD risk category than MDRD. Serum homocysteine and uric acid levels are associated with CKD independently of classical risk factors such as age, hypertension and diabetes.

Circulating antioxidant defences are decreased in healthy people after a high-fat meal.

The aim of this study was to examine the responses of uric acid, antioxidant defences and pro-oxidant variables after a high-fat meal. Twenty-five healthy persons without criteria for the metabolic syndrome, underwent a high-fat meal with Supracal (60 g fat). Measurements were made at baseline and 3 h after the meal of TAG, uric acid, HDL-cholesterol, total proteins and oxidative stress. Following the high-fat meal, we detected a significant increase in pro-oxidative variables and a decrease in antioxidative variables. The uric acid concentrations were significantly lower after the high-fat meal and the reduction correlated significantly with the oxidative stress variables. The inverse relation between reduced uric acid and increased carbonylated proteins remained in multiple regression analysis. We conclude that uric acid is a powerful antioxidant and its reduction following a high-fat meal may be related with its acute antioxidative action.

Accumulation of scandium in plasma in patients with chronic renal failure.

Scandium (Sc) is an element with many industrial applications, but relatively little is known about its physiological and/or toxicological effects, and very little data are available concerning the role of Sc in chronic renal failure (CRF). This paper examines the changes in plasma levels of Sc in predialysis patients with CRF and the relationship with blood parameters. The participants in this trial were 48 patients with CRF in predialysis and 53 healthy controls. Erythrocyte, haemoglobin, and haematocrit counts in blood were determined, and levels of creatinine, urea, uric acid, albumin, total protein and Sc were measured in plasma. The glomerular filtration rate (GFR) was calculated using the Cockcroft-Gault index. The CRF patients were found to have higher plasma levels of creatinine, urea, uric acid, albumin, total protein, and Sc and a lower GFR than that the controls. Scandium in plasma was positively correlated with creatinine and plasma urea and negatively correlated with GFR, haemoglobin, and haematocrit and was associated with the risk of lower levels of erythrocytes, haemoglobin, and haematocrit. CRF was associated with increases in the circulating levels of scandium.

Insuffisance rénale terminale d'origine lithiasique : fréquence, causes et prévention [Nephrolithiasis-induced ESRD: frequency, causes and prevention].

Nephrolithiasis still remains a too frequent - and under-appreciated - cause of end-stage renal disease (ESRD), and this is all the most unfortunate since such an untoward course is now preventable in most cases. Among 1391 patients who started maintenance dialysis at Necker hospital between 1989 and 2000, nephrolithiasis was identified as the cause of ESRD in 45 of them, an overall prevalence of 3.2%. Infection stones accounted for 42.2% of cases, calcium stones for 26.7%, uric acid stones for 17.8% and hereditary diseases for 13.3%. The proportion of nephrolithiasis-associated ESRD declined from 4.7% to 2.2% from the 1989-1991 to the 1998-2000 period, as a result of the decreased incidence of ESRD in patients with infection and calcium nephrolithiasis. Based on our observations and on published reports, it emerges that most cases of nephrolithiasis-associated ESRD were due to sub-optimal management (especially in the case of infection or cystine stones) or to late (or erroneous) etiologic diagnosis, precluding early institution of appropriate therapeutic measures. In particular, several patients with primary hyperoxaluria or 2,8-dihydroxyadeninuria were diagnosed while already on dialysis or after unsuccessful kidney transplantation, due to wrong initial diagnosis. In conclusion, thanks to recent advances in diagnosis and management of stone formers, ESRD should now be prevented in the great majority of patients, at the condition of early etiologic diagnosis based on accurate morphoconstitutional analysis of calculi and metabolic evaluation, and early implementation of appropriate preventive medical treatment.

Association between obesity indices and cardiovascular risk factors in late adolescence in the Seychelles.

ABSTRACT: BACKGROUND: The ability of different obesity indices to predict cardiovascular risk is still debated in youth and few data are available in sub Saharan Africa. We compared the associations between several indices of obesity and cardiovascular risk factors (CVRFs) in late adolescence in the Seychelles. METHODS: We measured body mass index (BMI), waist circumference, waist/hip ratio (WHiR), waist/height ratio (WHtR) and percent fat mass (by bioimpedance) and 6 CVRFs (blood pressure, LDL-cholesterol, HDL-cholesterol, triglycerides, fasting blood glucose and uric acid) in 423 youths aged 19-20 years from the general population. RESULTS: The prevalence of overweight/obesity and several CVRFs was high, with substantial sex differences. Except for glucose in males and LDL-cholesterol in females, all obesity indices were associated with CVRFs. BMI consistently predicted CVRFs at least as well as the other indices. Linear regression on BMI had standardized regression coefficients of 0.25-0.36 for most CVRFs (p<0.01) and ROC analysis had an AUC between 60%-75% for most CVRFs. BMI also predicted well various combinations of CVRFs: 36% of male and 16% of female lean subjects (BMI P90). CONCLUSION: There was an elevated prevalence of obesity and of several CVRFs in youths in Seychelles. BMI predicted single or combined CVRFs at least as well as other simple obesity indices.

Neue Erkenntnisse zur Pathophysiologie und Therapie der Gicht [New knowledge on the pathophysiology and therapy of gout]

Gout is caused by the deposition of monosodium urate crystals (MSU) in tissue and provokes a local inflammatory reaction. It is the most common form of inflammatory arthritis in the elderly. The formation of MSU crystals is facilitated by hyperuricemia. In the last two decades, both hyperuricemia and gout have increased markedly and similar trends in the epidemiology of the metabolic syndrome have been observed. Recent studies provide new insights into uric acid metabolism in the kidneys as well as possible links between hyperuricemia and hypertension. MSU crystals provoke inflammation by activating leukocytes to produce inflammatory cytokines and other inflammatory mediators. The uptake of MSU crystals by monocytes involves interactions with Toll-like receptors (TLR-2 and TLR-4) and CD14, components of the innate immune system. Intracellularly, MSU crystals activate inflammasomes to activate pro-IL-1 (interleukin 1) processing to yield mature IL-1beta. The inflammatory effects of MSU are IL-1-dependent and can be blocked by IL-1 inhibitors. These advances provide new therapeutic targets to treat hyperuricemia and gout.

Clustering of cardiovascular risk factors mimicking the human metabolic syndrome X in eNOS null mice.

AIMS/HYPOTHESIS: The metabolic syndrome comprises a clustering of cardiovascular risk factors but the underlying mechanism is not known. Mice with targeted disruption of endothelial nitric oxide synthase (eNOS) are hypertensive and insulin resistant. We wondered, whether eNOS deficiency in mice is associated with a phenotype mimicking the human metabolic syndrome. METHODS AND RESULTS: In addition to arterial pressure and insulin sensitivity (euglycaemic hyperinsulinaemic clamp), we measured the plasma concentration of leptin, insulin, cholesterol, triglycerides, free fatty acids, fibrinogen and uric acid in 10 to 12 week old eNOS-/- and wild type mice. We also assessed glucose tolerance under basal conditions and following a metabolic stress with a high fat diet. As expected eNOS-/- mice were hypertensive and insulin resistant, as evidenced by fasting hyperinsulinaemia and a roughly 30 percent lower steady state glucose infusion rate during the clamp. eNOS-/- mice had a 1.5 to 2-fold elevation of the cholesterol, triglyceride and free fatty acid plasma concentration. Even though body weight was comparable, the leptin plasma level was 30% higher in eNOS-/- than in wild type mice. Finally, uric acid and fibrinogen were elevated in the eNOS-/- mice. Whereas under basal conditions, glucose tolerance was comparable in knock out and control mice, on a high fat diet, knock out mice became significantly more glucose intolerant than control mice. CONCLUSIONS: A single gene defect, eNOS deficiency, causes a clustering of cardiovascular risk factors in young mice. We speculate that defective nitric oxide synthesis could trigger many of the abnormalities making up the metabolic syndrome in humans.

Hyperhomocysteinemia is independently associated with albuminuria in the population-based CoLaus study.

Increased serum levels of homocysteine and uric acid have each been associated with cardiovascular risk. We analyzed whether homocysteine and uric acid were associated with glomerular filtration rate (GFR) and albuminuria independently of each other. We also investigated the association of MTHFR polymorphisms related to homocysteine with albuminuria to get further insight into causality. This was a cross-sectional population-based study in Caucasians (n = 5913). Hyperhomocysteinemia was defined as total serum homocysteine ≥ 15 μmol/L. Albuminuria was defined as urinary albumin-to-creatinine ratio > 30 mg/g. Uric acid was associated positively with homocysteine (r = 0.246 in men and r = 0.287 in women, P < 0.001). The prevalence of albuminuria increased across increasing homocysteine categories (from 6.4% to 17.3% in subjects with normal GFR and from 3.5% to 14.5% in those with reduced GFR, P for trend < 0.005). Hyperhomocysteinemia (OR = 2.22, 95% confidence interval: 1.60-3.08, P < 0.001) and elevated serum uric acid (OR = 1.27, 1.08-1.50, per 100 μmol/L, P = 0.004) were significantly associated with albuminuria, independently of hypertension and type 2 diabetes. The 2-fold higher risk of albuminuria associated with hyperhomocysteinemia was similar to the risk associated with hypertension or diabetes. MTHFR alleles related to higher homocysteine were associated with increased risk of albuminuria. In the general adult population, elevated serum homocysteine and uric acid were associated with albuminuria independently of each other and of renal function.

Serum calcium levels are associated with novel cardiometabolic risk factors in the population-based CoLaus study.

BACKGROUND: Associations of serum calcium levels with the metabolic syndrome and other novel cardio-metabolic risk factors not classically included in the metabolic syndrome, such as those involved in oxidative stress, are largely unexplored. We analyzed the association of albumin-corrected serum calcium levels with conventional and non-conventional cardio-metabolic risk factors in a general adult population. METHODOLOGY/PRINCIPAL FINDINGS: The CoLaus study is a population-based study including Caucasians from Lausanne, Switzerland. The metabolic syndrome was defined using the Adult Treatment Panel III criteria. Non-conventional cardio-metabolic risk factors considered included: fat mass, leptin, LDL particle size, apolipoprotein B, fasting insulin, adiponectin, ultrasensitive CRP, serum uric acid, homocysteine, and gamma-glutamyltransferase. We used adjusted standardized multivariable regression to compare the association of each cardio-metabolic risk factor with albumin-corrected serum calcium. We assessed associations of albumin-corrected serum calcium with the cumulative number of non-conventional cardio-metabolic risk factors. We analyzed 4,231 subjects aged 35 to 75 years. Corrected serum calcium increased with both the number of the metabolic syndrome components and the number of non-conventional cardio-metabolic risk factors, independently of the metabolic syndrome and BMI. Among conventional and non-conventional cardio-metabolic risk factors, the strongest positive associations were found for factors related to oxidative stress (uric acid, homocysteine and gamma-glutamyltransferase). Adiponectin had the strongest negative association with corrected serum calcium. CONCLUSIONS/SIGNIFICANCE: Serum calcium was associated with the metabolic syndrome and with non-conventional cardio-metabolic risk factors independently of the metabolic syndrome. Associations with uric acid, homocysteine and gamma-glutamyltransferase were the strongest. These novel findings suggest that serum calcium levels may be associated with cardiovascular risk via oxidative stress.

The inflammasomes: guardians of the body.

The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and to eliminate them. The discovery of Toll-like receptors (TLRs) provided a class of membrane receptors that sense extracellular microbes and trigger antipathogen signaling cascades. More recently, intracellular microbial sensors have been identified, including NOD-like receptors (NLRs). Some of the NLRs also sense nonmicrobial danger signals and form large cytoplasmic complexes called inflammasomes that link the sensing of microbial products and metabolic stress to the proteolytic activation of the proinflammatory cytokines IL-1beta and IL-18. The NALP3 inflammasome has been associated with several autoinflammatory conditions including gout. Likewise, the NALP3 inflammasome is a crucial element in the adjuvant effect of aluminum and can direct a humoral adaptive immune response. In this review, we discuss the role of NLRs, and in particular the inflammasomes, in the recognition of microbial and danger components and the role they play in health and disease.