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Daria Pasalic1*, Natalija Marinkovic2, Lana Feher-Turkovic3. Uric acid as one of the important factors in multifactorial disorders – facts and controversies. Biochemia Medica 2012;22(1):63-75. http://dx.doi.org/10.11613/BM.2012.007
1Department of Chemistry, Biochemistry and Clinical Chemistry, University of Zagreb, School of Medicine, Zagreb, Croatia
2Quintiles Zagreb Ltd., Zagreb, Croatia
3Department of Chemistry, Biochemistry and Clinical Chemistry, University of Applied Health Studies, Zagreb, Croatia
*Corresponding author: daria [dot] pasalic [at] mef [dot] hr
With considering serum concentration of the uric acid in humans we are observing hyperuricemia and possible gout development. Many epidemiological studies have shown the relationship between the uric acid and different disorders such are obesity, metabolic syndrome, hypertension and coronary artery disease. Clinicians and investigators recognized serum uric acid concentration as very important diagnostic and prognostic factor of many multifactorial disorders. This review presented few clinical conditions which are not directly related to uric acid, but the concentrations of uric acid might have a great impact in observing, monitoring, prognosis and therapy of such disorders. Uric acid is recognized as a marker of oxidative stress. Production of the uric acid includes enzyme xanthine oxidase which is involved in producing of radical-oxigen species (ROS). As by-products ROS have a significant role in the increased vascular oxidative stress and might be involved in atherogenesis. Uric acid may inhibit endothelial function by inhibition of nitric oxide-function under conditions of oxidative stress. Down regulation of nitric oxide and induction of endothelial dysfunction might also be involved in pathogenesis of hypertension. The most important and well evidenced is possible predictive role of uric acid in predicting short-term outcome (mortality) in acute myocardial infarction (AMI) patients and stroke. Nephrolithiasis of uric acid origin is significantly more common among patients with the metabolic syndrome and obesity. On contrary to this, uric acid also acts is an ''antioxidant'', a free radical scavenger and a chelator of transitional metal ions which are converted to poorly reactive forms.
Key words: atherosclerosis; hypertension; hyperuricemia; metabolic syndrome; uric acid
Received: May 31, 2011 Accepted: December 23, 2011
Uric acid is a weak organic acid, the end product of purine nucleotides degradation (1). Source of purine nucleotides are ingestion, endogenous synthesis of purines from nonpurine precursors, and reutilization of preformed purine compounds (2). Degradation of purine nucleotides (Figure 1) starts with nucleotidase activity in reaction which releases phosphate from nucleotides and produces nucleosides, adenosine and guanosine (3). Adenosine is than deaminated into inosine in reaction catalyzed by adenosine deaminase. Purine nucleotide phosphorilase hydrolyses ribose group from inosine and guanosine to produce xypoxantine and guanine, respectively (3). Guanine is deaminated to xsantine. Xantine oxidoreductase is widely distributed enzyme. It oxidases hypoxantine to xsantine, and finally xantine to uric acid in the liver, gut, lung, kidney, heart, brain and plasma (4).
Figure 1. Degradation of purine nucleotides and formation of uric acid. 1 - Nucleotidase; 2 - Adenosine deaminase; 3 - Inosine phosphorilase; 4 - Xsanthine oxidase; 5 - Purine nucleosidase phosphorilase; 6 - Guanine deaminase.
Under the steady-state conditions the production of uric acid is in balance with the uric acid disposal (5). Deposition of monosodium urate monohydrate microcrystals or uric acid in various parts of the body leads to the development of gout, common painful rheumatic disease (6).Gout is not only disorder which might have altered concentrations of serum uric acid (SUA). The enzymes involved in uric acid production are also responsible for oxidative stress (1) and it was evidenced that SUA might be dependently or independently related to different multifactorial disordes. Elevated SUA positively correlates with development and progression of cardiovascular diseases (7). There is an evidence of positive association between SUA and risk of major coronary heart disease events. SUA is significantly positive correlated with hypertension and renal diseases (8). Nephrolithiasis of uric acid origin, as well as hyperuricemia, is more common among patients with the metabolic syndrome (MetS) and obesity (9).There is also a controversial opinion about prooxidative and antioxidant properties of uric acid.Uric acid is a powerful free radical scavenger in humans (10) but it also represents a marker for high levels of damaging oxidative stress associated with increased xanthine oxidase activity (11). Because of all mentioned facts, it is reasonable to determinate SUA concentrations in different conditions.
Determination of uric acid concentration includes phosphotungistic acid methods, uricase methods (in wide usage), high-performance liquid chromatograpy methods (reference methods) and dry chemistry systems (12).
The subject of this review is to present: a) different conditions with observed hyperuricemia; b) correlations and causal connections of uric acid and different disorders like cardiovascular and cerebrovascular diseases, hypertension and metabolic syndrome; c) the protective and pathogenic role of uric acid in those conditions; and d) advantage for widespread determination of uric acid.
Uric acid precipitation and gout
Gout is common painful rheumatic disease, resulting from the deposition of monosodium urate monohydrate microcrystals or uric acid in various parts of the body, primarily in joints and surrounding tissues due to overproduction or underexcretion of poorly soluble uric acid which is the end product of endogenous and dietary purine metabolism in humans (6). Uric acid ionizes with pKa at pH 5.75 (6). In the extracellular fluid, at physiological pH of 7.4, uric acid is mainly in the ionized form of urate, while in the urine, which is usually acidic, the un-ionized uric acid form predominates (13). Risk for crystal formation and precipitation increases when urate concentrations exceed 380 μmol/L. Uric acid concentration is controlled by synthesis and cell turnover and in the other hand by the rate of destruction, excretion and reabsorption by the kidney. In urine, at pH 5.0, predominates undissociated uric acid formed from urinary urate in the renal tubule. In healthy individuals two-thirds of uric acid is excreted by the kidney and one-third by the intestine with breakdown of urate by gut bacteria. Purine ingestion, endogenous synthesis of purines from nonpurine precursors, and reutilization of preformed purine compounds are the sources of urate production, an overall process that under steady-state conditions is in balance with the uric acid disposal (2). Human and higher primates lack peroxisomal enzyme urate oxidase (uricase) (14) that catalyzes degradation of uric acid to more soluble product allantoin that is easily eliminated by renal excretion in the most other mammals because the genes for uricase have mutated and become dysfunctional (15). Consequently, serum urate levels in humans are to its limit of solubility. Hyperuricaemia is a risk factor for gout, but gout can occur where serum uric acid levels are low (16). Also, individual can have uric acid concentrations above normal and not have gout. The prevalence of gout varies with age and gender, and is more common in older individuals (16). Gout is more common in men than in women, but women become increasingly susceptible to gout after menopause because of increased uricemia parallel with decreasing of estrogen levels (17). Risk factors for gout are also obesity, metabolic syndrome, diuretic therapy, high-purine diet and alcohol intake. Gout can be classified as primary or secondary, depending on the presence / absence of an identified cause of hyperuricemia. Primary gout is more common, without identifiable underlying disease causing of the hyperuricemia (18). Secondary gout, which is less common, can be a result of many conditions (6,19). Alcohol intoxication causes lactic acidemia and reduces renal urate excretion (19). Thiazide and loop diuretics (antihypertensives), increase serum urate levels by interfering with renal tubular ion transport (19). Several immunosuppressant like cyclosporine, used in patients undergoing solid organ transplantation, substantially reduces the renal clearance of serum urate (19). Malignant diseases are characterized with intensive purine metabolism which might lead to hyperuricemia and gout. In patient with renal failure, hyperuricemia is, behind the other, one of characteristic caused by impaired kidney function (20). Gout can be the consequence of hereditary interstitial kidney disease, because of renal failure which is caused with this hereditary disorder (21).
SUA concentration might be decreased by usage of a number of pharmacologic agents, dietary and other risk factor modifications. Gout management is very difficult because gout and hyperuricemia may have a great impact in some co morbidities, but on contrary higher urate levels potentially have some beneficial effects (22). Namely, uric acid itself may serve as an immune system stimulant, urate is a potent antioxidant, it helps to maintain blood pressure in a salt-poor environment and it impliessome benefits in several disease of central nervous system, probably because of its antioxidant properties (22).
It is also important to define if hyperuricemia and gout are either a consequence or a cause of these related conditions. The treatment of gout includes the changes in lifestyle, nutrition, and adjunctive therapies as well as different classes of drugs which are approved for lowering urate levels: xanthine oxidase inhibitors, uricosuric agents, uricase agents and some which are still under development, such are inhibitors of urate transporter, purine nucleoside phosphorylase and interleukin-1 antagonists (23). The safety and efficacy of combination therapies for the treatment of gout still remained unclear. Unfortunately, lowering of urate concentration does not relive gout symptoms and urate-lowering efficacy is poor as well as clinical outcomes in gout patients (24). Hyperuricemia with gout, isolated gout without hyperiuricemia or hyperuricemia without gout are conditions which require ordinarily monitoring. Therapy indications, as well as changes in lifestyle, depend also on the other risk factors.
Uric acid and oxidative stress
Oxidative stress is considered to be one of the main reasons of cells function impairment. It is a condition of excessive production of free radicals and reactive oxygen species (ROS), as well as reduced antioxidative system, due to decreased intake of antioxidants or their excessive consumption (25). It is also a condition in which oxido-reductive processes in cells are turned in favor of oxidation due to excessive formation of free radicals and reactive oxygen species (ROS) (25). Uric acid is a product of purine nucleotides catabolism in the process catalyzed by liver enzyme xanthine oxidoreductase (XOR), which enables the oxidation of hypoxanthine to xanthine and its further oxidation to uric acid (26). During the production of uric acid catalyzed by xsanthine-oxidase, ROS are generated as by product,which have a significant role in the increased vascular oxidative stress (26).
XOR is a hepatic enzyme which catalyzes the production of uric acid, nitric oxide, and reactive oxygen species, which potentially damage deoxyribonucleic acid, ribonucleic acid and proteins, inactivate enzymes, oxidize amino acids and convert poly-unsaturated fatty acids to lipids (27). XOR exists in two inter-convertible forms: XO-xantine oxidase and XDH-xanthine dehydrogenase (1,28). Humane XOR exists in vivo as the dehydrogenase form but is easily converted to XO by oxidation of the sulfhydryl residues or by proteolysis (4).There is the difference in substrate affinity of XO and XDH subforms (Table 1). XDH preferentially reduces NAD+, whereas XO cannot reduce NAD+, preferring molecular oxygen (28).Reduction of molecular oxygen by either form of the enzyme yields superoxide and hydrogen peroxide (1,4,28), Uric acid is recognized as a marker of oxidative stress, but also as a protective factor acting as an antioxidant (10,29).
Table 1. Xanthine oxidoreductase (XOR) isoforms and characteristic reactions (4,28).
Regarding XO role in oxidative stress and pathophysiology of CVD, most therapeutic approaches are oriented on inhibiting the XO activity and disabling free radicals accumulation as a feasible target. Some studies showed that therapeutic use of allopurinol, xanthine oxidase inhibitor, which reduces serum levels of uric acid, show protective effects in situations associated with oxidative stress (27,30), because of decreasing of ROS. In clinical studies, for example in coronary bypass surgery, the protective effects of allopurinol are noticed as decreasedhospital mortality rate, increased cardiac index, better postoperative recovery and reduced lipid peroxidation (4). In heart failure allopurinol improves myocardial contractility by restoring myocardial calcium sensitivity and β-adrenergic responsiveness (31). The other explanation of benefitial allopurinol effect considers the effects on vascular endothelial function. Xanthine oxidase plays a key role in mediating intermittent hypoxia-induced vascular dysfunction and administration of allopurinol might prevent it (32). The investigations on animal models in the most cases also confirmed the beneficial effect of allopurinol after induction of myocardial infarction (4) with reducing myocardial damage, better recovery of ventricular function, better preservation of cellular ATP levels and mitochondrial ATP generation during ischemia and prevention of the decrease in left ventricular pressure. The beneficial effects of allopurinol may be unrelated to the inhibition of the XO, and decreasing the free radicals.The effects of allopurinol action as a xanthine-oxidase inhibitor are increasing of intermediates, hypoxanthine and xanthine, and decreasing of final product uric-acid (33). Taking into account that xanthine derivatives are widely used medicaments in treatment of different disease (inflammatory diseases, behavioral, neurodegenerative diseases, renal diseases, respiratory diseases, cancer pain etc, (34) the effect of xanthine or hypoxhantine should be considered in explanations of the mechanisms involved in effects of XOR inhibition (35).It is well known that widely used and examinated xanthine derivative is caffeine. The biological effects of caffeine and other xanthines have many molecular targets. Xanthines are antagonists of adenosine receptors, inhibitors of phosphodiesterases, antagonists of GABA receptors and sensibilators of calcium releaseryanodine-sensitive channels in the sarcoplasmic and endoplasmic reticulum (34). It appeared that caffeine also has stimulatory effects on Mg-ATPase and calcium sensitivity in cardiac myofibrils (36).
Uric acid itself also can have an impact in oxidative stress. Experimental data showed that NO- labeled 1,3-15N2-uric acid (15N2-UA) under anaerobic conditions in several different media, including human plasma and endothelial cell lysates results with production of 5-aminouracil (5-AU) and 6-aminouracil (6-AU) (37). These findings provide a mechanism for how uric acid may inhibit endothelial function by inhibition of NO-function under conditions of oxidative stress (37). Recent clinical studies demonstrated that high-dose allopurinol usage was associated with a lower risk of cardiovascular events and all-cause mortality (38), and that profoundly reduces vascular tissue oxidative stress and improves vascular/endothelial dysfunction (39).
Elevated serum concentration of uric acid are associated with increased risk for cardiovascular disease (CVD) (40), but there are also evidence of their potential role as antioxidants in CVD (41). Some protective and pathogenic roles of uric acid are summarized in table 2. Uric acid acts as an ''antioxidant'' substance with acting as a free radical scavenger and a chelator of transitional metal ions which are converted to poorly reactive forms (42).Both in vitro and in vivo studies confirmed that uric acid is a powerful free radical scavenger in humans (10). Antioxidant properties of uric acid could be expected to offer a number of benefits within the cardiovascular system or other oxidative stress related disorders. Thus, the role of high uric acid levels (supportive or protective) in development of cardiovascular disease is still unclear, and the explanations lie in different approach of in vitro experimental studies, as well as in different design of clinical studies.
Table 2. Some protective and pathogenic roles of uric acid (1,8,30).
The role of uric acid in cardiovascular and cerebrovascular disorders
Pathophisiology of atherosclerosis and its consequences coronary artery disease, cererebrovascular disease and finally acute myocardial infarction (AMI) and stroke are related to oxidative stress. Interrelationship between concentrations of SUA and cardiovascular or cerebrovascular diseases has been observed for a long time. Most of the cardiovascular risk factors are in potentially overlapping with SUA concentrations (43-45). The positive association of hyperuricemia with obesity, impaired glucose tolerance, hypertension and history of heart disease was observed on a large Finland cohort population (aged 40-69) (43). The study also showed significantly higher total mortality of hyperuricemic men and women in 5 years than in normouricemics (43). Retrospective analysis of general Italian population (N = 10,181) showed that study subjects with hyperuricemia were characterized by significantly higher prevalence of abnormal values of fasting plasma glucose and triglycerides as compared to subjects with reference concentrations (45).
The most important and well evidenced is possible predictive role of uric acid in predicting short-term outcome (mortality) in AMI patients and stroke (43,46).
Different prospective studies exploring the interrelationship between serum uric acid and cardiovascular outcomes in various categories of subjects are summarized by Strazzullo and Puig (30). In general conclusions, in population samples with relatively low risk of CVD, SUA is a very weak predictor of CVD, but it is a significant independent predictor among subjects at high or very high risk (30).Based on the study design it has been shown that hyperuricemia might be independent factor of cardiovascular events (46-48) primarily in subject groups with high cardiovascular risk (angiographically proven CHD,congestive heart failure and stroke survivors) (30). The first large prospective study was established on 83,683 Austrian men cohort who was prospectively followed for a median of 13.6 years (49). This investigation confirmed the independent relationship between elevated SUA and mortality from coronary heart failure and stroke, but the association of SUA with mortality from acute, subacute, or chronic forms of coronary heart disease (CHD) after adjustment for potential confounding factors was absent.
Cross-sectional population-based, follow-up study of epidemiological data (N = 5926 US-subjects, aged 25 to 74) showed that increased serum uric acid levels are independently and significantly associated with risk of cardiovascular mortality (46). In cross-sectional study on 982 Turkish patients,whom coronary angiography was performed for the suspicion of CAD (47), SUA concentrations wereindependently associated with the severity of coronary atherosclerotic plaques. In 212 Spanish patients, who were hospitalized because of acute HF and left ventricular systolic dysfunction, the presence of hyperuricemia was associated with a higher risk of death and/or new hospitalizations in the long-term, independently of ventricular function, renal function and functional ability (50). Results of some other studies, on contrary suggest that serum concentrations of uric acid were not an independent risk factor for CVD. In retrospective study, which included 716 Korean consecutive patients who underwent coronary angiography after adjusting for age, diabetes, smoking, cholesterol, and metabolic syndrome there were no independent association of SUA (51). Any apparent association with these outcomes is probably due to the association of uric acid level with other risk factors (52). This was shown especially in thestudies of general population and studies involving patients with history of arterial hypertension, which didn't show independent association with CVD (30). Different investigations also indicate that uric acid does not have a causal role in the development of coronary heart disease or death from CVD. The contribution of SUA in atherosclerosis development through effects on arterial calcification was absent in the multicentre American Family Heart Study on population-based cohorts in the US, which was designed to assess risk factors for heart disease, the association between SUA and carotid atherosclerotic plaques (53). It is evidenced that there is no consensus about its action in cardiovascular disease, although the confirmation of active participation of uric acid in heart failure exists (54). However, investigation based on large prospective studies and cross sectional follow-up studies confirmed the independent association of SUA with cardiovascular diseases. On contrary, retrospective studies, studies on general population and those performed on smaller number of study participants did not always provided the similar results.
Beside the study design, different observation results also might be explained on cellular level. Namely, there is a difference between uric acid in serum and intracellular uric acid or highly hydrophobic areas such are atherosclerotic plaquesand adipose tissue. Antioxidant activity is evidenced in serum while it seems that intracellular uric acid contributes in pathophysiology of heart failure (54).
It is evidenced from the literature data that these controversies are very interesting subject for discussion between different scientific groups (55,56). Conflicting conclusions of the different studies are the consequence of differences in the compositions of the population's studies (number, treatment, biochemical and clinical data), length of follow up, analysis of the different CAD-risk variables and corrections according those variables (49). Proctor et al. reported on the association between high urate levels and atherosclerosis. They state that hyperuricemia might have a protective role (antioxidant) or it could be a primary cause (pro-oxidant) in atherosclerosis (57). Protective role of uric acid has been established on animal model. Intraperitoneal injection of purine derivatives, caffeine or uric acid into male C57BL/6 mice significantly increased total glutathione (GSH) levels in the hippocampus (58). This study suggests that caffeine and uric acid induce neuronal GSH synthesis by promoting cysteine uptake, leading to neuroprotection (58). The clinical efficacy of uric acid as a protective antioxidant is currently under investigation in a Phase III trial because it was shown that co-administration of uric acid and recombinant tissue plasminogen activator provides synergistic neuroprotection in experimental thromboembolic models and protection of oxidative stress in patients with acute stroke (59,60).
It can be concluded that hyperuricemia is not directly responsible for vascular injury and increased risk for cerebrovascular disease but it simply represent a surrogate marker for high levels of damaging oxidative stress associated with increased xanthine oxidase activity (11). Indeed, hyperuricaemia is a significant predictor of disease state and progression of chronic heart failure (61). The assessment of UA is widely available at low cost, which may be an advantage for widespread determination of this marker. As it is preferably for biomarkers to fulfill the information for the evaluation of disease severity, prognosis and treatment (62) it is evidenced that uric acid determination is reasonable for heart failure. Manzano et al. have developed a novel risk model for elderly patients with heart failure which includes uric acid and left-atrial dimension and provide a reliable estimate of death or hospital admission rates over a 2-year follow-up period (63). This might help to identify higher risk patients who may benefit from more intensive treatment.
SUA and hypertension
Hypertension and increased SUA additionally complicate the controversies of uric acid role in cardiovascular events and the factors involved in pathogenesis of atherosclerotic consequences. Many clinical studies implicate on causative role of uric acid in hypertension (8,64). There are at least two aspects of interrelationships between hypertension and uric acid, molecular mechanisms and elimination pathways of urates.
For presentation of the first aspect we have reviewed a few clinical trials bellow. Randomized, double-blind, placebo-controlled, crossover trial involving 30 adolescents who had newly diagnosed, essential hypertension and SUA > 360 mmol/L and who were treated with allopurinol, resulted in reduction of blood pressure (65). Close association of new-onset essential hypertension in children; suggest that lowering of uric acid can lower blood pressure in some patients (66). SUA impacts blood pressure in pediatric hemodialysis patients, independent of volume, nutritional and weight status (67). The study on the Polish patients which was performed to evaluate the influence of allopurinol on blood pressure and aortic compliance in patients with arterial hypertension depending on hypotensive therapy with angiotensin-converting enzyme inhibitor (ACE-I) or thiazide diuretic, showed that allopurinol does not produce additional antihypertensive effects in patients with treated arterial hypertension (68). For understanding the mechanisms of uric acid roles either as a predictor or consequence, animal models has been investigated. In animal models it has been shown that induced mild hyperuricemia may contribute to endothelial dysfunction and reduction of nitric oxide (NO) levels (69). Uric acid causes hypertension in a rat model through the activation of the renin-angiotensin system, down regulation of nitric oxide, and induction of endothelial dysfunction and vascular smooth muscle proliferation (64). Some other studies showed that SUA protects against progression of hypertension in spontaneously hypertensive rats (70). Similarly to the vascular injury, understanding of the paradox should be pointed to metabolic pathway of uric acid production through xantine oxidase (1), as well as the differences between acting of uric acid inside the cells or in the extracellular milieu (71). We have already mentioned previously that uric acid acts as an antioxidant in extracellular fluid, while in cellular matrix exerts prooxidative effects (8,54).
It is well known how the impaired kidney function is involved in mechanisms of hypertension. The elimination of urate also depends on kidney function. The recent study on a large Korean cohort which determinate renal function and SUA levels showed that glomerular filtration rate negatively correlated with blood pressures, uric acid, fasting plasma glucose, lipid status and C-reactive protein and uric acid was found to be an independent factor associated with glomerular filtration rate (72).
2645 Greece systolic heart failure patients were involved in the Beta-Blocker Evaluation of Survival Trial (73). The results showed that hyperuricaemia might predict poor outcomes primary as a marker of increased xanthine oxidase activity. It confirmed significant association with poor outcomes in heart failure patients without chronic kidney disease (CKD) but not in those with CKD as a consequence of decreased renal excretion of uric acid (73).
Uric acid is primarily excreted via the urine. That excretion is dependent on a number of urate transporters, including urate transporter 1 (URAT1), organic ion transporters (OAT1 and OAT3) and ATP-dependent urate export transporters (MRP4) (74). Urate balance depends on those transporters activities. Transporter URAT 1 is responsible for the reabsorption of urate, which is normally 90% reabsorbed after glomerular filtration (75). When we are considering the influence of uric acid on hypertension it should be pointed to all factors which might be involved. Kidney function, functionality of the transporters, genetic polymorphisms of the transporters, factors of the oxidative stress have to be included in evaluation of interrelationships between hyperuricemia and hypertension. Impaired kidney function is responsible for many mechanisms involved in pathogenesis of hypertension, so the elevation of SUA might be one of them.
SUA and metabolic syndrome
It is well known that nephrolithiasis of uric acid origin is significantly more common among patients with the MetS, obesity and type 2 diabetes (9). Prevalence of metabolic abnormalities in Brazilian people with metabolic syndrome was associated with concentration of uric acid. After Roux-en-Y gastric bypass and consequently weight loss uric acid concentration were reduced (76). Lower urine pH was associated with an increase in waist circumference in over than thousand Japanese men (77). Waist circumference is a key feature for the metabolic syndrome and HOMA-R as an index of insulin resistance. Lower urine pH was also associated with an increase in BMI, and an increase in serum uric acid (77). SUA levels were significantly and negatively correlated with HDL-C in Korean males, but not in females but SUA levels increased significantly with an increasing number of MetS components and abdominal obesity in both genders (78). Elevated levels of uric acid in obese children, compared with lean subjects, at the prepubertal period, seems to be an early metabolic alteration that is associated with other features of insulin resistance syndrome (79). This might be explain with the presence of increased intracellular adenosine (uric acid precursor), a derivative of higher AMP concentrations due to increased synthesis of fatty acid-acyl-CoA in peripheral tissues (79), and the authors propose that in early obesity increased levels of uric acid are related to elevated plasma fatty acids. Molecular base for explanations of the interrelationship between hyperuricemia and MetS, we might also provide from high dietary carbohydrates intake especially for fructose or sucrose intake. On the other hand the animal model experiments showed that fructose feed rats vs. glucose feed rats, had higher body weight, blood pressure, and concentrations of insulin, uric acid and triglycerides (80).
Fructose enters hepatocytes and other cells (human and animal), where it is completely metabolized by fructokinase with the consumption of ATP, without negative regulatory mechanism to prevent the depletion of ATP like is in glucose metabolism. Lactic acid and uric acid are than generated in the process (81). Lowering of the urine pH is than the consequence of the organic acids accumulation. Metabolic fates of the fructose in the liver than increases the biosynthesis of endogenous triglyceride, VLDL excretion and LDL overproduction (82).
This also was confirmed in the clinical studies because it was shown that the reduction in serum uric acid correlated directly with the decrease in triglyceride levels (72). Any factor that may increase biosynthetic pathway in which ATP is consumed and adenilate is produces might be involved in overproduction of uric acid.
Severe and mild hyperuricemia have been recognized as an independent risk factor for endothelial dysfunction,flow-mediated vasodilatation of the brachial artery in subjects without MetS, whereas only severe hyperuricemia (but not mild hyperuricemia) appeared to exacerbate endothelial dysfunction in similar subjects with MetS in middle-aged healthy Japanese men (83).
The experiments on mice with targeted disruption of endothelial nitric oxide synthase (eNOS) showed that mice are hypertensive and insulin resistant. We have explained previously that uric acid may inhibit endothelial function by inhibition of NO-function under conditions of oxidative stress (37).
Measurement of uric acid concentration
Uric acid concentration might be measured in serum, plasma, urine (12) and in exhaled breath condensate (84). Determination of uric acid concentration includes phosphotungistic acid methods (PTA), uricase methods (in wide usage), high-performance liquid chromatography methods (reference methods), dry chemistry systems (12) and biosensor methods (85). PTA methods interfere with many endogenous and exogenous compounds. More specific and very low cost (less than 10 eurocents per analysis) are enzymatic methods with bacterial enzyme uricase, uricase- peroxidase standard method. Ascorbic acid and bilirubin interfere with urate determination, so the use of ascorbat oxidase and aminophenason is necessary (12). Up-to-date biosensor methods can also be used as a low-cost alternative to conventional methods (85).
Prior to determination of urate in urine, alkalinization of urine might be necessary, because of urate crystallize at pH lower than 5.75 (86). It is evidenced that uric acid concentrations are significantly associated with BMI, gender, glomerular filtration rate and hypertension (61). Many additional factors, including exercise (87), diet, drugs, and state of hydration, may result in transient fluctuations of uric acid levels (86). According to that the reference intervals for uric acid aren't equable, and there is no clear limit for hyperuricemia. So it is very important to document well the strategy and the individuals included in the reference interval (88).
Instead of its controversial role in pathogenesis of different disorders, uric acid may play an important role in diagnosis, prognostic and therapy monitoring. SUA is a good indicator of the oxidative stress which is involved in pathobiochemisty of cardiovascular disorders, obesity, impaired glucose tolerance, hypertension and hyperlipidemias (Table 3). Hyperuricemia is not directly responsible for vascular injury and increased risk for cardiovascular or cerebrovascular disease but simply represents a surrogate marker for high levels of damaging oxidative stress associated with increased xanthine oxidase activity. Indeed, hyperuricaemia is a significant predictor of disease state and progression of chronic heart failure. The assessment of UA is widely available at low cost, which may be an advantage for widespread determination of this marker.
Table 3. Disorders and mechanisms involved in hyperuricemia.
Uric acid is not only recognized as a marker of oxidative stress. It also has a protective role and acts an antioxidant which is involved in clinical investigations of therapy for cerebrovascular disorders in combination with the anticoagulants.
Potential conflict of interest
None declared.
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24. Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E, Lademacher C. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther 2010;12:R63.
25. Hussain SP, Hofseth LJ, Harris CC. Radical causes of cancer. Nat Rev Cancer 2003;3:276-85.
26. Schulz E, Gori T, Münzel T. Oxidative stress and endothelial dysfunction in hypertension. Hypertens Res 2011;34:665-73.
27. Riegersperger M, Covic A, Goldsmith D. Allopurinol, uric acid, and oxidative stress in cardiorenal disease. Int Urol Nephrol 2011;43:441-9.
28. Harrison R. Structure and function of xanthine oxidoreductase: where are we now? Free Radic Biol Med 2002;33:774-97.
29. Nabipour I, Sambrook PN, Blyth FM, Janu MR, Waite LM, Naganathan V, et al. Serum uric acid is associated with bone health in older men: A cross-sectional population-based study. J Bone Miner Res 2011;26:955-64.
30. Strazzullo P, Puig JG. Uric acid and oxidative stress: relative impact on cardiovascular risk? Nutr Metab Cardiovasc Dis 2007;17:409-14.
31. Saliaris AP, Amado LC, Minhas KM, Schuleri KH, Lehrke S, St John M, et al. Chronic allopurinol administration ameliorates maladaptive alterations in Ca2+ cycling proteins and β-adrenergic hyporesponsiveness in heart failure. Am J Physiol Heart Circ Physiol 2007;292:H1328-35.
32. Dopp JM, Philippi NR, Marcus NJ, Olson EB, Bird CE, Moran JJ, et al. Xanthine Oxidase Inhibition Attenuates Endothelial Dysfunction Caused by Chronic Intermittent Hypoxia in Rats. Respiration 2011;82:458-67.
33. Yamazaki I, Soma T, Ichikawa Y, Iwai Y, Kondo J, Matsumoto A. Usefulness of allopurinol for prevention of myocardial reperfusion injury in open heart surgery. Nippon Kyobu Geka Gakkai Zasshi 1995;43:26-31.
34. Daly JW. Caffeine analogs: biomedical impact. Cell Mol Life Sci 2007;64:2153-69.
35. Szentmiklósi AJ, Cseppentō A, Gesztelyi R, Zsuga J, Körtvély A, Harmati G, Nánási PP. Xanthine derivatives in the heart: blessed or cursed? Curr Med Chem 2011;18:3695-706.
36. Okafor C, Liao R, Perreault-Micale C, Li X, Ito T, Stepanek A, et al. Mg-ATPase and Ca2+ activated myosin ATPase activity in ventricular myofibrils from non-failing and diseased human hearts – effects of calcium sensitizing agents MCI-154, DPI 201 – 106, and caffeine. Mol Cell Biochem 2003;245:77-89.
37. Gersch C, Palii SP, Kim KM, Angerhofer A, Johnson RJ, Henderson GN. Inactivation of nitric oxide by uric acid. Nucleosides Nucleotides Nucleic Acids. 2008;27:967-78.
38. Wei L, Mackenzie IS, Chen Y, Struthers AD, MacDonald TM. Impact of allopurinol use on urate concentration and cardiovascular outcome. Br J Clin Pharmacol 2011;71:600-7.
39. Rajendra NS, Ireland S, George J, Belch JJ, Lang CC, Struthers AD. Mechanistic insights into the therapeutic use of high-dose allopurinol in angina pectoris.J Am Coll Cardiol 2011;58:820-8.
40. Bergamini C, Cicoira M, Rossi A, Vassanelli C. Oxidative stress and hyperuricaemia: pathophysiology, clinical relevance, and therapeutic implications in chronic heart failure. Eur J Heart Fail 2009;11:444-52.
41. Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis 2000;148:131-9.
42. Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA. Uric acid and oxidative stress. Curr Pharm Des 2005;11: 4145e51.
43. Reunanen A, Takkunen H, Knekt P, Aromaa A. Hyperuricemia as a risk factor for cardiovascular mortality. Acta Med Scand Suppl 1982;668:49-59.
44. Bonora E, Targher G, Zenere MB, Saggiani F, Cacciatori V, Tosi F, et al. Relationship of uric acid concentration to cardiovascular risk factors in young men. Role of obesity and central fat distribution. The Verona Young Men Atherosclerosis Risk Factors Study. Int J Obes Relat Metab Disord 1996;20:975-80.
45. Lippi G. Relationship between uric acid, hyperglycemia and hypertriglyceridemia in general population. Biochem Med 2008;18:37-41.
46. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992: National Health and Nutrition Examination Survey. JAMA 2000;283:2404-10.
47. Kaya EB, Yorgun H, Canpolat U, Hazırolan T, Sunman H, Ülgen A, Ates AH, et al. Serum uric acid levels predict the severity and morphology of coronary atherosclerosis detected by multidetector computed tomography. Atherosclerosis 2010;213:178-83.
48. Krishnan E, Pandya BJ, Chung L, Dabbous O. Hyperuricemia and the risk for subclinical coronary atherosclerosis - data from a prospective observational cohort study. Arthritis Res Ther 2011;13:R66.
49. Strasak A, Ruttmann E, Brant L, Kelleher C, Klenk J, Concin H, et al. Serum Uric Acid and Risk of Cardiovascular Mortality: A Prospective Long-Term Study of 83 683 Austrian Men. Clin Chem 2008;54:273-84.
50. Pascual-Figal DA, Hurtado-Martínez JA, Redondo B, Antolinos MJ, Ruiperez JA, Valdes M. Hyperuricaemia and long-term outcome after hospital discharge in acute heart failure patients. Eur J Heart Fail 2007;9:518-24.
51. Lim HE, Kim SH, Kim EJ, Kim JW, Rha SW, Seo HS, Park CG. Clinical value of serum uric Acid in patients with suspected coronary artery disease. Korean J Intern Med 2010;25:21-6.
52. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999;131:7-13.
53. Neogi T, Terkeltaub R, Ellison RC, Hunt S, Zhang Y. Serum Urate Is Not Associated with Coronary Artery Calcification: The NHLBI Family Heart Study. J Rheumatol 2011;38:111-7.
54. Alcaíno H, Greig D, Castro P, Verdejo H, Mellado R, García L, et al. The role of uric acid in heart failure. Rev Med Chile 2011;139:505-15.
55. Proctor PH. Uric Acid and Neuroprotection. Stroke 2008;39: e126.
56. Dawson J, Quinn TJ, Walters MR. Response to Letter by Proctor. Stroke 2008;39:e89.
57. Proctor PH. Uric acid: neuroprotective or neurotoxic? Stroke. 2008;39:e88.
58. Aoyama K, Matsumura N, Watabe M, Wang F, Kikuchi-Utsumi K, Nakaki T. Caffeine and uric acid mediate glutathione synthesis for neuroprotection. Neuroscience 2011;181:206-15.
59. Amaro S, Planas AM, Chamorro A. Uric acid administration in patients with acute stroke: a novel approach to neuroprotection. Expert Review of Neurotherapeutics 2008;8:259-70.
60. Amaro S, Chamorro A. Translational stroke research of the combination of thrombolysis and antioxidant therapy. Stroke 2011;42:1495-9.
61. Doehner W, von Haehling S, Anker SD. Uric acid as a prognostic marker in acute heart failure—new expectations from an old molecule. Eur J Heart Fail 2007;9:437-9.
62. Gruson D, Ahn SA, Rousseau MF. Biomarkers of inflammation and cardiac remodeling: the quest of relevant companions for the risk stratification of heart failure patients is still ongoing. Biochem Med 2011;21:254-63.
63. Manzano L, Babalis D, Roughton M, Shibata M, Anker SD, Ghio S, et al.; SENIORS Investigators. Predictors of clinical outcomes in elderly patients with heart failure. Eur J Heart Fail 2011;13:528-36.
64. Feig DI, Kang DH, Nakagawa T, Mazzali M, Johnson RJ. Uric acid and hypertension. Curr Hypertens Rep 2006;8:111-5.
65. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA. 2008;300:924-32.
66. Feig DI, Johnson RJ. The role of uric acid in pediatric hypertension. J Ren Nutr 2007;17:79-83.
67. Silverstein DM, Srivaths PR, Mattison P, Upadhyay K, Midgley L, Moudgil A, et al. Serum uric acid is associated with high blood pressure in pediatric hemodialysis patients. Pediatr Nephrol 2011;26:1123-8.
68. Kostka-Jeziorny K, Uruski P, Tykarski A. Effect of allopurinol on blood pressure and aortic compliance in hypertensive patients. Blood Press 2011;20:104-10.
69. Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int 2005;67:1739-42.
70. Durante P, Chávez M, Pérez M, Romero F, Rivera F. Effect of uric acid on hypertension progression in spontaneously hypertensive rats. Life Sci 2010;86:957-64.
71. Sautin YY, Nakagawa T, Zharikov S, Johnson. Adverse effects of the classic antioxidant uric acid in adipocytes: ADPH oxidase mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol 2007;93:C584-96.
72. Jung DH, Lee YJ, Lee HR, Lee JH, Shim JY. Association of renal manifestations with serum uric acid in Korean adults with normal uric acid levels. J Korean Med Sci 2010;25:1766-70.
73. Filippatos GS, Ahmed MI, Gladden JD, Mujib M, Aban IB, Love TE, et al. Hyperuricaemia, chronic kidney disease, and outcomes in heart failure: potential mechanistic insights from epidemiological data. Eur Heart J 2011;32:712-20.
74. Kutzing MK, Firestein BL. Altered uric acid levels and disease states. J Pharmacol Exp Ther 2008;324:1-7.
75. Anzai N, Kanai Y, Endou H. New insights into renal transport of urate. Curr Opin Rheumatol 2007;19:151-7.
76. Serpa Neto A, Rossi FM, Valle LG, Teixeira GK, Rossi M. Relation of uric acid with components of metabolic syndrome before and after Roux-en-Y gastric bypass in morbidly obese subjects. Arq Bras Endocrinol Metabol 2011;55:38-45.
77. Otsuki M, Kitamura T, Goya K, Saito H, Mukai M, Kasayama S, et al. Association of urine acidification with visceral obesity and the metabolic syndrome. Endocr J 2011;58:363-7.
78. Lim JH, Kim YK, Kim YS, Na SH, Rhee MY, Lee MM. Relationship between serum uric Acid levels, metabolic syndrome, and arterial stiffness in korean. Korean Circ J 2010;40:314-20.
79. Gil-Campos M, Aguilera CM, Cañete R, Gil A. Uric acid is associated with features of insulin resistance syndrome in obese children at prepubertal stage. Nutr Hosp 2009;24:607-13.
80. Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 2006;290:F625-31.
81. Johnson R J, Segal MS, Sautin Y, Nakagawa T, Feig DI, Kang D-H, et al. Potential role of sugar (fructose) in the epidemic of hypertension,obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr 2007;86:899-906.
82. Lê KA, Tappy L. Metabolic effects of fructose. Curr Opin Clin Nutr Metab Care 2006;9:469-75.
83. Tomiyama H, Higashi Y, Takase B, Node K, Sata M, Inoue T, et al. Relationships Among Hyperuricemia, Metabolic Syndrome, and Endothelial Function. Am J Hypertens 2011;24:770-4.
84. Vlasic V, Trifunovic J, Cepelak I, Nimac P, Zrinski Topic R, Dodig S. Urates in exhaled breath condensate of children with obstructive sleep apnea. Biochem Med 2011;21:139-44.
85. Ballesta-Claver J, Díaz Ortega IF, Valencia-Mirón MC, Capitán-Vallvey LF. Disposable luminol copolymer-based biosensor for uric acid in urine. Anal Chim Acta 2011;702:254-6.
86. Barr WG. Uric Acid. Editors In: Walker HK, Hall WD, Hurst JW, editors. Source Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 165.
87. Nishida Y, Iyadomi M, Higaki Y, Tanaka H, Hara M, Tanaka K. Influence of physical activity intensity and aerobic fitness on the anthropometric index and serum uric acid concentration in people with obesity. Intern Med 2011;50:2121-8.
88. Guidi CG, Salvagno GL. Reference intervals as a tool for total quality management. Biochem Med 2010;20:165-72.
89. Johnson RJ, Feig DI, Herrera-Acosta J, Kang DH. Resurrection of uric acid as a causal risk factor in essential hypertension Hypertension 2005;45:18-20.
90. Dahan K, Devuyst O, Smaers M, Vertommen D, Loute G, Poux JM, et al. A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin. J Am Soc Nephrol 2003;14:2883–93.
91. Dedoussis GV, Luo Y, Starremans P, Rossetti S, Ramos AJ, Cantiello HF, et al. Co-inheritance of a PKD1 mutation and homozygous PKD2 variant: a potential modifier in autosomal dominant polycystic kidney disease. Eur J Clin Invest 2008;38:180-90.
Mokraćna kiselina kao važan čimbenik multifaktorijelnih poremećaja – činjenice i kontroverze
Određujući koncentraciju mokraćne kiseline u serumu kod humanih uzoraka možemo primijetiti hiperuricemiju i moguć razvoj gihta. Mnoga su epidemiološka istraživanja pokazala povezanost između mokraćne kiseline i različitih poremećaja kao što su pretilost, metabolički sindrom, povišeni tlak i koronarna arterijska bolest. Kliničari i znanstvenici prepoznali su koncentraciju mokraćne kiseline u serumu kao važan dijagnostički i prognostički čimbenik mnogih multifaktorijelnih poremećaja. Ovaj pregled predstavlja nekoliko kliničkih stanja koja nisu izravno povezana s mokraćnom kiselinom, no na čije promatranje, praćenje, prognostiku i dijagnostiku određivanje koncentracije mokraćne kiseline može imati velik utjecaj. Mokraćna kiselina prepoznata je kao biljeg oksidativnog stresa. U stvaranje mokraćne kiseline uključen je enzim ksantin-oksidaza koji je prisutan i pri stvaranju reaktivnih kisikovih spojeva (engl. radical-oxigen species, ROS). Kao nusproizvodi, ROS imaju značajnu ulogu kod povišenog rizika od vaskularnog oksidacijskog stresa te su možda uključeni i u aterogenezu. Mokraćna bi kiselina mogla inhibirati endotelnu funkciju inhibirajući funkciju dušikovog oksida kod oksidativnog stresa. Moguće je da inhibicija dušikovog oksida i indukcija endotelne disfunkcije sudjeluju u patogenezi hipertenzije. Najvažnija i potkrijepljena s dovoljno dokaza je potencijalna prediktivna uloga mokraćne kiseline pri predviđanju kratkotrajnih ishoda (smrtnost) kod bolesnika nakon akutnog infarkta miokarda i moždanog udara. Nefrolitijaza uzrokovana mokraćnom kiselinom češće se pojavljuje među bolesnicima s metaboličkim sindromom i pretilošću. Suprotno tome mokraćna kiselina također djeluje kao
antioksidans, čistač slobodnih radikala i kao kelator iona tranzicijskih metala koji prelaze u slabo rea tivne oblike.
Ključne riječi: ateroskleroza; hipertenzija; hiperuricemija; metabolički sindrom; mokraćna kiselina


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A mom from the Golden Gate Mother's group just posted an excellent summary on the Yahoo! Groups list with all the places to buy local food in the San Francisco area. Here's the summary:
1. CSA (Community Supported Agriculture) a weekly/bi-weekly/monthly delivery service of fresh produce that goes directly from the farmer to you.
2. Eatwell Farms (also delivers eggs) http://www.eatwell.com/
3. Two Small Farms http://www.twosmallfarms.com/
4. Capay Farms http://www.farmfreshtoyou.com
5. Terra Firma http://www.terrafirmafarms.com
6. Mariquita Farms http://www.mariquita.com/
7. Eating with the Seasons http://www.eatwiththeseasons.com/
8. Organic Express (I tried this service and didn't like it.) http://www.organicexpress.com
9. Planet Organics http://www.planetorganics.com
1. Marin Sun Farms (beef, pork, chicken, lamb) http://marinsunfarms.com/
2. Clark Summit Farm (pork, beef and chicken)
3. Prather Ranch (beef, pork, lamb, chicken) http://www.prmeatco.com
4. Rosie and Rocky Chicken http://www.petalumapoultry.com/
5. Drewes Brothers Meats (1706 Church) http://www.drewesbros.com
6. Guerra Meats (490 Taraval) http://guerrameats.com
7. Morris Grassfed Beef http://www.morrisgrassfed.com
8. Chileno Valley Ranch http://www.chilenobeef.com
9. Avedano's (235 Cortland ) http://www.avedanos.com/
1. Strauss Family Creamery (milk, yogurt, butter, ice cream) http://www.strausfamilycreamery.com
2. Cowgirl Creamery (cheese) http://www.cowgirlcreamery.com/
3. Point Reyes Cheese http://www.pointreyescheese.com
4. Clover-Stornetta http://www.cloverstornetta.com
5. Claravale Farm (raw milk) http://www.claravalefarm.com
6. Organic Pastures (Raw milk, butter, cheese) http://organicpastures.com
7. St Benoit Yogurt http://www.stbenoit.com/
8. Achadinha (goat cheese) http://www.achadinha.com/
9. Andante Dairy (cheese) http://www.andantedairy.com
1. Ferry Building Market http://www.ferrybuildingmarketplace.com/
2. Ferry Plaza Farmer's Market (Tues and Sat) http://www.cuesa.org/markets/
3. Alemany Farmer's Market (Saturdays)
4. Fillmore Farmer's Market (Sat) http://pcfma.com/marketdetail.php?market_id=13
5. Noe Valley Farmer's Market (Sat)http://noevalleyfarmersmarket.com/
1. Bi-Rite ( 3639 18 th St ) http://www.biritemarket.com
2. Rainbow (1745 Fulton ) http://www.rainbowgrocery.org
3. Andronico's (1200 Irving Street) http://www.andronicos.com
4. Whole Foods
1. Center for Urban Education About Sustainable Agriculture. Includes
list of farmers markets, farmers, etc. http://www.cuesa.org
2. SF Gate article about buying meat directly from the ranch
3. California directory of grass fed foods
4. Info on eating food grown or harvested locally http://www.locavores.com
5. Deconstructing Dinner podcast http://www.cjly.net/deconstructingdinner/about.htm
6. Living a greener lifestyle in SF (by a GGMG mom) http://www.urbancrunchymama.com
7. Local blog regarding sustainable, organic, local food http://www.ethicurean.com
8. Chow Hound discussion of local CSAs
9. Local Slow Food organization http://www.slowfoodsanfrancisco.com
Thursday, October 4, 2007
Where to buy locally grown food in San Francisco?
A mom from the Golden Gate Mother's group just posted an excellent summary on the Yahoo! Groups list with all the places to buy local food in the San Francisco area. Here's the summary:
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Labels: Shopping
1 Comment:
- Green Lorene said...
Hey Honey...Spinach and Honey that is-hehe.
I just subscribed to your blog. How could I not? You listed my business as a place to buy local produce-yeah!! And did you know that Planet Organics (that's my biz) also carries loads of local sustainable groceries as well? In fact, many of the companies you listed are companies I carry; Cowgirl Creamery, Marin Sun Farms, Petaluma Poultry, Straus Family Creamery, to name just a few.
I'm looking forward to receiving your blog. I just started one myself and being an inexperienced blogger I'll look forward to getting some pointers from reading yours.:)
Have a great day and thanks for mentioning my company on your blog as a source for Small Local Food Purveyors. That's our goal!
Keep up the good work on getting the message out about staying local!
~ Green Lorene
- October 8, 2007 at 3:55 PM

subset: commoncrawl


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Nokia microsoft lumia 950 spare parts. get latest price of lcd screen with touchpad module. housing body panel side key and charging port flex cable. audio buzzer earpiece speakers. replacement batterys. travel chargers. don't hesitate to register as an cellspare member and qualify for even greater savings.


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We travel, you train!
- Travelling Trainers specializes in client focused training requirements.
- Travelling Trainers is a niche health care and fitness organization.
- Travelling Trainers providing training programs for clients directly in their homes, offices or any other location.
- Having a good body image is a key factor in an individual's ability to be self motivated.
- Travelling Trainers provides the necessary setup required by being the voice of constant motivation.
- Trainers are fully equipped to be able to provide onsite training with all the necessary equipment


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Product Description
The ProPrompter HD iPro2 Mobile Teleprompter is the finest iPad prompter in the world.
The unit's pre-assembled components easily set-up in minutes. The iPro2 works with just about any camera from DSLR to Handheld's, and even large Shoulder-Mount camcorders. Lightweight and portable also means the iPro2 can be used in a handheld configuration.
The iPro2 with MLD's iPad2 includes the highly-rated Teleprompt+ software. Teleprompt+ is the most advanced, full-featured professional prompting App for the iPad. Teleprompt+ is a simple yet powerful program.


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Bathroom door might not work properly due to some reasons. How to open a locked bathroom door? This is simple question with slightly easy answer. You need to know how the door work then start to prepare for unlocking. Further information is available in the next section.
Implement the Tricks for How to Open a Locked Bathroom Door
Knob is common type that installed for bathroom. You can lock this door from inside by pushing the center of knob. To unlock it, just turn knob a little bit then the door is ready to open. This knob has hole at the center from outside position. To unlock the door, you can do from outside which is useful when something unexpected happens. To do such matter, you just follow some instructions.
First thing in how to open a locked bathroom door is preparation. What are the tools to use? The tools are long sturdy hair or paper clip to put inside the hole. Make sure such thing is long to hit opposite side of the door. Another tool is screwdriver to remove the door knob directly. It is last resort to use when you cannot open it with small wire.
Wire should be bold and strong. Straighten that thing in order to fit the hole size. Put it inside until it touches certain part in opposite section. You can turn left to open locking. It is like you open the door at the same method as people from inside position. After that, the lock is back to normal. Sometimes, the hole is quite wide and you may use small and long screwdriver to hit the opposite lock position.
As mentioned previously, last resort is crew driver to open knob from door. You can remove the screw that holds the knob one by one. Hold for moment before pulling outside. When the door is locked, you can pull it easily. However, the knob is not in stable position. Try to turn left in order let locking loose from its recent position. This process is one of good use in how to open a locked bathroom door.
Doorknob is easy, but you will take time to unlock the handle mode. Handle and knob have different locking system. You need to use a key to lock and unlock handle then pull the lever to open. When the key is no longer in proper condition, the door is in locked mode. Using screwdriver to remove handle is not easy. For such reason, you should use bold method to cut the handle carefully. Of course, that matter is one of solutions in how to open a locked bathroom door.
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Free Weather Alerts Now Available
May 03, 2013
New features have been added to DeWitt County's Mass Notification System. Citizens may now receive free weather alerts as they are issued by the National Weather Service. In order to receive the weather alerts, you must click here and enroll. The new feature takes advantage of the geographically based weather alerts issued by the National Weather Service.
This system can also be used to relay weather alerts and emergency public safety messages effecting your home while you are away from the area.
If you previously enrolled in the emergency notification system, but wish to receive the new weather alerts, you will need to re-enroll. It should only take a few minutes.
If you live in a rural area of DeWitt County, enrollment may require you to locate your home on an interactive map during the sign-up process. When the interactive map appears, simply left click on the blue icon and drag it to the location of your home.


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Patsy Kensit to appear on Celebs Go Dating?
- Bang Showbiz
- 8 April 2017
Patsy Kensit is reportedly in talks to star in 'Celebs Go Dating', as she's currently looking for a partner after having been married four times
Patsy Kensit is in talks to star in 'Celebs Go Dating'.
The 49-year-old actress is currently single after having been married four times - to Dan Donovan, Jim Kerr, Liam Gallagher, and Jeremy Healy - and bosses for the E4 celebrity dating show are reportedly keen to get her on board as they believe she'll be a "really good laugh".
A source told The Sun newspaper: "Patsy is currently in talks to join the new season of 'Celebs Go Dating'. Producers think she would be a great addition to the show and it obviously helps that she's currently on the lookout for a man.
"As she proved on 'Celebrity Big Brother' she always speaks her mind, she's straight talking and she's a really good laugh.
She's had several high profile weddings and divorces and they think it would be great to get a bit of an older lady on the show too among the youngsters.
"Having dated the likes of Liam Gallagher, they're slightly worried about finding the sort of men Patsy is interested in but they know she would be a huge hit with viewers."
And the 'Tina and Bobby' actress - who has sons James, 23, with Simple Minds musician Jim Kerr, and Lennon, 17, with former Oasis rocker Liam Gallagher - recently admitted she's a "hopeless romantic" despite not having the best luck with relationships.
She said: "I have to say at this point that I am a hopeless romantic. I truly am. I do believe in love and still believe in love and I shall continue to do so."
Meanwhile, it was previously reported that 'The Only Way Is Essex' star Gemma Collins is desperate to appear on the next series of the E4 show, but bosses think it will be hard to find a match for her.
An insider explained: "Gemma is keen to go on 'Celebs Go Dating'. She has seen lots of her friends and colleagues go on the show and thinks it will help her find a boyfriend.
"The show's producers aren't quite as keen. They worry that finding the sort of men Gemma is interested in would be difficult as she known for dating bad boys and criminals.
"She would obviously make great value on the show though."


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A new profession perhaps? Made my own audio for the upcoming Hunger Games trailer. Pretty happy with it. [youtube width="525 " height="410″]http://www.youtube.com/watch?v=H_XrOC3EXcY[/youtube] Check out the original below. [youtube]http://www.youtube.com/watch?v=eAWODq_dMFI[/youtube]
Tag archives for games
Hunger Games Trailer Audio
category: For Students, For Teachers, Grade 5 Website, Grade 5/6 Teachers, Grade 6 Website
tags: audio, games, garageband, hunger
Game Maker
Game Maker is fun. You create games by many creating Events for each Object. You can design games like Pong and Shooting-type games. You can add lives and leave messages. People who are interested in arcade games would to design games with Game Maker.-Sanjana
category: For Students, iDesign, Student Work
tags: games


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I've had the pleasure of photographing these sweet girls before.
Documenting their sweetness at these ages is so great- because as we all know- they grow and change so, so quickly.
Their parents are quick to say they aren't always perfect…but I'm not buying that they are not always adorable~ seriously.
So much impresses me with these little ones- but mostly- it was so heart warming to see how they are so kind to each other- especially their little sister.
Thanks A and S for a great afternoon with the littles! xoxo!


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In a surprising nod to the increasing internationalization of American moviegoing, the Motion Picture Academy of Arts and Sciences nominated Kiss of the Spider Woman as best picture Wednesday. Though made in English, this philosophical drama about love between two men in a Latin American prison cell was directed by Brazilian Hector Babenco on location in Argentina. Babenco was nominated for best director and the screenplay was nominated for best adaptation (from a novel by Manuel Puig).
That`s not all, folks. William Hurt was nominated for best actor in Kiss as a flamboyant homosexual who longs to be swept up in a melodrama, like the 1940s movies he talks about incessantly.
Kiss of the Spider Woman`s handful of high-visibility nominations demonstrate that the Hollywood filmmaking community is paying attention to movies made elsewhere. An art film in limited release around the country, Kiss is thematically risky stuff, unlikely to sit well with Joe and Jill Moviegoer in the suburbs. It features political torture and a love scene between two men, as Babenco builds a case for the moral imperative of taking a stand. (The movie is playing at the Art Towne in Plantation and the Carefree Theater in West Palm Beach.)
The controversial subject matter of Kiss is all the more reason to wonder why it has gotten the Academy`s recognition in a big way, at the same time that worthy American films such as Blood Simple, Year of the Dragon, The Purple Rose of Cairo, Twice in a Lifetime, Lost in America, Birdy and Cease Fire were overlooked.
The nomination of Akira Kurosawa, the almost blind Japanese director of the masterful Ran, as best director also illustrates this stunning turnabout for the Academy. Based on Shakespeare`s King Lear, Ran is the sweeping story of a feudal-era Japanese leader who divides his lands between his two eldest sons, only to set himself up for their betrayal. Five years in the making, the movie is the most expensive ever to be made in Japan and indisputably one of the most important. (Ran closes at the Manor Art Cinema in Wilton Manors with today`s matinee.)


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Mail Order Food Subscription
We recently tried Pantry Boy (https://pantryboy.com), it is a Mail Order Food Subscription that I had seen on Groupon. I have been wanting to try these services for some time but I have always been worried about the quality and quantity of these services. I mean come on anyone with males in their home know that you have to cook for an army in order to satisfy them, and I also like to have leftovers for lunch the next day. Let me stress this, NO ONE in our family is overweight, the guys are just good eaters - HAHAHAHA! The appeal to these services are obvious: they come pre sorted, pre decided, pre cut, pre measured and all you have to do is follow the instructions!!! How easy. No wasting money at the grocery store on impulse buys, no over thinking what you will cook, no wasting ingredients that you purchase too much of... it just makes cooking - EASY AS PIE!!!! Hey who knows maybe even after you are relaxed from not having the stresses of cooking dinner you may just be in the mood to bake that PIE!!!!
Then one day I was just browsing Groupon and I seen Pantry Boy, and I immediately couldn't resist. The reason that I chose Pantry Boy is because it is primarily for Slow Cookers/Crockpots and we all know how much I love meals that are easy to cook in a Slow Cooker. With Pantry Boy you can choose Omnivore, Carnivore, or Vegetarian and then you choose 2 or 4 people shipments. Heck they will even through in a Slow Cooker with a 10 week commitment. You can cancel, hold or edit your shipments as needed - which is awesome because we travel fairly often and this would defeat the purpose of saving money if we couldn't put a week on hold. I checked out their menu and was a little nervous because I have picky people in my home, but thought this might be a way to get everyone to try new things. It took about 8 days for the first order to be processed and shipped, but I got updates the entire time so that I knew what was going on.
The day came and I received a message that the box was out for shipment and I couldn't be happier, no honestly, I was excited to try this service. The Fedex dude set the box on the door step (they usually don't even ring the door bell or knock which is so annoying but that is another topic) and I heard his truck so I went and grabbed the box. Immediately, I began opening it up .... and I was so happy with everything that I seen. First the box comes extremely insulated and has several ice packs located near the meat. Each meal was bundled and labeled and the recipe sheets were right on top. You couldn't mess this up if you tried. One thing I was surprised about because I either missed it on their website or it wasn't there but all the items were labeled with "organic, local farm fresh" type stickers. That was an extra added bonus because the ingredients looked fresh and extremely good.
I did my first meal that day and realized that my fears of the quantity were real. I had to add a little something extra from my own pantry to make enough food for my family of 4. But, I will say it wasn't missing much, it just needs a little extra of each item and it would have been plenty. I received 3 meals total and to break up the "Slow Cooker" meals I did them every other day. I just sat the bundles in the fridge so that nothing could get misplaced and checked on them every now and then just to make sure things didn't go bad or look bad. The following days I did the other two meals and quantity is my only compliant because with all three meals I had to add a little something extra to make it a big enough meal for our family. I loved the variety and the freshness of the items, they were sealed and well packed so they didn't go bad during these few days. The instructions were clear and easy to follow (it also gave instruction so you could also cook these meals by stove if you liked). My son wasn't pleased with the meals but as I said earlier, I have picky eaters. I was happy that he at least tried everything. Everyone else seemed to enjoy the menu but just wished their was more of it.
In the end, I canceled the subscription just because of the quantity, I felt like if I have to add my own items then I wasn't saving much money or time by doing this and wasn't that the point? I may try some of the other services just to compare the price, quantity and menus in the future but I may have to order 6 person meals if they have them since 4 person meals may just be too little. The same goes for this service, if I ever receive notice that Pantry Boy has increased their quantity then I would love to try them again as well!!! If you stress over what to cook or the price of food at the grocery store or not having enough time to go to the store then trust me this service is amazing and I highly recommend it!!! The quality was great and maybe for most families the quantity will be as well.
Keywords: Expat, Explore, Family, Love, Marriage, Photography, Sundays, Sundays, Travel, cook, cooking, cooking, crockpot, dinner, family, food, healthy, home, home cooking, meals, no time, pantry boy, slow cooker, try it
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My dearest Celine-y,
How has this year gone by so fast?! It seems like just yesterday I was fighting the Benadryl and painkillers to stay awake and alert enough to hold you and stare at your little swollen face just hours after my surgery to get you here. I cannot believe how much you have changed and I can't wait to see you become more truly and beautifully yourself.
You are a sassafras, a drama queen, and you love being the center of attention when you're doing your tricks ("so big," peekaboo (one handed), waving, clapping, blowing kisses, snuggling, taking your pacifier out on command, and some other ones I can't think of.
You love to be around people and you are more than eager to smile and wave at pretty much anyone who makes eye contact with you. I wish I could still be that brave and carefree in public. Your bright eyes and big smile (sporting still just the two bottom teeth) light up a room.
Love love love,
Mommy and Daddy


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Although the glaciers never reached the area, they did have a major influence on the drainage patterns and topography of the region. The preserve system is located about 10 miles south of the Illinoian and about 30 miles south of the Wisconsin advance (Braun 1928a). However, the glacial advances affected the water flow in the region. The preglacial Teays River, which flowed northwesterly across Ohio, was the major river of Ohio around 1.5 million years ago and was the main drainage for 20 to 30 million years or more (Stout et al. 1943). The river had its headwaters in the Piedmont Plateau of Virginia and North Carolina. It entered Ohio from West Virginia just east of Portsmouth. The Teays River was similar in size to the present day Ohio River and drained most of Ohio and surrounding states.
The Portsmouth River, which flowed north into the Teays River, was the drainage system of the Edge of Appalachia prior to the glaciers. The glaciers of the pre-Kansan and Kansan advances blocked the flow of the Teays and formed a large lake that contributed to the isolation of many plants (Tight 1903; Transeau 1941). The high waters eventually broke an old divide between two tributaries of the Portsmouth River. Buzzardroost Rock was part of this former divide (Durrell 1974; Elfner 1971). When the divide was breached, it created a new drainage system known as the Deep Stage. Ohio Brush Creek was formed during this period and it drained into the newly formed Cincinnati River. About 100,000 years ago, the Illinoian glacial advance dammed the flow of the Cincinnati River and again impounded lakes formed after the waters receded the New Martinsville River was formed (Jones 1945). The present day Ohio River was created after the Wisconsin glacial advance about 15,000 years ago. Ohio Brush Creek, after it was formed, has flowed in the same valley.
Image: Teays River, Courtesy of ODNR Geologic Survey


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Out of Print
- Amsterdam
- Everything
Ellen James Society was the very first band signed to Daemon Records.
Their records are out of print now, but their music still lives on in its obvious influence on the southern punk rock music scene. Intelligent and hard-edged with two female front persons/guitar players, Ellen James Society was the cream of the indie crop during the early-nineties. They had a unique sound and knew how to write a great pop hook while still being true to their underground sensibilities. The very energy that caused this band to implode served to create unforgettable music. Ellen James Society is a legend of the Atlanta indie scene, a band that was a labor of love fronted by two equally talented women who explored every facet of their musical world.


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What is Coaching & Mentoring ?
" Tell me and I forget, teach me and I may remember, involve me and I learn "
Benjamin Franklin
ILM regard coaching as "a particularly powerful tool in the modern workplace, helping managers get the most from their teams, boosting employee engagement and developing high performing workplaces".
Coaching enables individuals to become 'unstuck' from traditional modes of thinking and consider new perspectives.
Our ILM Coaching & Mentoring qualifications at Levels 5 & 7 are increasingly becoming recognised as critical to managerial and organisational development, they will equip you with the knowledge, skills and confidence you need to perform effectively.
We also now offer a 4-day conversion course to take you from the ILM Level 5 qualification to the ILM Level 7 in Executive Coaching & Mentoring:
Dates 18th September – 2nd November
Cost £995
For more information click here or email us on [email protected].
Read our coaching & mentoring brochure:
Who is it for?
ILM Level 5 Coaching & Mentoring
If you are a manager with significant responsibility for coaching and mentoring, this programme is ideal for you. It will also support you if you are planning to move into a development role or starting a career as a freelance coach and mentor.
ILM Level 7 Coaching & Mentoring
This qualification is designed for those working with senior managers or professionals who want to develop their expertise and credibility in the fields of coaching and mentoring. It is also for professional coaches and mentors seeking to enhance and accredit their experience with a nationally recognised qualification.
What will you learn?
ILM Level 5 Coaching & Mentoring
On the programme, you will gain an understanding of the skills, principles and practice of effective management, coaching and mentoring. You will also gain the ability to critically review your own personal qualities, skills and competence.
ILM Level 7 Coaching & Mentoring
On this programme you will learn how to critically review the role and contribution of coaching and mentoring at a senior level, and gain the tools and techniques required to review and improve your own practice.
Why choose this course?
ILM Level 5 Coaching & Mentoring
- Gain a critical understanding of the role and responsibilities of the workplace coach and mentor
- Be able to assess your own skills, behaviours ad knowledge as a coach and mentor
- Develop a coaching and mentoring culture in your organisation
ILM Level 7 Coaching & Mentoring
- Learn how to evaluate the effectiveness of coaching and mentoring in an organisation
- Know how to review and build the context, strategy, culture and processes for coaching and mentoring at a senior and strategic level
- Benchmark your organisation's approach against the latest best practise
Enrolment onto a coaching programme also enables access to membership to our active coaching network, which offers CPD and invitations to official Association for Coaching Co-coaching evenings.
ILM Level 7 Coaching & Mentoring
|12 Sep 2018 - 6 Mar 2019
|Trefforest Campus Call Us to Book
ILM Level 5 Coaching & Mentoring
|12 Sep 2018 - 6 Mar 2019
|USW Conference Centre Call Us to Book
The assessment for the ILM Level 5 programme consists of three mandatory units with a combined credit value of 13.
For the ILM Level 7, the assessment consists of three mandatory units with a combined credit value of 15.
Assessment is broken down into three assignments covering:
- Work-based Assignment
- Reflective Review
- Coaching/Mentoring Diary


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Prolonged mold exposure can lead to a variety of health issues and it can also damage your home severely. 1. If you spring a leak ensure that you have it repaired as soon as possible. It's important to regularly check … Continue reading
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If mold is picked up early enough, and isn't causing any problems within your home or workplace, it doesn't usually warrant assistance from a mold removal company. But if it has managed to escape the surface and get into your … Continue reading
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Part of why mold is such a nuisance is that it's hard to detect. While some types of mold are more visible than others, it's always a possibility that mold is growing where you can't see it. In such cases, … Continue reading
If you've got a mold problem in your home or office, you might be tempted to search 'mold removal specialist' and hire the first company you see. This might actually work out well, since reputable mold removal specialists are often … Continue reading
When you discover a mold problem in your home or business, you basically have three options. You can 1) Ignore the problem and hope it doesn't get worse, 2) Call in the professionals to assess the problem and remove the … Continue reading


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Welcome to Physiotherapy + Pilates
At ak Physiotherapy we pride ourselves in personalised consultations focused on improving your injuries and pain management. We offer experienced "hands on" treatment with expert advice in exercise therapy and sports management.
Our physiotherapists provide attentive and thorough care to every client. Our sessions are longer in length with a hands on and self management focus. Unlike many other physiotherapy clinics, each appointment is exclusively dedicated to the individual client with faster, more effective treatment results.
Pilates is a great way to achieve and maintain your core strength and fitness. Classes can taken for fitness or rehabilitation purposes such as post injury, pain or surgery. Our classes are taken by qualified and experienced physiotherapists with a small group focus (up to six people). You might even want to try our Kilates classes for overall body conditioning.
Recovery / Rehab Treatment
Our recovery treatments are designed to assist with faster recovery and reduced muscle soreness after intense bouts of exercise, surgery or long plane flights. Treatments such as cupping, massage, COMPEX, recovery boots and dry needling may be combined to enhance blood flow, reduce lactate in the muscle and improve lymphatic drainage.
About Us
April King
Physiotherapist / Level 3 CrossFit Trainer / Pilates Instructor
Emma Ellison
Physiotherapist / Pilates Instructor / Sports Trainer
Sandy Newton-king
Physiotherapist / Dry Needling / Pilates Instructor
AK Testimonials
'I am addicted to Reformer Pilates. Being a mother of two and in my 40's my core strength has never been stronger. Having physiotherapists taking the classes gives you full confidence that you are being trained correctly. Awesome staff and a positive environment provides the encouragement you need to improve your health and fitness
April has fingers of steel! I suffer from spondylolithesis and I didn't realise how bad I had let my back get until I wasn't able to go to the gym anymore and simple things like getting in and out of the car caused pain. I tried other physios but I wasn't making any progress. April has a hands on 1:1 patient ratio which really worked for my back issue. I saw April twice a week for about 8 weeks then once a week for 2 weeks and in that time she helped me become completely pain free and able to perform my normal daily activities and rebuild my strength and fitness. I still have a long way to go before I will be exercising at the same level I was before but with seeing April and doing Pilates 2-3 times a week I feel I am making huge progress with the health of my back. Thanks April!
Quite literally the best physios around. Very specific to your exact needs. Highly recommended.
April is amazing! She is the only physio who has managed to get me pain free. Her team is equally fabulous. Highly recommended.
I am very impressed with the professionalism and expertise provided by April and her team. My back has never felt better. It doesn't matter which Physio I see, I come away feeling remarkably better. April has magic hands.
April is an amazing physio who genuinely cares about her clients. She is also a fantastic pilates instructor, who combines a wealth of knowledge with a fun and friendly atmosphere. Whether you have an injury or are considering pilates for core strength, April King Physiotherapy is definitely the place to go!
I have been doing Reformer Pilates for about 18 months. The classes are small and friendly. They are also intense and personal to particular needs. Best evening of the week, lots of fun.
I started doing Pilates with April and Emma in the last trimester of my pregnancy and at the time I thought that it was just something I would do until I could return to CrossFit. Little did I realise that Pilates would be central to my post partum recovery and something that I would continue even after I returned to Crossfit. April and Emma are brilliant at taking each person's individual circumstances into account and ensuring and each session is challenging yet safe. They really know their stuff!
April is fantastic – I highly recommend her reformer pilates classes. She is attentive and I feel very comfortable with her!
To Book for Pilates and Kilate classes, please visit MindBody using the details below:
- Set up a username (email address) and password
- Search Fitness then CrossFit then CrossFit King
- Go to Refomer Pilates
- From here you can see the calendar (you may need to click on the calendar icon) and you may book in to classes.
- You may also cancel your classes using the same method. We require 24 hours notice on cancellations to avoid paying a fee due to the small numbers in our classes.
- Don't forget to save us as your Favourite to make it easier every time you login.