[Show abstract][Hide abstract] ABSTRACT: Primary gout has been associated with single-nucleotide polymorphisms (SNP) in several tubular urate transporter genes. No study has assessed the association of reabsorption and secretion urate transporter gene SNP with gout in a single cohort of documented primary patients with gout carefully subclassified as normoexcretors or underexcretors.
[Show abstract][Hide abstract] ABSTRACT: Patients with Lesch-Nyhan disease (LND) often engage in self-injurious biting. This problem requires difficult management choices, sometimes including removal of the teeth. Although many health care professionals are reluctant to remove teeth in a child because of the permanent negative cosmetic consequences of the edentulous state, disfigurement of the face and tongue from self-biting can be worse. We analyzed the records of 5 LND patients who used mouth guards to spare the teeth. Success was variable, and dental extraction ultimately was required in 4 cases. We also reviewed previously published cases on the use of dental devices to spare teeth in LND. Various devices have been recommended, but failure rates are high, and tooth extraction often is still needed. Although dental extraction is not required in all cases, it should not be delayed when biting is severe.
[Show abstract][Hide abstract] ABSTRACT: The biennial 15(th) symposium on Purine and Pyrimidine metabolism was held in Madrid, June 2013 (PP13). During the meeting, several novel developments on the diagnosis, pathophysiology, and treatment of several inborn errors of purine and pyrimidine metabolism were presented. These ranged from new drugs for gout to enzyme replacement therapies for mitochondrial diseases. A relatively novel aspect in this meeting was the interest in purine and pyrimidine metabolism in nonmammalian systems, such as parasites, mycoplasms, and bacteria. Development of novel analogs for parasite infections, cardiovascular diseases, inflammatory diseases, and cancer were also discussed.
[Show abstract][Hide abstract] ABSTRACT: Background and Objectives. Primary gout has traditionally been associated with obesity, arterial hypertension, and abnormal lipid and glucose homeostasis, but we do not know the prevalence of these vascular risk factors in patients with primary gout from a Mediterranean country. Patients and Method. All patients with primary gout and 2 or more acute arthritis episodes documented by a physician were selected for the study. The diagnosis of MS required ≥3 criteria (ATP III). Patients were classified in two groups: decreased (underexcretors) and normal (normoexcretors) uric acid excretion related to serum urate levels. Results. One hundred and four patients (mean age, 59 years; 100 males) with primary gout were included in the study. MS was diagnosed in 38 subjects (37%). The most frequent triad defining MS was an increased waist circumference, blood pressure, and trygliceride levels. The prevalence of type 2 diabetes mellitus (T2D) was significantly higher in patients with the MS (21/38, 55%) as compared with subjects without the MS (3/66, 5%; p < 0.001). Mean serum urate level in patients with and without MS was identical (8.1 mg/dL), but mean 24-hour uric acid excretion was significantly lower in the former than in the latter (444 ± 110 mg/24-hour/1,73 m(2) versus 546 ± 221 mg/day/1,73 m(2); p = 0.009). Conclusions. The condition of the MS occurs in about one-third of the patients with primary gout. Increased waist circumference, blood pressure, and triglycerides levels is the most frequent MS triad. Diminished urinary uric acid excretion is more severe in gout patients with the MS.
[Show abstract][Hide abstract] ABSTRACT: Background and Objectives. Pharmacologic urate lowering therapy (ULT), at full maintenance doses, has been associated with acute gout arthritis (in up to 80% of patients). The American College of Rheumatology has recently advocated gradually titrating the maintenance dose upward to chosen serum urate target. Few studies have examined the efficacy and safety of a ULT in primary gout. Patients and Methods. The ULT regimen examined included allopurinol (50 mg/day, with increases of 50 mg/month up to 300 mg/day) and colchicine, as prophylaxis to prevent acute gouty attacks. The efficacy and safety of this regimen was examined in 42 patients in whom allopurinol was withheld for ≥3 months and restarted after this assessment and followed up for 12 months. The efficacy and safety of the ULT regimen was related to the serum urate decrease and to the incidence of acute gout flares, respectively. Results. Fifty-nine patients (mean age 59 years, 56 men) with primary gout received the gradually titrated ULT regimen. Baseline serum urate was (mean ± SD) 8.4 ± 0.8 mg/dL. At 3, 6, 9, and 12 months serum urate fell by a mean of 1.8, 2.5, 2.7, and 2.5 mg/dL, respectively (p < 0.001). A serum urate level <6.0 mg/dL was achieved by 38/59 (64%) patients. During the 12 months following the start of the ULT we documented 10 acute arthritis episodes (17% of patients). Conclusions. A gradually titrated hypouricemic regimen for 6 months in patients with primary gout appears to be effective and safe.
[Show abstract][Hide abstract] ABSTRACT: Establishing meaningful relationships between genetic variations and clinical disease is a fundamental goal for all human genetic disorders. However, these genotype-phenotype correlations remain incompletely characterized and sometimes conflicting for many diseases. Lesch-Nyhan disease is an X-linked recessive disorder that is caused by a wide variety of mutations in the HPRT1 gene. The gene encodes hypoxanthine-guanine phosphoribosyl transferase, an enzyme involved in purine metabolism. The fine structure of enzyme has been established by crystallography studies, and its function can be measured with very precise biochemical assays. This rich knowledge of genetic alterations in the gene and their functional effect on its protein product provides a powerful model for exploring factors that influence genotype-phenotype correlations. The present study summarizes 615 known genetic mutations, their influence on the gene product, and their relationship to the clinical phenotype. In general, the results are compatible with the concept that the overall severity of the disease depends on how mutations ultimately influence enzyme activity. However, careful evaluation of exceptions to this concept point to several additional genetic and non-genetic factors that influence genotype-phenotype correlations. These factors are not unique to Lesch-Nyhan disease, and are relevant to most other genetic diseases. The disease therefore serves as a valuable model for understanding the challenges associated with establishing genotype-phenotype correlations for other disorders.
[Show abstract][Hide abstract] ABSTRACT: Objectives
To evaluate the night-time drop in blood pressure in patients with light hypertension and to determine its possible relationship with damage in key organs.
Eight urban health centres.
Four hundred and eighteen adults with light-moderate hypertension.
a) Blood pressure reading on three visits; b) ambulatory monitoring of pressure for 24 hours; c) echocardiograph (in 219 patients); d) albuminuria determination (in 134 patients). A night-time drop in blood pressure was defined as the difference between day and night ambulatory pressures; and relative drop, as the night-time pressure drop as a percentage of the day-time pressure.
Night-time drop in systolic and diastolic pressures was 13.6 (10.7) and 12.1 (8.6) mmHg, respectively. The predictive factors of night-time drop in blood pressure were, directly, daily ambulatory blood pressure (p < 0.05) and female gender (p < 0.05) and, inversely, age (p < 0.05). No association was observed between nighttime drop in blood pressure and left ventricular mass. Only in women was an independent relationship found, inversely, between night-time drop in blood pressure and urinary excretion of albumin (p < 0.05).
Relative night-time drop in blood pressure is greater in women than in men, diminishes with age and depends on the day-time ambulatory pressure. In women a minor night-time drop in blood pressure is associated with greater organic damage.
[Show abstract][Hide abstract] ABSTRACT: Lesch-Nyhan disease (LND) is caused by lack of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity. Mutations in HPRT1 gene show variability in type and location within the gene, and in certain patients the HPRT coding sequence is normal and the molecular defect cannot be found. These patients presented a decreased HPRT1 expression of unknown cause. This is the first report of a carrier and prenatal diagnosis of LND due to a defect in HPRT gene expression regulation.
[Show abstract][Hide abstract] ABSTRACT: Lesch-Nyhan disease (LND) is caused by complete deficiency of the hypoxanthine-guanine phosphoribosyltransferase enzyme. It is characterized by overproduction of uric acid, jointly with severe motor disability and self-injurious behaviour which physiopathology is unknown. These neurological manifestations suggest a dysfunction in the basal ganglia, and three neurotransmitters have been implicated in the pathogenesis of the disease: dopamine, adenosine and serotonin. All of them are implicated in motor function and behaviour, and act by binding to specific G-protein coupled receptors in the synaptic membrane where they seem to be integrated through receptor-receptor interactions. In this work we have confirmed at protein level the previously reported increased expression of DRD5 and the variably aberrant expression of ADORA2A, in LND PBL respect to control PBL. We have also described, for the first time, a decreased expression and protein level of 5-HTR1A in LND PBL respect to control PBL. If these results were confirmed in the Lesch-Nyhan patients basal ganglia cells, this would support the hypothesis that pathogenesis of neurological manifestations of Lesch-Nyhan patients may be related to an imbalance of neurotransmitters, rather than to the isolated disturbance of one of the neurotransmitters, and this fact should be taken into account in the design of pharmacologic treatment for their motor and behavioural disturbances.
[Show abstract][Hide abstract] ABSTRACT: Congenital deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) results in a spectrum of clinical phenotypes. All of these phenotypes are associated with marked overproduction of uric acid and related problems such as hyperuricemia, urate nephrolithiasis, tophi, and gout. The mildest phenotypes include only problems related to overproduction of uric acid. The most severe phenotype is known as Lesch-Nyhan disease, in which the phenotype also includes severe motor handicap, intellectual disability, and self-injurious behavior. In between these two extremes is a continuous spectrum of phenotypes with varying degrees of motor and cognitive handicap but no self-injurious behavior. The pathogenesis of overproduction of uric acid in HPRT deficiency is well-understood, and treatments are available to control it. The pathogenesis of the neurobehavioral problems is less well-understood, and effective treatments for them are lacking.
Current Rheumatology Reports 12/2011; 14(2):189-94.
[Show abstract][Hide abstract] ABSTRACT: The editors of Revista Clínica Española (Rev Clin Esp) inform on their editorial activity during the last 12 months (November 2010 to October 2011): (a) Objectives and attainments during 2011, (b) editorial activity, and (c) objectives for 2012. In 2011 we have updated the editorial algorithm (revision by the responsible editor of all manuscripts sent to peer review and incorporated an «editorial coordinator»), we have renovated two advise facilities (editorial and scientific committees), we have created a new section called «monthly e-image», and we have promoted Rev Clin Esp annual prizes. From the first January 2010 to 31(st) October 2011 we handled 422 manuscripts (42,2 manuscripts per month, higher than the 2010 figure of 40,4 manuscript/month). Overall we have accepted 26% (originals, 16%). We asked for 343 revisions and obtained 231 (67%). Seventy two percent of the reviewers sent their comments in less than two weeks. The mean time taken to accept or reject a given manuscript has been 26 days. The mean time taken since a manuscript is received to publication (october, novembrer and december issues) has dropped from 334 days in 2010 to 254 in 2011 (24% decrease). The collaboration with the working groups has reported about 2 published manuscripts per issue. Our objectives for 2012 are: (a) to improve the editorial process; (b) main article translation into English; (c) improve some sections (i.e. clinical conference); (d) estimulate working groups collaboration; and (e) improve continued medical education. Revista Clínica Española is an open forum for all internal medicine specialists. We all have the responsibility to make our journal, each day, better.
Revista Clínica Española 12/2011; 212(1):31-9. · 2.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To estimate the prevalence of diabetes mellitus and impaired fasting glycemia in an adult population living in Madrid (Spain).
In this cross-sectional, population-based survey, we studied 1,344 adults aged 31-70 years, randomly selected from the population living in 14 primary care districts of the Madrid region. All participants underwent a clinical evaluation that included a clinical interview, physical examination and fasting blood analysis (glycemia, cholesterol and triglyceride levels). The participants were considered to be diabetic if they had been previously diagnosed with diabetes by their general physician or had a fasting glycemia ≥ 126 mg/dl without a previous diabetes diagnosis. Impaired fasting glycemia was defined as fasting glycemia between 100mg/dl and 125 mg/dl in non-diabetic participants.
The sex- and age-adjusted prevalence figures for diabetes and impaired fasting glucose were 6.6% (95% CI: 5.9-8.7) and 14.1% (95% CI: 12.1-15.8), respectively. A substantial proportion of diabetic patients [17.2% (95% CI: 10.9-23.5)] had not been previously diagnosed. The variables independently associated with diabetes were age, male gender, abdominal obesity and hypertension.
Our prevalence figure for diabetes is similar to those reported in other Spanish regions. The high frequency of impaired fasting glucose is worrisome, particularly when combined with obesity, as this association confers a high risk for developing diabetes mellitus.
[Show abstract][Hide abstract] ABSTRACT: The reference range for urinary uric acid excretion has not been precisely defined. Different urinary variables have been proposed to determine the renal contribution to increased or decreased serum urate concentrations. We examined which urinary variable best indicates uric acid excretion over a wide range of serum urate concentrations. Purine metabolism was studied in 10 healthy male subjects (aged 26-58 years) both at their endogenous normal serum urate levels (normouricemic state) and after the oral administration of allopurinol (300 mg/24 h for 5 days) and ribonucleic acid (4 g/8 h for 4 days) to decrease (hypouricemic state) and increase (hyperuricemic state) serum urate concentrations, respectively. The results from patients with several conditions known to affect uric acid synthesis and/or the renal excretion of uric acid were used to validate a constructed nomogram. Over a wide range of mean serum urate levels (from 2.7 to 9.5 mg/dL) and mean 24-hour urinary uric acid excretion (171 to 1368 mg/[24 h 1.73 m(2)]), the highest correlation coefficient between serum urate and uric acid excretion was obtained for the 24-hour uric acid determination (r = 0.928; P < .001). The constructed nomogram allowed the definition of the mechanism underlying hyperuricemia and hypouricemia in patients with a myriad of diseases known to affect purine metabolism. The urinary variable that best correlates with a wide range of serum urate concentrations is 24-hour urinary uric acid excretion. The constructed nomogram allows the identification of the kidney contribution to a given purine metabolic abnormality.
Metabolism: clinical and experimental 10/2011; 61(4):512-8. · 3.10 Impact Factor