Changes at the CYP2C locus and disruption of CYP2C8/9 linkage disequilibrium in patients with essential tremor

To identify low-penetrance genes related to sporadic essential tremor (ET) at the CYP2Clocus, located in chromosome 10 q23.33. Leukocytary DNA from 200 ET patients and a control group of 300 unrelated healthy individuals with known CYP2C19 genotypes was studied for common CYP2C8 and CYP2C9 allelic variants by using amplification-restriction analyses. Patients with ET showed the following differences compared with healthy subjects: a 1.6-fold reduction in the frequency for CYP2C8*3 (p=0.006), a 1.35-fold reduction of CYP2C9*2 (p=0.05) and a 1.52-fold reduction in the frequency for CYP2C9*3 (p=0.07). The frequency for patients with ET carrying at least one defective allele was 1.33-fold reduced as compared with healthy subjects (p=0.002). In addition, a disruption of the CYP2C8*3/CYP2C9*2 linkage disequilibrium was observed in ET patients, with a 2.1-fold reduction in the percentage for carriers of the haplotype CYP2C8*3 plus CYP2C9*2 in ET patients (p=0.0001). These findings were independent of gender, age, age of onset, or clinical symptoms. These results suggest that alterations at the CYP2C gene locus are associated with the risk for ET.     

Comparación de 2 estrategias de derivación en el diagnóstico de la espondiloartritis axial en España. Estudio RADAR

ObjectivesImproving referral of patients with back pain to rheumatologists could accelerate the diagnosis of axial spondyloarthritis. The RADAR study compared two strategies in the referral of patients with chronic back pain (> 3 months) with an onset before the age of 45 years from primary care centers to rheumatology departments, in relation to the diagnosis of axial spondyloarthritis.Patients and methodsEach primary care center was assigned a referral strategy for its patients: (a) strategy 1, patients who had one of the 3 following criteria: inflammatory back pain, HLA-B27 positivity or sacroiliitis in imaging; or (b) strategy 2, patients who had 2 of the following 6: inflammatory back pain, HLA-B27 positivity, sacroiliitis in imaging, family history of axial spondyloarthritis, extra-articular manifestations or good response to nonsteroidal antiinflammatory drugs. The rheumatologist established the final diagnosis.ResultsEighty-eight Spanish patients (mean age 36.8 years [SD 8.7], 55.7% females and 44.3% males) were referred for evaluation, 60 patients under strategy 1 and 28 under strategy 2. A definitive diagnosis of axial spondyloarthritis was established in 25.4% with strategy 1 and in 28.6% with strategy 2 (p = NS). Inflammatory back pain was the criterion most commonly used for referral, and the agreement rate between the primary care physician and rheumatologist was 75%.ConclusionsA simple referral strategy based on one of three3 criteria proved as effective as a strategy based on two of 6 criteria in diagnosing axial spondyloarthritis. Inflammatory back pain was the criterion most commonly used for patient referral     

Insulin-like growth factor I administration in young rats with acute renal failure

The outcome of ischemic acute renal failure (IARF) is better in young than adult rats. Insulin-like growth factor I (IGF-I) treatment may increase mortality of adult rats with IARF, probably because of an exaggerated inflammatory response. We report the response to IGF-I therapy in young rats with IARF. Male rats, aged 28+/-1 days, with IARF were given subcutaneous IGF-I, 50 microg/100 g at 0, 8, and 16 h after reperfusion (IGF) or were untreated (ARF). Sham-operated rats were used as controls. At 2 and 7 days after ischemia, serum urea nitrogen and histological damage score, cell proliferation, apoptosis, neutrophil infiltration, and IGF-I receptor mRNA in kidneys were analyzed. The degree of renal failure, mortality rate, histological damage, cell proliferation, and neutrophil infiltration were not different between IGF-I and ARF rats. Hence, short-term IGF-I treatment did not modify the course of IARF in young rats.     

Oxidative profile of tonsil infection. Study of antioxidant enzymes in tonsil and blood

In order to investigate the effect of oxidative damage due to free radicals on ENT infectious diseases, levels of superoxide dismutase (SOD), glutathione-peroxidase (GPx) and reductase (GRt) and the total antioxidant status (TAS) were measured by spectrophotometry on tonsillar tissue obtained from tonsillectomy in 538 patients, who were divided in three groups according to their surgical indication: tonsillar hypertrophy (n = 235), recurrent tonsillitis (n = 280) or peritonsillar abscess (n = 23). SOD concentration were also measured on adenoid tissue and middle ear exudate in 75 patients from the first two groups. Erythrocyte and tonsillar SOD levels were significantly greater in the abscess group, and lower in the hypertrophic one. These differences were similar for GPx and TAS. For GRt, its level in abscess were lower than in the other two groups in a statistically significant way. There were strong correlations between erythrocyte and tonsillar SOD, tonsillar SOD and GPx, tonsillar SOD and TAS, and tonsillar GPx and TAS. SOD concentrations from adenoid tissue and middle ear exudate did not affect its blood level. So, we can conclude that tonsillar oxidative damage is determined by the frequency or the severity of local infections, and it can be evaluated by measuring the SOD concentration in the tonsillar tissue or in the peripheral blood. So, it can be considered a good marker of tonsillar damage.     

Clinical and functional analysis of long-term results of uvulopalatopharyngoplasty

In order to evaluate the clinical and functional effectiveness of uvulopalatopharyngoplasty (UPPP) in chronic roncopathy, we studied the subjective improvement of operated patients and compared to pulsioximetry findings before and after surgery. A follow-up was made on 72 patients entitled of chronic roncopathy--51 with obstructive sleep apnea syndrome (OSAS) and 21 with simple snoring-, for a mean period of time of 41 months. Preoperatory study included on ENT exploration, fibre optic endoscopy, Müller maneuver, pharyngeal CT, value of daytime sleepiness with Epworth's scale, espirometry and pulsioximetry, and the postoperatory study included of pulsioximetry and a health questionnaire over snoring and daytime sleepiness. Snoring improved or disappeared in 13 of 21 patients (61.8%), and daytime sleepiness did it in 26 of 39 (66.6%). Therapeutic failure in snoring was mainly due to an increase in the body mass index. After UPPP in OSAS, only 21 patients (41.1%) showed all positive response criteria (decrease into ODI > or = 50% or in absolute values < 6, CT 90% < 1%, and SaO2 Min > or = 85%). UPPP failed in long term evaluation in the rest of individuals. Patient selection is mandatory to optimize clinical response of UPPP for snoring, without OSAS success depends on body mass index, respiratory disturbances ratios and the eventual presence of another upper airways collapses below velopharyngeal segment.     

Mutations linked to dyskeratosis congenita cause changes in the structural equilibrium in telomerase RNA

Autosomal dominant dyskeratosis congenita (DKC), as well as aplastic anemia, has been linked to mutations in the RNA component of telomerase, the ribonucleoprotein responsible for telomere maintenance. Here we examine the effect of the DKC mutations on the structure and stability of human telomerase RNA pseudoknot and CR7 domains by using NMR and thermal melting. The CR7 domain point mutation decreases stability and alters a conserved secondary structure thought to be involved in human telomerase RNA accumulation in vivo. We find that pseudoknot constructs containing the conserved elements of the pseudoknot domain are in equilibrium with a hairpin conformation. The solution structure of the wild-type hairpin reveals that it forms a continuous helix containing a novel run of three consecutive U.U and a U.C base pairs closed by a pentaloop. The six base pairs unique to the hairpin conformation are phylogenetically conserved in mammals, suggesting that this conformation is also functionally important. The DKC mutation in the pseudoknot domain results in a shift in the equilibrium toward the hairpin form, primarily due to destabilization of the pseudoknot. Our results provide insight into the effect of these mutations on telomerase structure and suggest that the catalytic cycle of telomerase involves a delicate interplay between RNA conformational states, alteration of which leads to the disease state.     

Morphologic study of the intestine in an experimental model of amnioinfusion in fetal rabbits with gastroschisis

An experimental model of serial amnioinfusion has been developed in fetal rabbits with gastroschisis, using an intraamniotic catheter connected to a subcutaneous port. Fetuses of 4 groups were compared 7 days after surgery: group A: gastroschisis and daily amnioinfusion through an implanted catheter; group C: gastroschisis and blind amniotic catheter; group G: gastroschisis without catheter; group O: nonoperated fetuses. Survival rate, fetal body weight, lung weight, intestinal weight and length were determined. Computer aided morphometric analysis was performed, in which intestinal diameter, thickness and villi length were measured. Amniotic fluid samples were recovered along the experimental period. Intestinal length was significantly shorter and had a significantly thicker wall than nonoperated fetuses; we found no other morphometric differences between gastroschisis treated with amnioinfusion (group A) and the other gastroschisis groups (C and G). Amnioinfusion did not affect fetal survival rate; the amniotic catheter alone did not cause pulmonary hypoplasia due to significant amniotic leak. The physiological decrease in amniotic volume towards the end of gestation has not been modified by this regime of amnioinfusion.