Leber Congenital Amaurosis (LCA), the most severe inherited retinal dystrophy, is genetically heterogeneous, with 14 genes accounting for 70% of patients. Here, 91 LCA probands underwent LCA chip analysis and subsequent sequencing of 6 genes (CEP290, CRB1, RPE65, GUCY2D, AIPL1and CRX), revealing mutations in 69% of the cohort, with major involvement of CEP290 (30%). In addition, 11 patients with early-onset retinal dystrophy (EORD) and 13 patients with Senior-Loken syndrome (SLS), LCA-Joubert syndrome (LCA-JS) or cerebello-oculo-renal syndrome (CORS) were included. Exhaustive re-inspection of the overall phenotypes in our LCA cohort revealed novel insights mainly regarding the CEP290-related phenotype. The AHI1 gene was screened as a candidate modifier gene in three patients with the same CEP290 genotype but different neurological involvement. Interestingly, a heterozygous novel AHI1 mutation, p.Asn811Lys, was found in the most severely affected patient. Moreover, AHI1 screening in five other patients with CEP290-related disease and neurological involvement revealed a second novel missense variant, p.His758Pro, in one LCA patient with mild mental retardation and autism. These two AHI1 mutations might thus represent neurological modifiers of CEP290-related disease. © 2010 Wiley-Liss, Inc.

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In order to determine the influence of two artificially induced alkalotic states on the ability to perform maximal exercise, six male subjects (mean age, 22.0 years; mean height, 176.8 cm; mean weight, 69.1 kg; mean VO2 max, 3.83 l min-1) were studied during three experimental trials. The subjects performed six 60-s cycling bouts, at a work rate corresponding to 125% VO2 max, with 60 s recovery between work bouts; these regimens were performed 1 h after the ingestion of a solution containing either; I, placebo; II, NaHCO3 in a dosage of 0.15 g per kg body weight; or III, NaHCO3 0.30 g per kg body weight. The sixth work bout was continued until the pedal velocity dropped below 50 rev min-1. Total work done for the entire work period was calculated. Blood samples were taken from a forearm vein prior to the exercise bouts for analysis of pH and HCO3. The results showed a significant pre-exercise difference in pH and HCO3 for all conditions (P less than 0.01). In conditions where artificial alkalosis had been achieved prior to exercise there was significant increase in the work produced: I, 121.6 kJ; II, 133.1 kJ; III, 133.5 kJ (P less than 0.05). The time to fatigue in the six bout was also significantly increased; I, 74.7 s; II, 111.0 s; III, 106.0 p (P less than 0.05). There were no significant differences between conditions II and III. Thus augmentation of the bicarbonate reserves has a significant positive effect on the energy metabolism in interval-type exercise, leading to an increase in the work done and in the time to fatigue.(ABSTRACT TRUNCATED AT 250 WORDS)

Background/Aims: Vascular access thrombosis is one of the most morbid problems encountered by hemodialysis patients. Surveillance protocols utilizing venous pressure (Vp) and vascular access blood flow (VABF) measurements have been employed to preserve vascular access. We undertook a study to evaluate combined dynamic Vp and VABF measurements in the identification of vascular access impairment. We also assessed the effect of preventive repair on thrombosis rates in impaired vascular accesses identified by surveillance. Methods: Eighty-six chronic hemodialysis patients with a functioning vascular access were enrolled into the surveillance protocol. All vascular accesses with greater than 50% of monthly Vp readings >120 mm Hg or VABF <500 ml/min in arteriovenous fistulas (AVFs) and VABF <650 ml/min in arteriovenous grafts (AVGs), or a decrease in VABF >25% compared to the highest previously measured value, were considered positive. Stenosis >50% on fistulography or a thrombotic event were defined as a ‘vascular access impairment episode’ while a stenosis <50% or the absence of a thrombotic event was defined as ‘no vascular access impairment episode’. Thrombosis rates and intervention rates were calculated per access year at risk. Results: The sensitivity and specificity of the combined surveillance protocol for AVFs were 73.3 and 91%, respectively. In AVGs, they were 68.8 and 87.5%, respectively. The rate of thrombotic events was lower in patients who underwent early repair. The addition of dynamic Vp did not reduce the thrombosis rate any further than surveillance based on VABF alone. Conclusion: Combined monitoring for surveillance of AVFs improved sensitivity but had little benefit in AVGs over VABF monitoring alone. Raising VABF cutoff levels might increase and improve identification of vascular access risk for thrombosis, but at the expense of lower specificity.

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