Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR

Ophthalmological and molecular genetic studies were performed in a consanguineous family with individuals showing either retinitis pigmentosa (RP) or cone-rod dystrophy (CRD). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at 1p21-p13 (lod score 4.22), a genomic segment known to harbor the ABCR gene involved in Stargardt's disease (STGD) and age- related macular degeneration (AMD). We completed the exon-intron structure of the ABCR gene and detected a severe homozygous 5[prime] splice site mutation, IVS30+1G->T, in the four RP patients. The five CRD patients in this family are compound heterozygotes for the IVS30+1G- >T mutation and a 5[prime] splice site mutation in intron 40 (IVS40+5G- >A). Both splice site mutations were found heterozygously in two unrelated STGD patients, but not in 100 control individuals. In these patients the second mutation was either a missense mutation or unknown. Since thus far no STGD patients have been reported to carry two ABCR null alleles and taking into account that the RP phenotype is more severe than the STGD phenotype, we hypothesize that the intron 30 splice site mutation represents a true null allele. Since the intron 30 mutation is found heterozygously in the CRD patients, the IVS40+5G->A mutation probably renders the exon 40 5[prime] splice site partially functional. These results show that mutations in the ABCR gene not only result in STGD and AMD, but can also cause autosomal recessive RP and CRD. Since the heterozygote frequency for ABCR mutations is estimated at 0.02, mutations in ABCR might be an important cause of autosomal recessive and sporadic forms of RP and CRD.      

黑翠碱甲和黑翠碱乙的化学结构

从黑水翠雀(Delphinium potaninii W.T.Wang)根中分得2个新的牛扁碱型C₁₉-二萜生物碱(I和II),由光谱分析(¹HNMR,¹³CNMR和MS)和化学方法,确定碱I为黑翠碱甲(potanidineA)、碱II为黑翠碱乙(potanidineB)。     

Contribution of genetic and nutritional factors to DNA damage in heavy smokers

Prior epidemiological evidence suggests that genes controlling the metabolism of carcinogens and antioxidant/nutritional status are associated with lung cancer risk, possibly through their ability to modulate DNA damage by carcinogens. We performed a cross-sectional analysis of 159 heavy smokers from a cohort of subjects enrolled in a smoking cessation program. A total of 159 blood samples were analyzed to determine the relative contributions of genetic polymorphisms [CYP1A1 MspI and exon 7 and glutathione S-transferase M1 (GSTM1)] and plasma micronutrients to polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adduct levels. DNA damage in smokers was affected by genetic polymorphisms and nutritional status. Smokers with the CYP1A1 exon 7 valine polymorphism had significantly higher (2-fold, P < or = 0.03) levels of DNA damage than those without. In parallel models, PAH-DNA adducts were inversely associated with plasma levels of retinol (beta = -0.93, P = 0.01), beta-carotene (beta = -0.18, P = 0.09), and alpha- tocopherol (beta = -0.28, P = 0.21) in 159 subjects. The association between smoking-adjusted plasma beta-carotene levels and DNA damage was only significant in those subjects lacking the GSTM1 detoxification gene (beta = -0.30, P = 0.05, n = 75). There was a statistical interaction between beta-carotene and alpha-tocopherol; when beta- carotene was low, alpha-tocopherol had a significant protective effect (beta = -0.78, P = 0.04) on adducts, but not when beta-carotene was high (beta = -0.16, P = 0.57). Plasma alpha-tocopherol was significantly correlated with beta-carotene (r = 0.36, P = 0.0005) and less strongly with retinol (r = 0.20, P = 0.0005). These results suggest that several micronutrients may act in concert to protect against DNA damage and highlight the importance of assessing overall antioxidant status. In conclusion, a subset of smokers may be at increased risk of DNA damage and possibly lung cancer due to the combined effect of low plasma micronutrients and genetic susceptibility factors. The use of biological markers to assess efficacy of interventions and to study mechanisms of micronutrients is timely given the current debate regarding the use of chemopreventive agents in high risk populations.      

Comparison of two effervescent agents for double-contrast upper gastrointestinal tract radiography

We prospectively evaluated the efficacy in 100 patients of two effervescent contrast agents commonly used in routine double-contrast upper gastrointestinal (GI) tract examinations: Baros and E-Z-Gas II granules. The study was double blinded. Two radiologists, who were not aware of which effervescent agent was being used, objectively evaluated the radiographic studies. Patient ease in swallowing and acceptance of the effervescent granules was 94% for Baros and 68% for E-Z-Gas II granules. The objective evaluation of the radiographs showed adequate gastric distension (Baros, 94%; E-Z-Gas II, 90%) and adequate to excellent mucosal coating for both agents (Baros, 92%, E-Z-Gas II, 94%). Areae gastricae were better seen with Baros (64% vs. 30%), and air bubbles were less of a problem with Baros. We conclude that Baros effervescent granules have certain distinct advantages over E-Z-Gas II granules regarding patient tolerance and acceptance, better visualization of the areae gastricae, and less degradation of the quality of the radiographs by air bubbles. The differences in mucosal coatings for the two agents was insignificant.     

Effect of hydrogel lens wear on the major tear proteins during extended wear

Purpose: The purpose of the present study was to determine whether contact lens wear disturbed the levels of tear proteins and to further determine whether this was a transient or continuous disruption. Methods: Lactoferrin, lysozyme and albumin were quanti-tated from tears of neophyte patients and were compared with the levels of these proteins in contact lens wearers after one and six nights and 6 months of extended wear The quantitation of these tear proteins was performed by sandwich ELISA and turbidimetric assay. Results: Results showed that there were no statistically significant changes in the concentration of any of the proteins investigated. Conclusions: Extended wear of hydrogel lenses does not appear to alter the concentration of the major tear film proteins, indicating that the tear film is constantly replenished to maintain protein levels, which are depleted due to protein adsorption to the lens surface.     

Cardiac arrhythmias mimicking primary neurological disorders: a difficult diagnostic situation

Cardiac arrhythmias can present with the signs and symptoms of a seizure disorder. This potentially life–threatening underlying cause of non–febrile seizures should be recognized early, since successful specific treatment is possible. The purpose of this retrospective study was to examine common features in such patients. Over a period of 25 years, eight patients were initially treated for up to 5 years at our institution for a seizure disorder until dysrhythmia as the underlying cause of the seizures was disclosed. The main symptom was drop attacks coinciding with physical activity or emotional stress. Convulsions were only rarely observed. In five of the eight patients the underlying disorder was the long–QT–syndrome (Romano–Ward syndrome). In one patient intermittent complete atrioventricular block was found, another patient showed ventricular tachydysrhythmia of unknown etiology and the last patient suffered from hypertrophic cardiomyopathy.