In congenital bilateral absence of the vas deferens patients, the T5 allele at the polymorphic Tn locus in the CFTR (cystic fibrosis transmembrane conductance regulator) gene is a frequent disease mutation with incomplete penetrance. This T5 allele will result in a high proportion of CFTR transcripts that lack exon 9, whose translation products will not contribute to apical chloride channel activity. Besides the polymorphic Tn locus, more than 120 polymorphisms have been described in the CFTR gene. We hypothesized that the combination of particular alleles at several polymorphic loci might result in less functional or even insufficient CFTR protein. Analysis of three polymorphic loci with frequent alleles in the general population showed that, in addition to the known effect of the Tn locus, the quantity and quality of CFTR transcripts and/or proteins was affected by two other polymorphic loci: (TG)m and M470V. On a T7 background, the (TG)11 allele gave a 2.8-fold increase in the proportion of CFTR transcripts that lacked exon 9, and (TG)12 gave a sixfold increase, compared with the (TG)10 allele. T5 CFTR genes derived from patients were found to carry a high number of TG repeats, while T5 CFTR genes derived from healthy CF fathers harbored a low number of TG repeats. Moreover, it was found that M470 CFTR proteins matured more slowly, and that they had a 1.7-fold increased intrinsic chloride channel activity compared with V470 CFTR proteins, suggesting that the M470V locus might also play a role in the partial penetrance of T5 as a disease mutation. Such polyvariant mutant genes could explain why apparently normal CFTR genes cause disease. Moreover, they might be responsible for variation in the phenotypic expression of CFTR mutations, and be of relevance in other genetic diseases.

Buffering Ca2+ rises with BAPTA prevented ATP from activating the current. 3. Ca2+-activated Cl-currents could be distinguished from volume-activated Cl-currents, which were sometimes coactivated in the same cell. The latter showed much less outward rectification, their activation was voltage independent, and they could be inhibited by exposing the cells to hypertonic solutions. 5. This Ca2P-activated Cl-current, Iclca' inactivated rapidly at negative potentials and activated slowly at positive potentials. Outward tail currents were slowly decaying, while inward tail currents decayed much faster. 6. 4,4'-Diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and niflumic acid inhibited Ica in a voltage-dependent manner, i.e. they exerted a more potent block at positive potentials. The block by N-phenylanthracilic acid (NPA), 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) and tamoxifen was voltage independent. Niflumic acid and tamoxifen were the most potent blockers. 7. The single-channel conductance was 7-9 + 0 7 pS (n = 15) at 300 mm extracellular CF. The channel open probability was high at positive potentials, but very small at negative potentials.8. It is concluded that [Ca2+]i activates small-conductance Cl-channels in endothelial cells, which coexist with the volume-activated Cl-channels described previously.In many cell types, the membrane permeability for K+ and Cl-is modulated by changes in the free intracellular Ca2P

Background. Parkinson’s disease (PD) is a common neurodegenerative disease associated with accumulation of misfolding proteins and increased neuroinflammation, which may further impair the glymphatic system. The purpose of this study was to utilize diffusion tensor image analysis along the perivascular space (DTI-ALPS) to evaluate glymphatic system activity and its relationship with systemic oxidative stress status in PD patients. Methods. Magnetic resonance imaging and neuropsychological tests were conducted on 25 PD patients with normal cognition (PDN), 25 PD patients with mild cognitive impairment (PD-MCI), 38 PD patients with dementia (PDD), and 47 normal controls (NC). Oxidative stress status was assessed by plasma DNA level. Differences in ALPS-index among the subgroups were assessed and further correlated with cognitive functions and plasma DNA levels. Results. The PD-MCI and PDD groups showed significantly lower ALPS-index compared to normal controls. The ALPS-index was inversely correlated with plasma nuclear DNA, mitochondrial DNA levels, and cognitive scores. Conclusions. Lower diffusivity along the perivascular space, represented by lower ALPS-index, indicates impairment of the glymphatic system in PD patients. The correlation between elevated plasma nuclear DNA levels and lower ALPS-index supports the notion that PD patients may exhibit increased oxidative stress associated with glymphatic system microstructural alterations.

Obstructive sleep apnea impairs white matter integrity in vulnerable regions, and this impairment is associated with increased disease severity. The possible interactions between systemic inflammation and central nervous system microstructural damage may represent variant hypoxic patterns and their consequent processes in OSA.