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The association between organ laterality abnormalities and ciliary ultrastructural defect or genotype in primary ciliary dyskinesia is poorly understood.To determine if there is an association between presence/type of laterality abnormality and ciliary ultrastructural defect and genotype.Participants with primary ciliary dyskinesia in a multicenter, prospective study were grouped based on ciliary ultrastructural defect or genotype. In a retrospective analysis of this data, the association of ciliary ultrastructural defect or genotype and likelihood of a laterality abnormality was evaluated by logistic regression adjusted for presence of two loss-of-function versus one or more not-loss-of-function variants.Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversus totalis, and situs ambiguus, respectively; heterotaxy, defined as situs ambiguus with complex cardiovascular defects, was present in 14 (2.5%). Compared to group with inner dynein arm defects with microtubular disorganization, laterality defects were more likely in the outer dynein arm defects group (OR 2.07, 95% CI 1.21-3.54, P0.01) and less likely in the normal/near normal ultrastructure group (OR 0.04, 95% CI 0.013-0.151, P0.01). Heterotaxy was present in 11 of 242 (4.5%) in the outer dynein arm defects group but zero of 96 in the inner dynein arm defects with microtubular disorganization group (P=0.038).In primary ciliary dyskinesia, risk of a laterality abnormality differs by ciliary ultrastructure defect. Pathophysiologic mechanisms underlying these differences require further exploration.

Primary ciliary dyskinesia (PCD) is a rare lung disease caused by mutations that impair the function of motile cilia, resulting in chronic upper and lower respiratory disease, reduced fertility, and a high prevalence of situs abnormalities. The disease is genetically and phenotypically heterogeneous, with causative mutations in50 genes identified, and clinical phenotypes ranging from mild to severe. Absence of

Neuronal degeneration increases with age in response to stressors, but the sub-cellular mechanism is unknown, partly because of previous difficulty in studying aged neurons in isolation. We studied the mechanism of enhanced neuronal susceptibility to glutamate and beta-amyloid in terms of condensed nuclei and other upstream events in hippocampal neurons cultured from old rats (24 months) compared to middle-age (10 months) and embryonic rats. Treatment of neurons from old animals with beta-amyloid (or glutamate) produced condensed nuclei 1.5x (2x) more frequently than middle-age and 3x (4x) more frequently than embryonic neurons. In addition to age-related baseline levels of caspase activation, neurons from old animals showed a 50% greater increase in caspase activation compared to middle-age and embryonic neurons. In contrast to glutamate treatment, beta-amyloid caused oxyradical damage as protein carbonyls increased 2-fold higher for old neurons than middle-age and 10-fold higher than embryonic neurons. Contrary to expectations, steady-state calcium levels for adult neurons did not increase in response to beta-amyloid. Overall, these results suggest that aged neurons have an inherent increased susceptibility to beta-amyloid toxicity through an early action of oxyradicals followed by caspase activation and nuclear condensation, a common pathway of apoptosis. Age-related glutamate toxicity involves other steps that lead to nuclear condensation, but neuron responses to calcium influx appear more important to cell death than the amount of influx.