New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Assessment of the respiratory actions of intramuscular morphine in conscious dogs

The actions on the respiratory system of 0.25, 0.5 and 1.0 mg kg -1 morphine given intramuscularly were studied in conscious dogs. Dogs breathed oxygen with 0, 2 and 4 per cent CO 2, in that order, through a mask attached to a flow sensor and connected to a respiratory mechanics monitor. When a steady state period of respiration was reached breathing pure oxygen, respiratory rate, tidal volume, respiratory minute volume, peak expiratory flow rate and end tidal CO 2 (PetCO 2) were measured. The respiratory minute volume and PetCO 2 were measured when the dogs breathed 2 and 4 per cent CO 2 in oxygen, the points plotted onto a graph and the gradient of the line, describing the PCO 2/ventilation response, plus the intercept with the y-axis were determined. Measurements for each morphine dose were taken before injection and at 30 minutes, 1, 2, 3, 4, 6 and 8 hours post injection. The incidence of panting after morphine was dose related and it occurred in all dogs given the high dose. Morphine reduced the gradients of the PCO 2/ventilation response lines and raised the intercept. Other changes were increased respiratory minute volume and peak expiratory flow and decreased PetCO 2 and tidal volume

Fibred knots and disks with clasps.

It is known that every closed, orientable 3-manifold contains a fi-bered knot—a simple closed curve whose complement is a surface bundle over S1. For K such a fibered knot in a rational homology 3-sphere M it is shown that for any compact submanifold X of M containing K as a null-homologous subset, each component of ∂X is compressible in M−K. If K is a doubled knot (bounds a disk with one clasp) then it follows that K is a double of the trivial knot. More generally, it follows that the genus of X (minimum number of one-handles) is less than the genus of M