The neurovascular dysfunction induced by angiotensin II in the mouse neocortex is sexually dimorphic

Women are less susceptible to the cerebrovascular complications of hypertension, such as a stroke and vascular dementia. The mechanism of such protection may be related to a reduced vulnerability of women to the cerebrovascular actions of hypertension. To test this hypothesis, we used a model of hypertension based on infusion of angiotensin II (ANG II), an octapeptide that plays a key role in hypertension and produces cerebrovascular dysregulation. Cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry in anesthetized (urethane-chloralose) C57BL/6J male and female mice equipped with a cranial window. ANG II administration (0.25 mug.kg(-1).min(-1) iv x 30-45 min) elevated arterial pressure equally in both sexes but attenuated the CBF increase induced by whisker stimulation or by the endothelium-dependent vasodilator acetylcholine (ACh) in male but not in female mice. The administration of ANG II for 7 days (2.74 mg.kg(-1).day(-1)), using osmotic minipumps, also attenuated these cerebrovascular responses in male, but not female, mice. The reduced susceptibility to the effect of ANG II in female mice was abolished by ovariectomy and reinstated by estrogen administration to ovariectomized mice. Administration of estrogen to male mice abolished the ANG II-induced attenuation of CBF responses. We conclude that female mice are less susceptible to the cerebrovascular dysregulation induced by ANG II, an effect related to estrogen. Such protection from the deleterious cerebrovascular effects of hypertension may play a role in the reduced vulnerability to the cerebrovascular complications of hypertension observed in women.     

BACE-1 inhibitors part 2: identification of hydroxy ethylamines (HEAs) with reduced peptidic character

This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)(') and P(2)(') substituents, two different binding modes were observed in X-ray co-crystal structures.     

The ecological importance of unregulated tributaries to macroinvertebrate diversity and community composition in a regulated river

Hydrobiologia - In regulated rivers, dams alter longitudinal gradients in flow regimes, geomorphology, water quality and temperature with associated impacts on aquatic biota. Unregulated...     

Prospective study of school injuries: incidence,types, related factors and initial management.

The rates of school injuries were examined by means of a prospective study of 212 schools during the 1981-82 school year. The results showed an annual incidence rate of 5.4 injury events/100 children, which appears to be an underestimate of the actual rate. Of all the injury events 28.7% resulted in serious injuries. Injuries were significantly more frequent in the elementary as opposed to the secondary schools, and the boys were injured significantly more often than the girls. Most of the injuries occurred during athletic activities. Most of the children with either serious or minor injuries were sent to the school office or returned to the classroom, which indicates that the present level of first-aid training among school personnel is inadequate.     

In Vitro Shear Stress Measurements Using Particle Image Velocimetry in a Family of Carotid Artery Models: Effect of Stenosis Severity,Plaque Eccentricity,and Ulceration

Atherosclerotic disease, and the subsequent complications of thrombosis and plaque rupture, has been associated with local shear stress. In the diseased carotid artery, local variations in shear stress are induced by various geometrical features of the stenotic plaque. Greater stenosis severity, plaque eccentricity (symmetry) and plaque ulceration have been associated with increased risk of cerebrovascular events based on clinical trial studies. Using particle image velocimetry, the levels and patterns of shear stress (derived from both laminar and turbulent phases) were studied for a family of eight matched-geometry models incorporating independently varied plaque features – i.e. stenosis severity up to 70%, one of two forms of plaque eccentricity, and the presence of plaque ulceration). The level of laminar (ensemble-averaged) shear stress increased with increasing stenosis severity resulting in 2–16 Pa for free shear stress (FSS) and approximately double (4–36 Pa) for wall shear stress (WSS). Independent of stenosis severity, marked differences were found in the distribution and extent of shear stress between the concentric and eccentric plaque formations. The maximum WSS, found at the apex of the stenosis, decayed significantly steeper along the outer wall of an eccentric model compared to the concentric counterpart, with a 70% eccentric stenosis having 249% steeper decay coinciding with the large outer-wall recirculation zone. The presence of ulceration (in a 50% eccentric plaque) resulted in both elevated FSS and WSS levels that were sustained longer (∼20 ms) through the systolic phase compared to the non-ulcerated counterpart model, among other notable differences. Reynolds (turbulent) shear stress, elevated around the point of distal jet detachment, became prominent during the systolic deceleration phase and was widely distributed over the large recirculation zone in the eccentric stenoses.