Aliskiren, a novel oral renin inhibitor, provides dose-dependent efficacy and placebo-like tolerability in Japanese patients with hypertension.

Aliskiren is a novel orally active renin inhibitor for the treatment of hypertension. This study evaluated the antihypertensive efficacy, safety and tolerability of aliskiren in Japanese patients with hypertension. Forty hundred and fifty-five Japanese men and women with a mean sitting diastolic blood pressure of 95-110 mmHg were randomized to receive once-daily double-blind treatment for 8 weeks with aliskiren 75, 150 or 300 mg or placebo. Aliskiren produced significant, dose-dependent reductions in mean sitting diastolic blood pressure (p<0.0005 vs. placebo for each dose) and mean sitting systolic blood pressure (p<0.001 vs. placebo for each dose). The placebo-corrected reductions in mean sitting systolic/diastolic blood pressure were 5.7/4.0, 5.9/4.5 and 11.2/7.5 mmHg in the aliskiren 75, 150 and 300 mg groups, respectively. After 8 weeks' treatment, 27.8%, 47.8%, 48.2% and 63.7% of patients in the placebo and aliskiren 75, 150 and 300 mg groups, respectively, achieved a successful treatment response (diastolic blood pressure <90 mmHg and/or reduced by > or =10 mmHg from baseline; p<0.005 vs. placebo for each dose). Aliskiren treatment was well tolerated, with the incidence of adverse events reported in the active treatment groups (53-55%) being similar to that in the placebo group (50%). This study, which is the first to assess the antihypertensive efficacy and safety of aliskiren in Japanese patients with hypertension, demonstrates that the once-daily oral renin inhibitor aliskiren provides significant, dose-dependent reductions in blood pressure with placebo-like tolerability.     

A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease,seizures and cotton wool plaques,but not spastic paraparesis

Over 100 mutations in the presenilin‐1 gene (PSEN1) have been shown to result in familial early onset Alzheimer disease (EOAD), but only a relatively few give rise to plaques with an appearance like cotton wool (CWP) and/or spastic paraparesis (SP). A family with EOAD, seizures and CWP was investigated by neuropathological study and DNA sequencing of the PSEN1 gene. Aβ was identified in leptomeningeal vessels and in cerebral plaques. A single point mutation, p.L420R (g.1508T > G) that gives rise to a missense mutation in the eighth transmembrane (TM8) domain of PS1 was identified in two affected members of the family. p.L420R (g.1508T > G) is the mutation responsible for EOAD, seizures and CWP without SP in this family.     

Development of miotic cross-tolerance between pyridostigmine and sarin vapor.

The organophosphorous nerve agent sarin (GB) and the carbamate pyridostigmine bromide (PB) both inhibit acetylcholinesterase (AChE), leading to overstimulation of muscarinic receptors. Both GB and PB produce miosis through stimulation of ocular muscarinic receptors. This study investigated 2 hypotheses: (1) that the miotic response to PB would decrease following repeated injections; and (2) that repeated administration of PB would result in tolerance to the miotic effect of GB vapor. Rats were injected intramuscularly with saline, 0.04 mg/kg, 0.5 mg/kg, or 1.4 mg/kg of PB twice daily for 8 consecutive days. After day 3, animals injected with 1.4 mg/kg PB developed miotic tolerance. Twenty-four (24) h following the final PB injection, the rats were exposed to GB vapor (4.0 mg/m(3)). A similar magnitude of miosis was observed in all groups after GB exposure. However, the rate of recovery of pupil size in animals pretreated with 0.5 and 1.4 mg/kg PB was significantly increased. Twenty (20) h following exposure to GB vapor, the pupils of animals pretreated with 1.4 mg/kg PB had recovered to 77% +/- 4% of their pre-exposure baseline, whereas the saline-injected controls had recovered to only 52% +/- 2% of their pre-exposure baseline. The increased rate of recovery does not appear to be a result of protection of pupillary muscarinic receptors by the higher doses of PB, as there was no longer PB present in the animal at the time of GB exposure. These results demonstrate the development of tolerance to the miotic effect of PB following repeated exposures, and also suggest that cross-tolerance between PB and GB occurs. However, because the magnitude of the response was not reduced, the PB pretreatment and its associated miotic cross-tolerance does not appear to diminish the effectiveness of miosis as a biomarker of acute exposure to nerve agent vapor.     

Evolution of the sperm aster after microinjection of isolated human sperm centrosomes into meiotically mature human oocytes

This study examined the feasibility of isolating and transferringthe centrosome-containing region of spermatozoa to mature humanoocytes. The findings demonstrate that individual sperm centrosomescan be transferred and are capable of nucleating maternal tubulinto form a well-developed sperm aster in the recipient oocyte.The results are discussed with respect to centrosome functionin early human development and applications in clinical in-vitrofertilization in the treatment of certain forms of male factorinfertility.