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OBJECTIVEThis study reviewed patients with unilateral facial paralysis and normal clinical and imaging findings who underwent diagnostic facial nerve exploration.STUDY DESIGN AND SETTINGFifteen patients with facial paralysis and normal findings were seen in the Mayo Clinic Department of Otorhinolaryngology.RESULTSEleven patients were misdiagnosed as having Bell palsy or idiopathic paralysis. Progressive facial paralysis with sequential involvement of adjacent facial nerve branches occurred in all 15 patients. Seven patients had a history of regional skin squamous cell carcinoma, 13 patients had surgical exploration to rule out a neoplastic process, and 2 patients had negative exploration. At last follow‐up, 5 patients were alive.CONCLUSIONSPatients with facial paralysis and normal clinical and imaging findings should be considered for facial nerve exploration when the patient has a history of pain or regional skin cancer, involvement of other cranial nerves, and prolonged facial paralysis.SIGNIFICANCEOccult malignancy of the facial nerve may cause unilateral facial paralysis in patients with normal clinical and imaging findings. (Otolaryngol Head Neck Surg 2004;130:459–65.)

Background— We studied the benefits and risks of adding clopidogrel to different doses of aspirin in the treatment of patients with acute coronary syndrome (ACS). Methods and Results— In the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, 12 562 patients with ACS using aspirin, 75 to 325 mg daily, were randomized to clopidogrel or placebo for up to 1 year. In this analysis, patients were divided into the following 3 aspirin dose groups: ≤100 mg, 101 through 199 mg, and ≥200 mg. The combined incidence of cardiovascular death, myocardial infarction, or stroke was reduced by clopidogrel regardless of aspirin dose, as follows: ≤100 mg, 10.5% versus 8.6% (relative risk [RR], 0.81 [95% CI, 0.68 to 0.97]); 101 to 199 mg, 9.8% versus 9.5% (RR, 0.97 [95% CI 0.77 to 1.22]); and ≥200 mg, 13.6% versus 9.8% (RR, 0.71 [95% CI, 0.59 to 0.85]). The incidence of major bleeding increased with increasing aspirin dose both in the placebo group (1.9%, 2.8%, and 3.7%, respectively; P =0.0001) and the clopidogrel group (3.0%, 3.4%, and 4.9%, respectively; P =0.0009); thus, the excess risk with clopidogrel was 1.1%, 1.2%, and 1.2%, respectively. The adjusted hazard ratio for major bleeding for the highest versus the lowest dose of aspirin was 1.9 (95% CI 1.29 to 2.72) in the placebo group, 1.6 (95% CI 1.19 to 2.23) in the clopidogrel group, and 1.7 (95% CI 1.36 to 2.20) in the combined group. Conclusions— In patients with ACS, adding clopidogrel to aspirin is beneficial regardless of aspirin dose. Bleeding risks increase with increasing aspirin dose, with or without clopidogrel, without any increase in efficacy. Our findings suggest that the optimal daily dose of aspirin may be between 75 and 100 mg, with or without clopidogrel.

Albuminuria increases the risk of cardiovascular events in patients with essential hypertension and diabetic subjects. The heritability (h 2 ) of albuminuria in multiplex hypertensive families is unknown. We calculated the familial aggregation of urine albumin:creatinine ratio (ACR) and performed a genome-wide scan to assess for loci contributing to ACR in participants enrolled in the Hyper tension G enetic E pidemiology N etwork (HyperGEN). To perform the genome scan, we analyzed genotype results from 2589 individuals from 805 families in the Family Blood Pressure Program. ACR and covariates were available in 1727 individuals (mean age, 57.1 years). Estimates of h 2 were obtained by using variance component methodology as implemented in the SOLAR software package. Linkage was tested between 387 markers spanning the genome at an average interval of 9.32 cM, using SOLAR multipoint analysis. The h 2 of log urine ACR was 0.49 ( P <1×10 −7 ) after controlling for significant main and interactive effects of age, gender, race, body mass index, blood pressure, and use of ACE inhibitors or angiotensin-2 receptor blockers. The genome-wide scan revealed a maximum LOD score of 2.73 on chromosome 19 (robust corrected LOD, 2.40; P =0.0009) at marker D19S591 and a LOD score of 2.0 on chromosome 12 (robust corrected LOD, 1.75; P =0.005) at marker PAH. These analyses demonstrate the marked heritability of urine ACR in families enriched for the presence of members with essential hypertension. They suggest that a gene(s) associated with urinary ACR may be present on human chromosomes 19 and 12.

ABSTRACT Intracellular calcium signaling plays a central role in cell proliferation. In leukemic cells, the calcium release‐activated calcium channels provide a major pathway for calcium entry (I CRAC ) perpetuating progression through the cell cycle. Although I CRAC is under mitochondrial regulation, targeting mitochondrial function has not been exploited to control malignant cell growth. The benzothiadiazine diazoxide, which depolarized respiration‐dependent mitochondrial membrane potential, reduced the rate of proliferation and arrested human acute leukemic T cells in the G0/G1 phase. Diazoxide did not alter cellular energetics, but rather inhibited the mitochondria‐controlled I CRAC and reduced calcium influx into tumor cells. The antiproliferative action of diazoxide was mimicked by removal of extracellular calcium or by the tyrphostin A9, an I CRAC inhibitor. Deletion of the mitochondrial genome, which encodes essential respiratory chain enzyme subunits, attenuated the inhibitory effect of diazoxide on I CRAC ‐mediated calcium influx and cell proliferation. Thus, manipulation of mitochondrial function and associated calcium signaling provides a basis for a novel anticancer strategy.—Holmuhamedov, E., Lewis, L., Bienengraeber, M., Holmuhamedova, M., Jahangir, A., Terzic, A. Suppression of human tumor cell proliferation through mitochondrial targeting. FASEB J. 16, 1010–1016 (2002)

JNPL3 transgenic mice expressing a mutant tau protein, which develop neurofibrillary tangles and progressive motor disturbance, were crossed with Tg2576 transgenic mice expressing mutant β-amyloid precursor protein (APP), thus modulating the APP-Aβ (β-amyloid peptide) environment. The resulting double mutant (tau/APP) progeny and the Tg2576 parental strain developed Aβ deposits at the same age; however, relative to JNPL3 mice, the double mutants exhibited neurofibrillary tangle pathology that was substantially enhanced in the limbic system and olfactory cortex. These results indicate that either APP or Aβ influences the formation of neurofibrillary tangles. The interaction between Aβ and tau pathologies in these mice supports the hypothesis that a similar interaction occurs in Alzheimer's disease.

ABSTRACT The amyloid β‐protein (Aβ) deposited in Alzheimer's disease (AD) is a normally secreted proteolytic product of the amyloid β‐protein precursor (APP). Generation of Aβ from the APP requires two sequential proteolytic events: an initial β‐secretase cleavage at the amino terminus of the Aβ sequence followed by γ ‐secretase cleavage at the carboxyl terminus of Aβ. We describe the development of a robust in vitro assay for γ ‐secretase cleavage by showing de novo Aβ production in vitro and establish that this assay monitors authentic gamma‐secretase activity by documenting the production of a cognate γ ‐CTF, confirming the size of the Aβ produced by mass spectrometry, and inhibiting cleavage in this system with multiple inhibitors that alter γ‐ secretase activity in living cells. Using this assay, we demonstrate that the γ‐secretase activity 1 ) is tightly associated with the membrane, 2 ) can be solubilized, 3 ) has a pH optimum of 6.8 but is active from pH 6.0 to pH >8.4, and 4 ) ascertain that activities of the γ ‐40 and γ ‐42 are indeed pharmacologically distinct. These studies should facilitate the purification of the protease or proteases that are responsible for this unusual activity, which is a major therapeutic target for the treatment of AD.