Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer's disease

BackgroundWe evaluated the amounts of amyloid beta (Aβ)) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Aβ plasma levels and Alzheimer's disease (AD) pathology.MethodsAmyloid β levels were measured in (1) the plasma of AD and nondemented (ND) controls in a longitudinal study, (2) the plasma of a cohort of AD patients receiving a cholinesterase inhibitor, and (3) the skeletal muscle, liver, aorta, platelets, leptomeningeal arteries, and in gray and white matter of AD and ND control subjects.ResultsPlasma Aβ levels fluctuated over time and among individuals, suggesting continuous contributions from brain and peripheral tissues and associations with reactive circulating proteins. Arteries with atherosclerosis had larger amounts of Aβ40 than disease-free vessels. Inactivated platelets contained more Aβ peptides than activated ones. Substantially more Aβ was present in liver samples from ND patients. Overall, AD brain and skeletal muscle contained increased levels of Aβ.ConclusionsEfforts to use plasma levels of Aβ peptides as AD biomarkers or disease-staging scales have failed. Peripheral tissues might contribute to both the circulating amyloid pool and AD pathology within the brain and its vasculature. The wide spread of plasma Aβ values is also due in part to the ability of Aβ to bind to a variety of plasma and membrane proteins. Sources outside the CNS must be accounted for because pharmacologic interventions to reduce cerebral amyloid are assessed by monitoring Aβ plasma levels. Furthermore, the long-range impact of Aβ immunotherapy on peripheral Aβ sources should also be considered.     

Successful treatment of gefitinib-induced acute interstitial pneumonitis with high-dose corticosteroid: a case report and literature review

Cytotoxic chemotherapy offers a modest benefit for patients with advanced non-small cell lung cancer (NSCLC), with response rates of 20–35% and median survival of 10–12 months. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib are active against lung cancer. In retrospective studies, EGFR-TKI therapy among patients harboring EGFR mutations showed response rates higher than 65% and a median survival of 20–30 months. Gefitinib is well tolerated and less toxic compared to conventional cytotoxic drugs, but gefitinib-related interstitial lung disease (ILD) has been reported as a serious adverse effect. Although the mechanism remains unknown, multivariate analysis revealed male sex, history of smoking, and the coexistence of interstitial pneumonia or pre-existence of pulmonary fibrosis and poor performance status were all significant risk factors. Here, we reported a case of gefitinib pneumonitis with severe hypoxemia and impending respiratory failure who showed poor response to intermediate dose of systemic steroids but good recovery with high-dose pulse therapy.     

Arecoline stimulated Cyr61 production in human gingival epithelial cells: inhibition by lovastatin

Cyr61 is associated with growth and progression of many types of tumors and is an independent poor prognostic indicator for oral cancer patients. Areca nut (AN) chewing is the most important etiological factor in the pathogenesis of oral cancer in India and many Southeast Asian countries. Yet, the molecular mechanisms involved in the AN-induced oral cancer remain largely unknown. In this study, we show that arecoline, a main alkaloid found in AN, stimulated Cyr61 synthesis in human gingival epithelial S-G cells. Constitutive overexpression of Cyr61 protein in oral epithelial cells during AN chewing may play a role in the pathogenesis of oral cancer. ERK inhibitor PD98059, N-acetyl-L-cysteine, Rho-associated protein kinase (ROCK) selective inhibitor Y-27632 and a geranylgeranyltransferase inhibitor reduced the arecoline-stimulated levels of Cyr61 protein by ～31%, 47%, 65% and 100%, respectively. Lovastatin also completely inhibited arecoline-induced Cyr61 synthesis and the inhibition is dose-dependent. Decreased of geranylgeranylated proteins could be the mechanism that lovastatin regulates Cyr61 synthesis and lovastatin could serve as a useful agent in controlling AN-induced oral cancer.     

Predictors of mammography use in older women with disability: the patients’ perspectives

To determine the factors associated with mammography use among Medicare beneficiaries and reasons for nonuse. Cohort of 4610 community-dwelling Medicare beneficiaries ≥65 years included in the 2004–2005 Medicare Current Beneficiary Survey. Regression models evaluated the association of disability with mammography use. Reasons for underuse are described. Women with disability were more likely than women with no disability to report lower mammography use (unadjusted, moderate disability OR = 0.76; 95% CI = 0.64, 0.91; severe disability OR = 0.46; 95% CI = 0.40, 0.54). Lower use was significant for women with severe disability (adjusted, OR = 0.67; 95% CI = 0.54, 0.83) and women with fair-poor self-rated health, no HMO enrollment and ≥3 comorbidities. No physician recommendation, no need, dislike/pain during the test and forget it were reasons for underutilization. Mammography use decreases with increasing level of disability. Common reasons for underutilization are no physician recommendation, no need, dislike/pain during the test and forgot it. Screening guidelines should be used to target women with disabilities who can benefit from mammography.     

Mechanism of asynchronous Ca2+ waves underlying agonist-induced contraction in the rat basilar artery

Background and purpose:

Uridine 5''-triphosphate (UTP) is a potent vasoconstrictor of cerebral arteries and induces Ca²⁺ waves in vascular smooth muscle cells (VSMCs). This study aimed to determine the mechanisms underlying UTP-induced Ca²⁺ waves in VSMCs of the rat basilar artery.

Experimental approach:

Isometric force and intracellular Ca²⁺ ([Ca²⁺]_i) were measured in endothelium-denuded rat basilar artery using wire myography and confocal microscopy respectively.

Key results:

Uridine 5''-triphosphate (0.1–1000 µmol·L⁻¹) concentration-dependently induced tonic contraction (pEC₅₀ = 4.34 ± 0.13), associated with sustained repetitive oscillations in [Ca²⁺]_i propagating along the length of the VSMCs as asynchronized Ca²⁺ waves. Inhibition of Ca²⁺ reuptake in sarcoplasmic reticulum (SR) by cyclopiazonic acid abolished the Ca²⁺ waves and resulted in a dramatic drop in tonic contraction. Nifedipine reduced the frequency of Ca²⁺ waves by 40% and tonic contraction by 52%, and the nifedipine-insensitive component was abolished by SKF-96365, an inhibitor of receptor- and store-operated channels, and KB-R7943, an inhibitor of reverse-mode Na⁺/Ca²⁺ exchange. Ongoing Ca²⁺ waves and tonic contraction were also abolished after blockade of inositol-1,4,5-triphosphate-sensitive receptors by 2-aminoethoxydiphenylborate, but not by high concentrations of ryanodine or tetracaine. However, depletion of ryanodine-sensitive SR Ca²⁺ stores prior to UTP stimulation prevented Ca²⁺ waves.

Conclusions and implications:

Uridine 5''-triphosphate-induced Ca²⁺ waves may underlie tonic contraction and appear to be produced by repetitive cycles of regenerative Ca²⁺ release from the SR through inositol-1,4,5-triphosphate-sensitive receptors. Maintenance of Ca²⁺ waves requires SR Ca²⁺ reuptake from Ca²⁺ entry across the plasma membrane via L-type Ca²⁺ channels, receptor- and store-operated channels, and reverse-mode Na⁺/Ca²⁺ exchange.