Association of exceptional parental longevity and physical function in aging

Offspring of parents with exceptional longevity (OPEL), who are more likely to carry longevity-associated genotypes, may age more successfully than offspring of parents with usual survival (OPUS). Maintenance of physical function is a key attribute of successful aging. While many genetic and non-genetic factors interact to determine physical phenotype in aging, examination of the contribution of exceptional parental longevity to physical function in aging is limited. The LonGenity study recruited a relatively genetically homogenous cohort of Ashkenazi Jewish (AJ) adults age 65 and older, who were defined as either OPEL (having at least one parent who lived to age 95 or older) or OPUS (neither parent survived to age 95). Subjective and objective measures of physical function were compared between the two groups, accounting for potential confounders. Of the 893 LonGenity subjects, 365 were OPEL and 528 were OPUS. OPEL had better objective and subjective measures of physical function than OPUS, especially on unipedal stance (p = 0.009) and gait speed (p = 0.002). Results support the protective role of exceptional parental longevity in preventing decline in physical function, possibly via genetic mechanisms that should be further explored.     

Difficult Preoperative Diagnosis of a Patient with Scierosing Splenic Hemangioma

We present a young asymptomatic woman with splenomegaly and a large isolated splenic mass demonstrated by ultrasonography, 99mTc sulfur colloid, and gallium scintigraphy studies. Computerized tomography (CT) and three-phase 99mTc-labeled red blood cell imaging suggested a malignant lesion. Repeated sonographically guided fine needle aspiration (FNA) obtained only blood, suggesting the possible vascular nature of the tumor. Splenectomy established the diagnosis of splenic hemangioma (SH) with marked sclerotic changes. We conclude from this case that 1) the sclerotic and cystic changes in the SH and the abdominal lymphadenopathy could explain why the three-phase red blood cell and CT scanning, respectively, suggested that the lesion was malignant rather than benign; 2) guided FNA of a splenic mass suspected to be hemangioma may be an additional safe and useful diagnostic procedure. Multiple aspirations yielding blood alone suggest hemangioma and may prevent an unnecessary operation. To the best of our knowledge, this is the first reported case in the literature of FNA of splenic hemangioma.     

Alterations in left ventricular structure and function in young healthy obese women: assessment by echocardiography and tissue Doppler imaging

OBJECTIVES: This study was designed to determine the effects of obesity on left ventricular (LV) structure and function in young obese women. BACKGROUND: Severe prolonged obesity in older adults results in increased plasma volume, eccentric LV hypertrophy, and systolic and diastolic dysfunction. Obese women are at increased risk for the development of heart failure. However, the effects of the obesity on cardiac structure and function in young, otherwise-healthy women are controversial. METHODS: Fifty-one women were evaluated: 20 were obese (body mass index [BMI] > or =30 kg/m(2)) and 31 were non-obese (BMI <30 kg/m(2)). Left ventricular structure and systolic and diastolic function were assessed by two-dimensional echocardiography and tissue Doppler imaging, including the load-independent systolic myocardial velocity (Sm global) and early diastolic myocardial velocity (Em global), respectively. The effects of BMI on LV structure and function were assessed using multivariate regression analyses. RESULTS: Obese women had higher end-diastolic septal and posterior wall thickness, LV mass, and relative wall thickness than non-obese women; BMI values showed significant correlations with these variables (r = 0.58, p < 0.0001; r = 0.50, p < 0.0002; r = 0.52, p < 0.0001, and r = 0.40, p < 0.005, respectively). The Sm global and Em global were lower in obese women, suggesting systolic and diastolic function are decreased; both were negatively correlated with BMI (r = -0.43, p <. 002 and r = -0.61, p < 0.0001, respectively). Multivariate analysis showed BMI was the only independent predictor of relative wall thickness, Sm global, and Em global. CONCLUSIONS: Obesity in young otherwise-healthy women is associated with concentric LV remodeling and decreased systolic and diastolic function. These early abnormalities in LV structure and function may have important implications for explaining the myocardial dysfunction that is associated with increased cardiovascular morbidity and mortality caused by obesity.     

Neuropsychiatric lupus and infectious triggers

Infections can act as environmental triggers inducing or promoting systemic lupus erythematosus (SLE) in genetically predisposed individuals. The aim of the present study was to compare the titres of antibodies (Abs) to infectious agents with neuropsychiatric (NPSLE) clinical manifestations. The sera of 260 individuals (120 patients with SLE and 140 geographic controls) were evaluated for the titres of Epstein bar virus (EBV), cytomegalovirus (CMV), toxoplasma, rubella and syphilis Abs using the BioPlex 2200 Multiplexed Immunoassay method (BioRad) and by the ELISA method for Helicobacter pylori and Hepatitis B core Ag. All BioPlex 2200 kits used were in developmental stages. Data analysis was performed using SPSS 9.0 statistical analysis software (SPSS Inc., Chicago, IL, USA, 1999). Correlation analysis indicated that rubella IgM Ab titres were marginally, positively associated with psychosis (P = 0.09). No other associations were detected between the 17 infectious Abs and five NP manifestations. When the positivity cut-off for anti-rubella IgM Abs was set at three standard deviations above normal, three positive subjects were identified: one patient with psychosis and one with depression, for a total NPSLE prevalence of 33.3%. On the contrary, the prevalence of NPSLE in the remaining subjects was 6.5%. Marginally significant correlations between elevated titres of rubella IgM Ab with psychosis and depression were found. Although this nearly 5-fold increase is not statistically significant, it appears that in a larger sample size, significance would be reached. This is the first study reported that examined the correlation of NPSLE manifestations with anti-infectious Abs.     

Subclinical atherosclerosis in psoriatic arthritis: a case-control study

OBJECTIVE: To investigate the prevalence of subclinical atherosclerosis among patients with psoriatic arthritis (PsA). METHODS: Forty patients with PsA were enrolled. Controls were matched by age, sex, and atherosclerotic risk factors. All patients and controls underwent duplex scan of the carotid arteries. Carotid intima-media thickness (IMT) was evaluated and the presence of atherosclerotic plaques was recorded. The plaques were graded and carotid plaque index was calculated. RESULTS: Patients with PsA had a higher IMT (mean +/- standard deviation, 1.04 +/- 0.35 mm vs 0.88 +/- 0.29 mm in controls; p = 0.03), and had a higher carotid plaque index than did matched controls (2.3 +/- 2.6, compared to 1.12 +/- 2.09; p = 0.03). Multivariate analysis demonstrated that PsA status as well as age and triglyceride levels were associated with the presence of carotid plaque. Other traditional risk factors were more prevalent among patients with PsA; however, they were not statistically significant. CONCLUSION: Our study demonstrates that patients with PsA may have an increased prevalence of subclinical atherosclerosis. These findings may not be solely attributable to traditional risk factors alone. Special attention and strict control of atherosclerotic risk factors in patients with PsA is warranted.     

Factors related to end-systolic volume are important determinants of peak early diastolic transmitral flow velocity.

BACKGROUND. Three important determinants of left ventricular (LV) peak early diastolic filling rate, which is related directly to the magnitude of the transmitral pressure difference, are the rate of LV isovolumic pressure fall (T1/2), left atrial (LA) pressure at mitral valve opening (X1), and end-systolic volume (ESV). METHODS AND RESULTS. To delineate the relative degrees to which these factors contribute to the magnitude of peak early diastolic filling rate, we measured LA and regional intra-LV pressures with micromanometers, LV volume with contrast angiography, and peak transmitral flow velocity (E) with transesophageal Doppler echocardiography in 16 anesthetized closed-chest dogs. E did not correlate significantly with either X1 (r = -0.255) or T1/2 (r = -0.281). Multivariate analysis, with E entered as the dependent variable and X1 and T1/2 as independent variables, also failed to reach significance (R = 0.310). E correlated significantly with ESV (r = -0.633, p less than 0.009). Using multivariate analysis, the major determinants of ESV were found to be LV contractility (+dP/dt), afterload (aortic diastolic pressure, AOdias), and preload (end-diastolic volume, EDV) (R = 0.848, p less than 0.001). E correlated significantly with two of the determinants of ESV (+dP/dt and AOdias) (R = 0.906, p less than 0.001); however, the addition of EDV did not significantly improve the multivariate relation (R = 0.911). To determine whether X1 or T1/2 would add significantly to the above multivariate relation, these factors were entered individually along with +dP/dt and AOdias as third independent variables. Neither the addition of X1 (R = 0.906) or T1/2 (R = 0.926) resulted in a significant improvement in the prediction of E. CONCLUSIONS. Our observations confirm the importance of factors related to ESV as important determinants of early diastolic filling. These relations suggest that the process of early diastolic function is intimately related to systolic function.     

Discovery of novel non-synonymous SNP variants in 988 candidate genes from 6 centenarians by target capture and next-generation sequencing

Despite evidence of a substantial genetic component, the genetic factors that underlie longevity in humans remain to be identified. Previous genome-wide linkage and association studies have not found strong evidence for the contribution of common variants besides the APOE gene, suggesting the role of rare variants in human longevity. To discover rare variants that might contribute to longevity, we selected 988 candidate genes and performed a pilot study to identify novel non-synonymous variants in 6 Ashkenazi Jewish centenarians older than 105. Our candidate genes act in pathways implicated in aging and longevity, including neurodegeneration, cognitive function, lipid metabolism, DNA repair, and genome maintenance. By implementing custom-designed Agilent SureSelect target capture and next-generation sequencing, we discovered a total of 89 novel non-synonymous SNPs (nsSNPs) and validated 51 nsSNPs by iPLEX MassArray assays. Genotyping analysis of these novel SNPs in 410 Ashkenazi Jewish controls and 390 centenarians showed significant enrichment (5.3 fold, p = 0.02) of the p.Y318C variant in PMS2 and significant depletion (7.5 fold, p = 0.04) of the p.V465A variant in GABRR3 in centenarians compared to controls. Our study presents the potential of targeted next-generation sequencing for discovery of rare but functional genetic variation which may lead to exceptional longevity in humans.     

Isolation, purification, and reconstitution of the Na+ gradient-dependent Ca2+ transporter (Na+-Ca2+ exchanger) from brain synaptic plasma membranes.

A [Na+]-gradient-dependent Ca2+ transporter from brain synaptic plasma membranes has been isolated, purified, and reconstituted into brain phospholipid vesicles. The purification was achieved by sucrose-gradient centrifugation after solubilization of the synaptic membranes in cholate in the presence of a 30-fold excess (by weight) of added brain phospholipids and [Na+]-gradient-dependent Ca2+ loading of the reconstituted vesicles. A 128-fold increase in specific activity of [Na+]-gradient-dependent Ca2+ uptake per mg of protein has been obtained. The purified and reconstituted vesicles took up Ca2+ only in response to an outward-oriented [Na+] gradient. The Ca2+ uptake could be inhibited by dissipation of the [Na+] gradient with nigericin. Successful purification was based on the initial [Na+]-gradient dependency of the Ca2+-transport process, the magnitude of the [Na+]-gradient-dependent uptake, and the presence of purified brain phospholipids. Analysis of the sucrose-gradient-purified reconstituted vesicles on NaDodSO4/polyacrylamide gels showed that the activity coincided with enriched appearance of a 70,000-Da protein.