Elevated lipoprotein(a) as a predictor for coronary events in older men.

Elevated circulating lipoprotein (a) [Lp(a)] is associated with an increased risk of first and recurrent cardiovascular events; however, the effect of baseline Lp(a) levels on long-term outcomes in an elderly population is not well understood. The current single-center prospective study evaluated the association of Lp(a) levels with incident acute coronary syndrome to identify populations at risk of future events. Lp(a) concentration was assessed in 755 individuals (mean age of 71.9 years) within the community and followed for up to 8 years (median time to event, 4.5 years; interquartile range, 2.5-6.5 years). Participants with clinically relevant high levels of Lp(a) (>50 mg/dl) had an increased absolute incidence rate of ASC of 2.00 (95% CI, 1.0041) over 8 years (P = 0.04). Moreover, Kaplan-Meier cumulative event analyses demonstrated the risk of ASC increased when compared with patients with low (<30 mg/dl) and elevated (30-50 mg/dl) levels of Lp(a) over 8 years (Gray's test; P = 0.16). Within analyses adjusted for age and BMI, the hazard ratio was 2.04 (95% CI, 1.0-4.2; P = 0.05) in the high versus low Lp(a) groups. Overall, this study adds support for recent guidelines recommending a one-time measurement of Lp(a) levels in cardiovascular risk assessment to identify subpopulations at risk and underscores the potential utility of this marker even among older individuals at a time when potent Lp(a)-lowering agents are undergoing evaluation for clinical use.

MicroRNA-496 and Mechanistic Target of Rapamycin Expression are Associated with Type 2 Diabetes Mellitus and Obesity in Elderly People.

BACKGROUND: Mechanistic target of rapamycin (mTOR) regulates lipid and glucose metabolism thus playing a key role in metabolic diseases like type 2 diabetes mellitus (T2DM). Recently, we demonstrated a functional interaction of microRNA-496 (miR-496) with mTOR and its impact on the regulation of human ageing. OBJECTIVES: As T2DM is most prevalent in older adults, we hypothesized that miR-496 may also have an impact on mTOR regulation in T2DM. METHODS: Based on real-time PCR and enzyme-linked immunosorbent assay, mTOR gene and protein expression as well as miR-496 expression were monitored in peripheral blood mononuclear cells (PBMC) from T2DM patients (median age: 71) and healthy age- and BMI matched controls (median age: 69). -Results: We demonstrated significant upregulation of phospho-mTOR and P70S6 Kinase (P70S6K) levels and significant downregulation of miR-496 in PBMC from elderly T2DM patients in comparison to a BMI and age-matched control cohort. Moreover, significant upregulation of phospho-mTOR protein and significant downregulation of miR-496 were observed in advanced stages of obesity. CONCLUSIONS: BMI-dependent upregulation of mTOR and the inverse expression profile of miR-496 observed in elderly T2DM patients suggest a correlation with T2DM. Hence, our results indicate a potential association of miR-496 with mTOR expression in elderly T2DM patients and obesity. Since phosphorylation of P70S6K was also elevated in T2DM patients, we conclude that mTOR signaling through TORC1 may be affected in the regulation of T2DM.

Family and developmental history of female versus male adolescents with ADHD: diagnosis-specific overlap, few gender/sex differences.

Background: Gender and sex differences in the development of children and adolescents are commonly found in the psychiatric examination. Family and developmental history is an important part of the clinical diagnostic interview, the basic examination technique. Attention-deficit/hyperactivity disorder (ADHD) is associated with diagnosis-specific markers in family and development history. However, it is unclear to what extent ADHD-specific signs and narratives differ between females and males. The aim of this study was to assess and to compare the family and developmental history profiles of female versus male adolescents with ADHD. Methods: Data were collected using the clinical diagnostic interview technique from parents of female and male patients diagnosed with ADHD (ICD-10 F90.0, F90.1 and F98.8) between the ages of 12 and 17 years (n = 92). The two groups were matched in pairs for sex, IQ and ICD-10 diagnosis (F90.0, F90.1 and F98.8). Interview data were operationalized in three categories: 0 - physiological marker, 1 - subclinical marker, 2 - clinical marker. The two groups were compared with two-way ANOVA. Results: Information about female in comparison to male adolescents were reported in the parental interview with few differences. Conclusion: Our study suggests that family and developmental history of the neurodevelopmental disorder ADHD is only poorly influenced by gender or sex.

NLRP3 Inflammasome Activation in Peripheral Arterial Disease.

Background Peripheral arterial disease (PAD) is estimated to affect 7% of the adult population in the United States; however, there is currently little understanding of the key cellular and molecular pathways at play. With PAD characterized by vascular inflammation and associated calcification, the current study set out to elucidate the role of NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome activation in the current cohort. Methods and Results Global proteomics of human vessels with and without PAD from a total of 14 donors revealed an increase of proinflammatory associated ontologies, specifically acute phase and innate immunity. Targeted mass spectrometry showed a significant increase in NLRP3, confirmed by NLRP3 ELISA. Histological analysis from the same patients demonstrated expression of NLRP3, colocalizing in immunoreactive CD68 (cluster of differentiation 68) and CD209 (cluster of differentiation 209) macrophages. Moreover, transmission electron microscopy showed the locality of macrophage-like cells in the presence of calcification, with confocal microscopy further validating the localization of CD68, NLRP3, and calcification via near-infrared calcium tracer. Systemic inflammation and the presence of the NLRP3 inflammasome was assessed via flow cytometry and ELISA, respectively. Compared with patients without PAD, NLRP3 expression was significantly increased in serum. In addition, proinflammatory cytokine presence was significantly increased in disease versus control, with IL (interleukin)-1ß, TNF-α (tumor necrosis factor α), and IL-33 demonstrating the greatest disparity, correlating with NLRP3 activation. Conclusions The current findings demonstrate a link between NLRP3, macrophage accumulation, and calcification in arteries of patients with PAD, suggesting an association or possible driver of PAD in these patients.

Innate and adaptive immunity: the understudied driving force of heart valve disease.

Calcific aortic valve disease (CAVD), and its clinical manifestation that is calcific aortic valve stenosis, is the leading cause for valve disease within the developed world, with no current pharmacological treatment available to delay or halt its progression. Characterized by progressive fibrotic remodelling and subsequent pathogenic mineralization of the valve leaflets, valve disease affects 2.5% of the western population, thus highlighting the need for urgent intervention. Whilst the pathobiology of valve disease is complex, involving genetic factors, lipid infiltration, and oxidative damage, the immune system is now being accepted to play a crucial role in pathogenesis and disease continuation. No longer considered a passive degenerative disease, CAVD is understood to be an active inflammatory process, involving a multitude of pro-inflammatory mechanisms, with both the adaptive and the innate immune system underpinning these complex mechanisms. Within the valve, 15% of cells evolve from haemopoietic origin, and this number greatly expands following inflammation, as macrophages, T lymphocytes, B lymphocytes, and innate immune cells infiltrate the valve, promoting further inflammation. Whether chronic immune infiltration or pathogenic clonal expansion of immune cells within the valve or a combination of the two is responsible for disease progression, it is clear that greater understanding of the immune systems role in valve disease is required to inform future treatment strategies for control of CAVD development.