Impact of night-time symptoms in COPD : a real-world study in five European countries

Peer reviewedPublisher PD

Physical Activity and Hippocampal Sub-Region Structure in Older Adults with Memory Complaints.

BackgroundPhysical activity (PA) plays a major role in maintaining cognition in older adults. PA has been shown to be correlated with total hippocampal volume, a memory-critical region within the medial temporal lobe (MTL). However, research on associations between PA and MTL sub-region integrity is limited.ObjectiveTo examine the relationship between PA, MTL thickness, and its sub-regions, and cognitive function in non-demented older adults with memory complaints.MethodsTwenty-nine subjects aged ≥60 years, with memory complaints were recruited for this cross-sectional study. PA was tracked for 7 days using accelerometers, and average number of steps/day determined. Subjects were categorized into two groups: those who walked ≤4000 steps/day (lower PA) and those with >4000 steps/day (higher PA). Subjects received neuropsychological testing and 3T MRI scans. Nonparametric ANCOVAs controlling for age examined differences between the two groups.ResultsTwenty-six subjects aged 72.7(8.1) years completed the study. The higher PA group (n = 13) had thicker fusiform gyrus (median difference = 0.11 mm, effect size (ES) = 1.43, p = 0.001) and parahippocampal cortex (median difference = 0.12 mm, ES = 0.93, p = 0.04) compared to the lower PA group. The higher PA group also exhibited superior performance in attention and information-processing speed (median difference = 0.90, ES = 1.61, p = 0.003) and executive functioning (median difference = 0.97, ES = 1.24, p = 0.05). Memory recall was not significantly different between the two groups.ConclusionOlder non-demented individuals complaining of memory loss who walked >4000 steps each day had thicker MTL sub-regions and better cognitive functioning than those who walked ≤4000 steps. Future studies should include longitudinal analyses and explore mechanisms mediating hippocampal related atrophy

Preoperative neutrophil-lymphocyte ratio and outcome from coronary artery bypass grafting

Background: An elevated preoperative white blood cell count has been associated with a worse outcome after coronary artery bypass grafting (CABG). Leukocyte subtypes, and particularly the neutrophil-lymphocyte (N/L) ratio, may however, convey superior prognostic information. We hypothesized that the N/L ratio would predict the outcome of patients undergoing surgical revascularization. Methods: Baseline clinical details were obtained prospectively in 1938 patients undergoing CABG. The differential leukocyte was measured before surgery, and patients were followed-up 3.6 years later. The primary end point was all-cause mortality. Results: The preoperative N/L ratio was a powerful univariable predictor of mortality (hazard ratio [HR] 1.13 per unit, P 3.36). Conclusion: An elevated N/L ratio is associated with a poorer survival after CABG. This prognostic utility is independent of other recognized risk factors.Peer reviewedAuthor versio

Subregional Hippocampal Thickness Abnormalities in Older Adults with a History of Heavy Cannabis Use.

Background and Aims: Legalization of cannabis (CB) for both medicinal and, in some states, recreational use, has given rise to increasing usage rates across the country. Of particular concern are indications that frequent CB use may be selectively harmful to the developing adolescent brain compared with adult-onset usage. However, the long-term effects of heavy, adolescent CB use on brain structure and cognitive performance in late-life remain unknown. A critical brain region is the hippocampus (HC), where there is a striking intersection between high concentrations of cannabinoid 1 (CB1) receptors and age-related pathology. Design: We investigated whether older adults (average age=66.6+7.2 years old) with a history of early life CB use show morphological differences in hippocampal subregions compared with older, nonusers. Methods: We performed high-resolution magnetic resonance imaging combined with computational techniques to assess cortical thickness of the medial temporal lobe, neuropsychological testing, and extensive drug use histories on 50 subjects (24 formerly heavy cannabis users [CB+ group] abstinent for an average of 28.7 years, 26 nonusers [CB- group]). We investigated group differences in hippocampal subregions, controlling for age, sex, and intelligence (as measured by the Wechsler Test of Adult Reading), years of education, and cigarette use. Results: The CB+ subjects exhibited thinner cortices in subfields cornu ammonis 1 [CA1; F(1,42)=9.96, p=0.0003], and CA2, 3, and the dentate gyrus [CA23DG; F(1,42)=23.17, p<0.0001], and in the entire HC averaged over all subregions [F(1,42)=8.49, p=0.006]. Conclusions: Negative effects of chronic adolescent CB use on hippocampal structure are maintained well into late life. Because hippocampal cortical loss underlies and exacerbates age-related cognitive decline, these findings have profound implications for aging adults with a history of early life usage. Clinical Trial Registration: ClinicalTrials.gov # NCT01874886

Integrated multiomics approach identifies calcium and integrin-binding protein-2 as a novel gene for pulse wave velocity

Background: Carotid-femoral pulse wave velocity (PWV) is an important measure of arterial stiffness, which is an independent predictor of cardiovascular morbidity and mortality. In this study, we used an integrated genetic, epigenetic and transcriptomics approach to uncover novel molecular mechanisms contributing to PWV. Methods and results: We measured PWV in 1505 healthy twins of European descendent. A genomewide association analysis was performed using standardized residual of the inverse of PWV. We identified one single-nucleotide polymorphism (rs7164338) in the calcium and integrin-binding protein-2 (CIB2) gene on chromosome 15q25.1 associated with PWV [beta = -0.359, standard error (SE) = 0.07, P = 4.8 x 10(-8)]. The same variant was also associated with increased CIB2 expression in leucocytes (beta = 0.034, SE = 0.008, P = 4.95 x 10(-5)) and skin (beta = 0.072, SE = 0.01, P = 2.35 x 10(-9)) and with hypomethylation of the gene promoter (beta = -.899, SE = 0.098, P = 3.63 x 10(-20)). Conclusion: Our data indicate that reduced methylation of the CIB2 promoter in individuals carrying rs7164338 may lead to increased CIB2 expression. Given that CIB2 is thought to regulate intracellular calcium levels, an increase in protein levels may prevent the accumulation of serum calcium and phosphate, ultimately slowing down the process of vascular calcification. This study shows the power of integrating multiple omics to discover novel cardiovascular mechanisms

Glucocorticoids and angiogenesis

Angiogenesis is the creation of new blood vessels from the existing vasculature that occurs through a complex series of interactions and is tightly regulated. Glucocorticoids are acknowledged to inhibit angiogenesis at high concentrations but whether endogenous glucocorticoid concentrations are sufficient to regulate angiogenesis is unclear. Adrenal synthesis is not the sole determinant of glucocorticoid tissue concentration however and 11 ßhydroxysteroid dehydrogenase type 1 (11ßHSD1) that is present in the vessel wall may regenerate active glucocorticoids from 1 lketo-substrates and therefore amplify local tissue concentrations. Thus it was hypothesised that endogenous glucocorticoids regulated by 11ßHSD1 inhibit angiogenesis.In vitro C57B16 mouse aortic ring cultures established that physiologically relevant concentrations of glucocorticoids inhibit angiogenesis in a glucocorticoid receptor dependent manner. In addition vascular 11ßHSD1 was found to modulate glucocorticoid-induced angiostasis, for 1 ldehydrocorticosterone although angiostatic in C57B16 aortae did not inhibit angiogenesis in 11ßHSD1 deficient animals.In vivo using polyester sponge subcutaneous implants in mice, endogenous glucocorticoids were found to inhibit angiogenesis: sponges in adrenalectomised C57B16 mice grew more vessels compared to sponges from sham-operated animals. 11ßHSD1 regulated the angiostatic effects of glucocorticoids, for cortisone (the human equivalent of 11dehydrocorticosterone), although angiostatic in wild types did not inhibit angiogenesis in 11ßHSD1 deficient mice. In vivo it was also noted that in placebo-impregnated sponges angiogenesis was greater in 11ßHSD1 deficient compared to C57B16 mice.In pathology in cutaneous wounds and infarcted myocardium, endogenous glucocorticoids were found to inhibit angiogenesis. RU38486 (a glucocorticoid receptor antagonist) enhanced angiogenesis in both tissues in comparison to placebo treatment. In similar studies in C57B16 or 11ßHSD1 deficient mice, 11ßHSD1 was found to tonically repress angiogenesis and impair left ventricular remodelling post infarction. Thus 11ßHSD1 deficient mice had increased myocardial revascularisation and preserved left ventricular function.In conclusion, by using in vitro, in vivo and pathological models, endogenous glucocorticoids were seen to inhibit angiogenesis. In addition 11ßHSD1 regeneration of glucocorticoids tonically repressed angiogenesis and influenced left ventricular remodelling post myocardial infarction. Thus 11ßHSD1 appears to be an attractive therapeutic target for the management of tissue revascularisation

Comparison of DC Bead-irinotecan and DC Bead-topotecan drug eluting beads for use in locoregional drug delivery to treat pancreatic cancer

DC Bead is a drug delivery embolisation system that can be loaded with doxorubicin or irinotecan for the treatment of a variety of liver cancers. In this study we demonstrate that the topoisomerase I inhibitor topotecan hydrochloride can be successfully loaded into the DC Bead sulfonate-modified polyvinyl alcohol hydrogel matrix, resulting in a sustained-release drug eluting bead (DEBTOP) useful for therapeutic purposes. The in vitro drug loading capacity, elution characteristics and the effects on mechanical properties of the beads are described with reference to our previous work with irinotecan hydrochloride (DEBIRI). Results showed that drug loading was faster when the solution was agitated compared to static loading and a maximum loading of ca. 40–45 mg topotecan in 1 ml hydrated beads was achievable. Loading the drug into the beads altered the size, compressibility moduli and colour of the bead. Elution was shown to be reliant on the presence of ions to perform the necessary exchange with the electrostatically bound topotecan molecules. Topotecan was shown by MTS assay to have an IC50 for human pancreatic adenocarcinoma cells (PSN-1) of 0.22 and 0.27 lM compared to 28.1 and 19.2 lM for irinotecan at 48 and 72 h, respectively. The cytotoxic efficacy of DEBTOP on PSN-1 was compared to DEBIRI. DEPTOP loaded at 6 & 30 mg ml-1, like its free drug form, was shown to be more potent than DEBIRI of comparable doses at 24, 48 & 72 h using a slightly modified MTS assay. Using a PSN-1 mouse xenograft model, DEBIRI doses of 3.3–6.6 mg were shown to be well tolerated (even with repeat administration) and effective in reducing the tumour size. DEBTOP however, was lethal after 6 days at doses of 0.83–1.2 mg but demonstrated reasonable efficacy and tolerability (again with repeat injection possible) at 0.2–0.4 mg doses. Care must therefore be taken when selecting the dose of topotecan to be loaded into DC Bead given its greater potency and potential toxicity