Serotonin and Serotonergic Type-2 Antagonists in Hypertension and Adult Atopic Asthma

Serotonin is a naturally occuring amine with vaso-active properties; its role in the pathogenesis of hypertension is unknown. Serotonin in blood is stored in platelets, and is released during platelet aggregation. Normally, only negligable amounts of serotonin are present in the plasma. Platelets from patients with untreated essential hypertension (n=22) showed increased serotonin-induced aggregation in whole blood in-vitro compared to age and sex matched normotensive controls (n=20). Enhanced platelet aggregation could contribute to raised arterial pressure in hypertension, by increasing free plasma levels of vasoconstrictors such as serotonin. However, spontaneous platelet aggregation in whole blood was not enhanced in these hypertensive patients

Quantifying tumour-infiltrating lymphocyte subsets : a practical immuno-histochemical method

Background: Efficient histological quantification of tumour-infiltrating T and B lymphocyte (TIL) subsets in archival tissues would greatly facilitate investigations of the role of TIL in human cancer biology. We sought to develop such a method. Methods: Ten ×40 digital images of 4 μ sections of 16 ductal invasive breast carcinomas immunostained for CD3, CD4, CD8, and CD20 were acquired (a total of 640 images). The number of pixels in each image matching a partition of Lab colour space corresponding to immunostained cells were counted using the ‘Color range’ and ‘Histogram’ tools in Adobe Photoshop 7. These pixel counts were converted to cell counts per mm2 using a calibration factor derived from one, two, three or all 10 images of each case/antibody combination. Results: Variations in the number of labelled pixels per immunostained cell made individual calibration for each case/antibody combination necessary. Calibration based on two fields containing the most labelled pixels gave a cell count minimally higher (+ 5.3%) than the count based on 10-field calibration, with 95% confidence limits − 14.7 to + 25.3%. As TIL density could vary up to 100-fold between cases, this accuracy and precision are acceptable. Conclusion: The methodology described offers sufficient accuracy, precision and efficiency to quantify the density of TIL sub-populations in breast cancer using commonly available software, and could be adapted to batch processing of image files

Using Diets to Reveal Overlap and Egg Predation among Benthivorous Fishes in Lake Michigan

Ecological stability in the Laurentian Great Lakes has been altered by nonindigenous species, such as the Round Goby Neogobius melanostomus and dreissenid mussels, and by declines in native amphipods Diporeia spp. We evaluated whether these changes could influence diet overlap between three benthivorous fishes (Slimy Sculpin Cottus cognatus, Deepwater Sculpin Myoxocephalus thompsonii, and Round Goby) and whether predation on eggs of native species was occurring. We examined diets of fish collected at depths of 69â 128 m in Lake Michigan offshore of Frankfort and Muskegon, Michigan, and Two Rivers and Sturgeon Bay, Wisconsin, during Januaryâ May 2009 and 2010. Important prey (by dry weight proportion and by percent frequency of occurrence) for Slimy Sculpin were Mysis (0.34; 45%), Diporeia (0.16; 34%), and Limnocalanus macrurus (0.22; 68%); important prey for Deepwater Sculpin were Mysis (0.74; 92%) and Diporeia (0.16; 54%). Round Goby consumed mainly bivalves (i.e., dreissenids: 0.68; 95%) and Mysis (0.15; 37%). The two sculpin species consumed the eggs of Bloaters Coregonus hoyi (Slimy Sculpin: 0.04, 11%; Deepwater Sculpin: 0.02, 7%) and the eggs of Deepwater Sculpin (Slimy Sculpin: 0.03, 13%; Deepwater Sculpin: 0.05, 16%) during Februaryâ May at all sites. Round Goby also consumed eggs of these species but at lower levels (â ¤0.01; <1%). Diet overlap was identified between sculpin species at Frankfort and Sturgeon Bay, suggesting possible interspecific competition, but their diets did not overlap at Two Rivers; diet overlap was never observed between Round Goby and either sculpin species. Given that (1) diet overlap varied by site and (2) diet proportions varied spatially more than temporally, benthivores appear to be exhibiting localized responses to recent ecological changes. Overall, these results reveal that egg predation and interspecific competition could be important interactions to consider in future examinations of the population dynamics of these species or in ecosystem models that forecast how fisheries will respond to possible perturbations or management scenarios.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141248/1/tafs0492.pd

Fluxes and fate of dissolved methane released at the seafloor at the landward limit of the gas hydrate stability zone offshore western Svalbard

Widespread seepage of methane from seafloor sediments offshore Svalbard close to the landward limit of the gas hydrate stability zone (GHSZ) may, in part, be driven by hydrate destabilization due to bottom water warming. To assess whether this methane reaches the atmosphere where it may contribute to further warming, we have undertaken comprehensive surveys of methane in seawater and air on the upper slope and shelf region. Near the GHSZ limit at ?400 m water depth, methane concentrations are highest close to the seabed, reaching 825 nM. A simple box model of dissolved methane removal from bottom waters by horizontal and vertical mixing and microbially mediated oxidation indicates that ?60% of methane released at the seafloor is oxidized at depth before it mixes with overlying surface waters. Deep waters are therefore not a significant source of methane to intermediate and surface waters; rather, relatively high methane concentrations in these waters (up to 50 nM) are attributed to isopycnal turbulent mixing with shelf waters. On the shelf, extensive seafloor seepage at &lt;100 m water depth produces methane concentrations of up to 615 nM. The diffusive flux of methane from sea to air in the vicinity of the landward limit of the GHSZ is ?4–20 ?mol m?2 d?1, which is small relative to other Arctic sources. In support of this, analyses of mole fractions and the carbon isotope signature of atmospheric methane above the seeps do not indicate a significant local contribution from the seafloor source

Reduced Glomerular Filtration Rate and Its Association with Clinical Outcome in Older Patients at Risk of Vascular Events: Secondary Analysis

Using data from the PROSPER trial, Ian Ford and colleagues investigate whether reduced glomerular filtration rate is associated with cardiovascular and mortality risk among elderly people

Leptin Predicts Diabetes but Not Cardiovascular Disease: Results from a large prospective study in an elderly population

OBJECTIVE—To clarify the association of circulating levels of leptin with risk for cardiovascular disease (CVD) events and new-onset diabetes in men and women

Replication of LDL SWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses

&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusion:&lt;/b&gt; With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.&lt;/p&gt

New horizons: the management of hypertension in people with dementia

The optimal management of hypertension in people with dementia is uncertain. This review explores if people with dementia experience greater adverse effects from antihypertensive medications, if cognitive function is protected or worsened by controlling blood pressure (BP) and if there are subgroups of people with dementia for whom antihypertensive therapy is more likely to be harmful. Robust evidence is scant, trials of antihypertensive medications have generally excluded those with dementia. Observational data show changes in risk association over the life course, with high BP being a risk factor for cognitive decline in mid-life, while low BP is predictive in later life. It is therefore possible that excessive BP lowering in older people with dementia might harm cognition. From the existing literature, there is no direct evidence of benefit or harm from treating hypertension in people with dementia. So what practical steps can the clinician take? Assess capacity, establish patient preferences when making treatment decisions, use ambulatory monitoring to thoroughly assess BP, individualise and consider deprescribing where side effects (e.g. hypotension) outweigh the benefits. Future research might include pragmatic randomised trials of targeted deprescribing, which include patient-centred outcome measures to help support decision-making and studies to address mechanistic uncertainties

Unraveling the directional link between adiposity and inflammation: a bidirectional mendelian randomization approach

&lt;b&gt;Context&lt;/b&gt;: Associations between adiposity and circulating inflammation markers are assumed to be causal, although the direction of the relationship has not been proven. &lt;b&gt;Objective&lt;/b&gt;: The aim of the study was to explore the causal direction of the relationship between adiposity and inflammation using a bidirectional Mendelian randomization approach. &lt;b&gt;Methods&lt;/b&gt;: In the PROSPER study of 5804 elderly patients, we related C-reactive protein (CRP) single nucleotide polymorphisms (SNPs) (rs1800947 and rs1205) and adiposity SNPs (FTO and MC4R) to body mass index (BMI) as well as circulating levels of CRP and leptin. We gave each individual two allele scores ranging from zero to 4, counting each pair of alleles related to CRP levels or BMI. &lt;b&gt;Results&lt;/b&gt;: With increasing CRP allele score, there was a stepwise decrease in CRP levels (P for trend &#60; 0.0001) and a 1.98 mg/liter difference between extremes of the allele score distribution, but there was no associated change in BMI or leptin levels (P ≥ 0.89). By contrast, adiposity allele score was associated with 1) an increase in BMI (1.2 kg/m2 difference between extremes; P for trend 0.002); 2) an increase in circulating leptin (5.77 ng/ml difference between extremes; P for trend 0.0027); and 3) increased CRP levels (1.24 mg/liter difference between extremes; P for trend 0.002). &lt;b&gt;Conclusions&lt;/b&gt;: Greater adiposity conferred by FTO and MC4R SNPs led to higher CRP levels, with no evidence for any reverse pathway. Future studies should extend our findings to other circulating inflammatory parameters. This study illustrates the potential power of Mendelian randomization to dissect directions of causality between intercorrelated metabolic factors