Peripheral vascular responses to acetylcholine as a predictive tool for response to cholinesterase inhibitors in Alzheimer's disease.

BACKGROUND: Cholinesterase inhibitors remain the first line therapy for people with mild to moderate Alzheimer's disease (AD). Response is modest and difficult to predict from pre-treatment characteristics. We hypothesise that skin vascular response to iontophoresis of acetylcholine, which is partly determined by the level of cholinesterase activity, may be a pre-treatment measure that could predict response to therapy. METHODS: Twenty-four people with probable AD underwent iontophoresis of acetylcholine to the volar surface of the forearm skin prior to treatment with a cholinesterase inhibitor. The peak skin vascular response and the resolution to baseline levels were measured using laser Doppler perfusion imaging. Response to treatment was assessed after 6 months using criteria from the National Institute for Health and Care Excellence (NICE) and iontophoresis with acetylcholine was repeated. Blindness between clinical and laboratory assessments was maintained. RESULTS: Fourteen out of twenty-four people responded to treatment using NICE criteria. By comparison to non-responders, responders to treatment had a faster resolution to baseline from acetylcholine-induced vasodilation prior to treatment, which slowed with treatment. In this pilot study there was a high level of accuracy in the classification of response using this variable. No baseline cognitive or functional measures discriminated end-point responders from non-responders. CONCLUSION: Cholinesterase inhibitors are well tolerated but the number of people with adverse effects would be reduced if it was possible to predict response. The role of vasodilator response to acetylcholine and recovery as a potential biomarker for efficacy of treatment should now be evaluated and may possibly be of relevance in stratifying samples for interventional studies in AD and other forms of dementia. We feel that a more definitive study is now justified.

Effects of inaccuracies in arterial path length measurement on differences in MRI and tonometry measured pulse wave velocity.

BACKGROUND: Carotid-femoral pulse wave velocity (cf-PWV) and aortic PWV measured using MRI (MRI-PWV) show good correlation, but with a significant and consistent bias across studies. The aim of the current study was to evaluate whether the differences between cf.-PWV and MRI-PWV can be accounted for by inaccuracies of currently used distance measurements. METHODS: One hundred fourteen study participants were recruited into one of 4 groups: Type 2 diabetes melltus (T2DM) with cardiovascular disease (CVD) (n = 23), T2DM without CVD (n = 41), CVD without T2DM (n = 25) and a control group (n = 25). All participants underwent cf.-PWV, cardiac MRI and whole body MR angiography(WB-MRA). 90 study participants also underwent aortic PWV using MRI. cf.-PWVEXT was performed using a SphygmoCor device (Atcor Medical, West Ryde, Australia). The true intra-arterial pathlength was measured using the WB-MRA and then used to recalculate the cf.-PWVEXT to give a cf.-PWVMRA. RESULTS: Distance measurements were significantly lower on WB-MRA than on external tape measure (mean diff = -85.4 ± 54.0 mm,p < 0.001). MRI-PWV was significantly lower than cf.-PWVEXT (MRI-PWV = 8.1 ± 2.9 vs. cf.-PWVEXT = 10.9 ± 2.7 ms-1,p < 0.001). When cf.-PWV was recalculated using the inter-arterial distance from WB-MRA, this difference was significantly reduced but not lost (MRI-PWV = 8.1 ± 2.9 ms-1 vs. cf.-PWVMRA 9.1 ± 2.1 ms-1, mean diff = -0.96 ± 2.52 ms-1,p = 0.001). Recalculation of the PWV increased correlation with age and pulse pressure. CONCLUSION: Differences in cf.-PWV and MRI PWV can be predominantly but not entirely explained by inaccuracies introduced by the use of simple surface measurements to represent the convoluted arterial path between the carotid and femoral arteries.

Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes.

OBJECTIVE: Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus. APPROACH AND RESULTS: Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro- and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malmö Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malmö Diet and Cancer subjects who had a coronary event during follow-up. CONCLUSIONS: The plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk.

Association between renin and atherosclerotic burden in subjects with and without type 2 diabetes.

BACKGROUND: Activation of the renin-angiotensin-aldosterone-system (RAAS) has been proposed to contribute to development of vascular complications in type 2 diabetes (T2D). The aim of the present study was to determine if plasma renin levels are associated with the severity of vascular changes in subjects with and without T2D. METHODS: Renin was analyzed by the Proximity Extension Assay in subjects with (n = 985) and without (n = 515) T2D participating in the SUMMIT (SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools) study and in 205 carotid endarterectomy patients. Vascular changes were assessed by determining ankle-brachial pressure index (ABPI), carotid intima-media thickness (IMT), carotid plaque area, pulse wave velocity (PWV) and the reactivity hyperemia index (RHI). RESULTS: Plasma renin was elevated in subjects with T2D and demonstrated risk factor-independent association with prevalent cardiovascular disease both in subjects with and without T2D. Renin levels increased with age, body mass index, HbA1c and correlated inversely with HDL. Subjects with T2D had more severe carotid disease, increased arterial stiffness, and impaired endothelial function. Risk factor-independent associations between renin and APBI, bulb IMT, carotid plaque area were observed in both T2D and non-T2D subjects. These associations were independent of treatment with RAAS inhibitors. Only weak associations existed between plasma renin and the expression of pro-inflammatory and fibrous components in plaques from 205 endarterectomy patients. CONCLUSIONS: Our findings provide clinical evidence for associations between systemic RAAS activation and atherosclerotic burden and suggest that this association is of particular importance in T2D.

Acute oral dexamethasone administration reduces levels of orphan GPCR glucocorticoid-induced receptor (GIR) mRNA in rodent brain: potential role in HPA-axis function.

Glucocorticoid-induced receptor (GIR) is an orphan G-protein-coupled receptor (GPCR) with predominant expression in brain and thymus. More specifically, high levels of GIR expression have been described in brain regions of mouse, rat and human including limbic forebrain and hypothalamic regions, suggesting a role for GIR in memory, cognition, stress, reward or the control of emotion. Previous in vitro studies performed in murine thymocytes demonstrated an induction of GIR following dexamethasone treatment, suggesting the potential in vivo regulation of GIR by glucocorticoids. Glucocorticoids have been implicated in a number of disorders. In this study we employed in situ hybridisation with semi-quantitative image analysis to assess the level of GIR expression in mouse brain following acute dexamethasone administration. GIR was highly expressed in the nucleus accumbens, striatum, olfactory tubercle and nuclei of the hypothalamus. Three hours following acute dexamethasone treatment (0.05 mg/kg, p.o.), levels of GIR mRNA were found to be significantly decreased in striatum (25%, P<0.05), nucleus accumbens (19%, P<0.05), olfactory tubercle (19%, P<0.05) and CA2 sub-region of the hippocampus (30%, P<0.05) compared with vehicle. Significant decreases in GIR expression were also observed in hypothalamic nuclei including the dorsomedial (48%, P<0.05) and ventrolateral (58%, P<0.05) part of the ventromedial hypothalamic nuclei, dorsomedial hypothalamic nuclei (39%, P<0.01) and arcuate nucleus (54%, P<0.05), compared with vehicle. These data demonstrate the in vivo regulation of GIR in response to glucocorticoids and suggest a potential role for GIR in mediating the response to altered levels of glucocorticoids in disease states.

Changes in patient flow among five hospitals participating in a learning collaborative.

This was an evaluation of the efforts of five hospitals that participated in a collaborative aimed at improving patient flow and reducing emergency department (ED) crowding. Interviews with hospital implementation team members were conducted at two separate times, and multivariate linear regression models and bivariate logistic models were constructed to assess changes in ED length of stay (LOS) and left without being seen (LWBS). By the end of the collaborative, four of the five hospitals had at least one fully implemented improvement strategy. Those hospitals experienced modest improvements in patient flow: a hospital that implemented front-end improvements and devoted additional resources to fast track had a 51-min reduction in ED LOS, another that implemented only front-end improvements had a 9-min reduction in LOS, a third hospital that improved communication between the ED and inpatient units to facilitate admissions decreased LWBS from 0.6% to 0.4%, and a fourth hospital reduced LOS by 59 min for mid-acuity patients by establishing a new care process for them. Results suggest that relatively small changes may lead to improvements in measures of patient flow that are modest, at best.

Effect of short-term vitamin D supplementation on markers of vascular health in South Asian women living in the UK--a randomised controlled trial.

OBJECTIVE: Low vitamin D levels and risk factors for vascular disease are both common in South Asian women. This trial evaluated whether vitamin D supplementation could improve markers of vascular health in South Asian women with low 25-hydroxyvitamin D levels. METHODS: Parallel-group, double-blind, randomised placebo-controlled trial. Healthy South Asian women with baseline serum 25-hydroxyvitamin D levels of <75 nmol/L were randomised to receive a single dose of 100,000 units oral vitamin D3 or matching placebo. Outcomes were measured at baseline, 4 and 8 weeks. The primary outcome was change in endothelial function measured using brachial artery flow-mediated dilatation. Secondary outcomes included blood pressure, arterial stiffness, microvascular function measured using laser Doppler iontophoresis, insulin resistance, serum lipids, circulating markers of inflammation, thrombosis and adipokines. RESULTS: 50 women were randomised, 25 to each group. Mean age was 41 years; mean baseline 25-hydroxyvitamin D level was 27 nmol/L. 25-Hydroxyvitamin D levels rose in the vitamin D group relative to the placebo group by 4 weeks (16 nmol/L, 95% CI 11 to 21, p < 0.001). There was no improvement in flow-mediated dilatation in the vitamin D group relative to placebo at 4 weeks (0.1%, 95% CI -0.9 to 1.1, p = 0.84) or 8 weeks (0.0%, 95% CI -1.4 to 1.4, p = 0.98). There was no improvement in cholesterol, insulin resistance or markers of inflammation. Both platelet activation inhibitor-1 and tissue plasminogen activator levels fell significantly in the vitamin D group relative to placebo at 8 weeks. CONCLUSION: A single large dose of vitamin D3 did not improve blood pressure or endothelial function in South Asian women with low baseline 25-hydroxyvitamin D levels. TRIAL REGISTRATION: ISRCTN75081811.

Chronic lithium administration down regulates transthyretin mRNA expression in rat choroid plexus.

Transthyretin (TTR) accounts for a quarter of the protein content of ventricular cerebrospinal fluid (CSF) yet its exact role in the brain remains unknown. Patients with a diagnosis of depression have reduced CSF levels of TTR and the locus encoding the TTR gene has been implicated in a Danish pedigree of bipolar patients. Lithium, the major treatment for bipolar disorder in the UK, was subcutaneously infused into rats for 28 days in the form of lithium chloride using osmotic minipumps. In situ hybridizations using oligonucleotide probes targeted against the TTR transcript were performed on coronal brain sections. Lithium significantly reduced the level of transthyretin mRNA in the rat choroid plexus within the lateral and third ventricle. The down-regulation was confirmed using semi-quantitative reverse transcription PCR on dissected brain tissue. Recent studies in mice suggest that the TTR gene is implicated in depression-like behavior therefore this effect of lithium may be relevant to its use as a mood stabilizer or an adjuvant to antidepressant drugs.