Striatin heterozygous mice are more sensitive to aldosterone-induced injury.

Aldosterone modulates the activity of both epithelial (specifically renal) and non-epithelial cells. Binding to the mineralocorticoid receptor (MR), activates two pathways: the classical genomic and the rapidly activated non-genomic that is substantially modulated by the level of striatin. We hypothesized that disruption of MR's non-genomic pathway would alter aldosterone-induced cardiovascular/renal damage. To test this hypothesis, wild type (WT) and striatin heterozygous knockout (Strn+/-) littermate male mice were fed a liberal sodium (1.6% Na+) diet and randomized to either protocol one: 3 weeks of treatment with either vehicle or aldosterone plus/minus MR antagonists, eplerenone or esaxerenone or protocol two: 2 weeks of treatment with either vehicle or L-NAME/AngII plus/minus MR antagonists, spironolactone or esaxerenone. Compared to the WT mice, basally, the Strn+/- mice had greater (~26%) estimated renal glomeruli volume and reduced non-genomic second messenger signaling (pAkt/Akt ratio) in kidney tissue. In response to active treatment, the striatin-associated-cardiovascular/renal damage was limited to volume effects induced by aldosterone infusion: significantly increased blood pressure (BP) and albuminuria. In contrast, with aldosterone or L-NAME/AngII treatment, striatin deficiency did not modify aldosterone-mediated damage: in the heart and kidney, macrophage infiltration, and increases in aldosterone-induced biomarkers of injury. All changes were near-normalized following MR blockade with spironolactone or esaxerenone, except increased BP in the L-NAME/AngII model. In conclusion, the loss of striatin amplified aldosterone-induced damage suggesting that aldosterone's non-genomic pathway is protective but only related to effects likely mediated via epithelial, but not non-epithelial cells.

Histone demethylase LSD1 deficiency and biological sex: impact on blood pressure and aldosterone production.

Human risk allele carriers of lysine-specific demethylase 1 (LSD1) and LSD1-deficient mice have salt-sensitive hypertension for unclear reasons. We hypothesized that LSD1 deficiency causes dysregulation of aldosterone's response to salt intake resulting in increased cardiovascular risk factors (blood pressure and microalbumin). Furthermore, we determined the effect of biological sex on these potential abnormalities. To test our hypotheses, LSD1 male and female heterozygote-knockout (LSD1+/-) and WT mice were assigned to two age groups: 18 weeks and 36 weeks. Plasma aldosterone levels and aldosterone production from zona glomerulosa cells studied ex vivo were greater in both male and female LSD1+/- mice consuming a liberal salt diet as compared to WT mice consuming the same diet. However, salt-sensitive blood pressure elevation and increased microalbuminuria were only observed in male LSD1+/- mice. These data suggest that LSD1 interacts with aldosterone's secretory response to salt intake. Lack of LSD1 causes inappropriate aldosterone production on a liberal salt diet; males appear to be more sensitive to this aldosterone increase as males, but not females, develop salt sensitivity of blood pressure and increased microalbuminuria. The mechanism responsible for the cardiovascular protective effect in females is uncertain but may be related to estrogen modulating the effect of mineralocorticoid receptor activation.

Dysregulated aldosterone secretion in persons of African descent with endothelin-1 gene variants.

Compared with persons of European descent (ED), persons of African descent (AD) have lower aldosterone (ALDO) levels, with the assumption being that the increased cardiovascular disease (CVD) risk associated with AD is not related to ALDO. However, the appropriateness of the ALDO levels for the volume status in AD is unclear. We hypothesized that, even though ALDO levels are lower in AD, they are inappropriately increased, and therefore, ALDO could mediate the increased CVD in AD. To test this hypothesis, we analyzed data from HyperPATH - 1,788 individuals from the total cohort and 765 restricted to ED-to-AD in a 2:1 match and genotyped for the endothelin-1 gene (EDN1). Linear regression analyses with adjustments were performed. In the total and restricted cohorts, PRA, ALDO, and urinary potassium levels were significantly lower in AD. However, in the AD group, greater ALDO dysregulation was present as evidenced by higher ALDO/plasma renin activity (PRA) ratios (ARR) and sodium-modulated ALDO suppression-to-stimulation indices. Furthermore, EDN1 minor allele carriers had significantly greater ARRs than noncarriers but only in the AD group. ARR levels were modulated by a significant interaction between EDN1 and AD. Thus, EDN1 variants may identify particularly susceptible ADs who will be responsive to treatment targeting ALDO-dependent pathways (e.g., mineralocorticoid-receptor antagonists).

Development and validation of algorithms for the detection of statin myopathy signals from electronic medical records.

The purpose of this study was to develop and validate sensitive algorithms to detect hospitalized statin-induced myopathy (SIM) cases from electronic medical records (EMRs). We developed four algorithms on a training set of 31,211 patient records from a large tertiary hospital. We determined the performance of these algorithms against manually curated records. The best algorithm used a combination of elevated creatine kinase (>4× the upper limit of normal (ULN)), discharge summary, diagnosis, and absence of statin in discharge medications. This algorithm achieved a positive predictive value of 52-71% and a sensitivity of 72-78% on two validation sets of >30,000 records each. Using this algorithm, the incidence of SIM was estimated at 0.18%. This algorithm captured three times more rhabdomyolysis cases than spontaneous reports (95% vs. 30% of manually curated gold standard cases). Our results show the potential power of utilizing data and text mining of EMRs to enhance pharmacovigilance activities.

Statin Use and Adrenal Aldosterone Production in Hypertensive and Diabetic Subjects.

BACKGROUND: Statins substantially reduce cardiovascular mortality and appear to have beneficial effects independent of their lipid-lowering properties. We evaluated the hypothesis that statin use may modulate the secretion of aldosterone, a well-known contributor to cardiovascular disease. METHODS AND RESULTS: We measured adrenal hormones in 2 intervention studies. In study 1 in hypertensive subjects, aldosterone was analyzed at baseline and after angiotensin II stimulation on both high- and low-sodium diets (1122 observations, 15% on statins for >3 months). Statin users had 33% lower aldosterone levels in adjusted models (P<0.001). Cortisol was not modified by statins. In secondary analyses, the lowest aldosterone levels were seen with lipophilic statins and with higher doses. Statin users had lower blood pressure and reduced salt sensitivity of blood pressure (both P<0.001). In study 2, aldosterone was measured in diabetic patients on a high-sodium diet, before and after angiotensin II stimulation (143 observations, 79% statin users). Again, statin users had 26% lower aldosterone levels (P=0.006), particularly those using lipophilic statins. Ex vivo studies in rat adrenal glomerulosa cells confirmed that lipophilic statins acutely inhibited aldosterone, but not corticosterone, in response to different secretagogues. CONCLUSIONS: Statin use among hypertensive and diabetic subjects was associated with lower aldosterone secretion in response to angiotensin II and a low-sodium diet in 2 human intervention studies. This effect appeared to be most pronounced with lipophilic statins and higher doses. Future studies to evaluate whether aldosterone inhibition may partially explain the robust cardioprotective effects of statins are warranted.

Cooperative Role of Mineralocorticoid Receptor and Caveolin-1 in Regulating the Vascular Response to Low Nitric Oxide-High Angiotensin II-Induced Cardiovascular Injury.

Aldosterone interacts with mineralocorticoid receptor (MR) to stimulate sodium reabsorption in renal tubules and may also affect the vasculature. Caveolin-1 (cav-1), an anchoring protein in plasmalemmal caveolae, binds steroid receptors and also endothelial nitric oxide synthase, thus limiting its translocation and activation. To test for potential MR/cav-1 interaction in the vasculature, we investigated if MR blockade in cav-1-replete or -deficient states would alter vascular function in a mouse model of low nitric oxide (NO)-high angiotensin II (AngII)-induced cardiovascular injury. Wild-type (WT) and cav-1 knockout mice (cav-1(-/-)) consuming a high salt diet (4% NaCl) received Nω-nitro-l-arginine methyl ester (L-NAME) (0.1-0.2 mg/ml in drinking water at days 1-11) plus AngII (0.7-2.8 mg/kg per day via an osmotic minipump at days 8-11) ± MR antagonist eplerenone (EPL) 100 mg/kg per day in food. In both genotypes, blood pressure increased with L-NAME + AngII. EPL minimally changed blood pressure, although its dose was sufficient to block MR and reverse cardiac expression of the injury markers cluster of differentiation 68 and plasminogen activator inhibitor-1 in L-NAME+AngII treated mice. In aortic rings, phenylephrine and KCl contraction was enhanced with EPL in L-NAME+AngII treated WT mice, but not cav-1(-/-) mice. AngII-induced contraction was not different, and angiotensin type 1 receptor expression was reduced in L-NAME + AngII treated WT and cav-1(-/-) mice. In WT mice, acetylcholine-induced relaxation was enhanced with L-NAME + AngII treatment and reversed with EPL. Acetylcholine relaxation in cav-1(-/-) mice was greater than in WT mice, not modified by L-NAME + AngII or EPL, and blocked by ex vivo L-NAME, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or endothelium removal, suggesting the role of NO-cGMP. Cardiac endothelial NO synthase was increased in cav-1(-/-) versus WT mice, further increased with L-NAME + AngII, and not affected by EPL. Vascular relaxation to the NO donor sodium nitroprusside was increased with L-NAME + AngII in WT mice but not in cav-1(-/-) mice. Plasma aldosterone levels increased and cardiac MR expression decreased in L-NAME + AngII treated WT and cav-1(-/-) mice and did not change with EPL. Thus, during L-NAME + AngII induced hypertension, MR blockade increases contraction and alters vascular relaxation via NO-cGMP, and these changes are absent in cav-1 deficiency states. The data suggest a cooperative role of MR and cav-1 in regulating vascular contraction and NO-cGMP-mediated relaxation during low NO-high AngII-dependent cardiovascular injury.

Effect of overweight and obesity on pregnancy and birth outcomes

OBJECTIVES: To determine the effect of maternal overweight and obesity on pregnancy and birth outcome. DESIGN AND METHODS: This prospective study invited 160 women who attended their first antenatal visit at the University Hospital of the West Indies to participate in the study between June 2012 and February 2013. Maternal demographics, socioeconomic status, past medical and obstetric history, complications in pregnancy and birth outcome were collected. Body mass index (BMI) categories were created. Descriptive statistics reporting means ñ SD, Analysis of Variance (ANOVA), Chi Squared Test and regression analyses to determine whether maternal BMI or weight were independent predictors of birth and placental size were performed. RESULTS: Of the 160 women recruited, 126 (78.8%) were used for final analysis. There was an even distribution of mothers in each BMI category. A significant difference in blood pressure was seen between normal weight and obese women (systolic BP: p = 0.002, diastolic BP: p = 0.01). There was no statistical difference in women who developed an illness in pregnancy and in the admission rates across BMI categories (p = 0.92; p = 0.09 respectively). There was no significant difference in birth outcome across BMI categories. CONCLUSION: Overweight or class I obese women did not have an increased risk of adverse maternal and birth outcomes as compared to women with a normal BMI.

Aldosterone's rapid, nongenomic effects are mediated by striatin: a modulator of aldosterone's effect on estrogen action.

The cellular responses to steroids are mediated by 2 general mechanisms: genomic and rapid/nongenomic effects. Identification of the mechanisms underlying aldosterone (ALDO)'s rapid vs their genomic actions is difficult to study, and these mechanisms are not clearly understood. Recent data suggest that striatin is a mediator of nongenomic effects of estrogen. We explored the hypothesis that striatin is an intermediary of the rapid/nongenomic effects of ALDO and that striatin serves as a novel link between the actions of the mineralocorticoid and estrogen receptors. In human and mouse endothelial cells, ALDO promoted an increase in phosphorylated extracellular signal-regulated protein kinases 1/2 (pERK) that peaked at 15 minutes. In addition, we found that striatin is a critical intermediary in this process, because reducing striatin levels with small interfering RNA (siRNA) technology prevented the rise in pERK levels. In contrast, reducing striatin did not significantly affect 2 well-characterized genomic responses to ALDO. Down-regulation of striatin with siRNA produced similar effects on estrogen's actions, reducing nongenomic, but not some genomic, actions. ALDO, but not estrogen, increased striatin levels. When endothelial cells were pretreated with ALDO, the rapid/nongenomic response to estrogen on phosphorylated endothelial nitric oxide synthase (peNOS) was enhanced and accelerated significantly. Importantly, pretreatment with estrogen did not enhance ALDO's nongenomic response on pERK. In conclusion, our results indicate that striatin is a novel mediator for both ALDO's and estrogen's rapid and nongenomic mechanisms of action on pERK and phosphorylated eNOS, respectively, thereby suggesting a unique level of interactions between the mineralocorticoid receptor and the estrogen receptor in the cardiovascular system.

Human isolates of Listeria monocytogenes in Sweden during half a century (1958-2010).

Isolates of Listeria monocytogenes (n = 932) isolated in Sweden during 1958-2010 from human patients with invasive listeriosis were characterized by serotyping and pulsed-field gel electrophoresis (PFGE) (AscI). Of the 932 isolates, 183 different PFGE types were identified, of which 83 were each represented by only one isolate. In all, 483 serovar 1/2a isolates were distributed over 114 PFGE types; 90 serovar 1/2b isolates gave 32 PFGE types; 21 serovar 1/2c isolates gave nine PFGE types; three serovar 3b isolates gave one PFGE type; and, 335 serovar 4b isolates gave 31 PFGE types. During the 1980s in Sweden, several serovar 4b cases were associated with the consumption of European raw soft cheese. However, as cheese-production hygiene has improved, the number of 4b cases has decreased. Since 1996, serovar 1/2a has been the dominant L. monocytogenes serovar in human listeriosis in Sweden. Therefore, based on current serovars and PFGE types, an association between human cases of listeriosis and the consumption of vacuum-packed gravad and cold-smoked salmon is suggested.

Dissociation of hyperglycemia from altered vascular contraction and relaxation mechanisms in caveolin-1 null mice.

Hyperglycemia and endothelial dysfunction are associated with hypertension, but the specific causality and genetic underpinning are unclear. Caveolin-1 (cav-1) is a plasmalemmal anchoring protein and modulator of vascular function and glucose homeostasis. Cav-1 gene variants are associated with reduced insulin sensitivity in hypertensive individuals, and cav-1(-/-) mice show endothelial dysfunction, hyperglycemia, and increased blood pressure (BP). On the other hand, insulin-sensitizing therapy with metformin may inadequately control hyperglycemia while affecting the vascular outcome in certain patients with diabetes. To test whether the pressor and vascular changes in cav-1 deficiency states are related to hyperglycemia and to assess the vascular mechanisms of metformin under these conditions, wild-type (WT) and cav-1(-/-) mice were treated with either placebo or metformin (400 mg/kg daily for 21 days). BP and fasting blood glucose were in cav-1(-/-) > WT and did not change with metformin. Phenylephrine (Phe)- and KCl-induced aortic contraction was in cav-1(-/-) < WT; endothelium removal, the nitric-oxide synthase (NOS) blocker L-NAME (N(ω)-nitro-L-arginine methyl ester), or soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) enhanced Phe contraction, and metformin blunted this effect. Acetylcholine-induced relaxation was in cav-1(-/-) > WT, abolished by endothelium removal, L-NAME or ODQ, and reduced with metformin. Nitric oxide donor sodium nitroprusside was more potent in inducing relaxation in cav-1(-/-) than in WT, and metformin reversed this effect. Aortic eNOS, AMPK, and sGC were in cav-1(-/-) > WT, and metformin decreased total and phosphorylated eNOS and AMPK in cav-1(-/-). Thus, metformin inhibits both vascular contraction and NO-cGMP-dependent relaxation but does not affect BP or blood glucose in cav-1(-/-) mice, suggesting dissociation of hyperglycemia from altered vascular function in cav-1-deficiency states.

Activation of the mineralocorticoid receptor increases striatin levels.

BACKGROUND: Aldosterone (ALDO), a critical regulator of sodium homeostasis, mediates its effects via activation of the mineralocorticoid receptor (MR) through mechanisms that are not entirely clear. Striatin, a membrane associated protein, interacts with estrogen receptors in endothelial cells. METHODS: We studied the effects of MR activation in vitro and in vivo on striatin levels in vascular tissue. RESULTS: We observed that dietary sodium restriction was associated with increased striatin levels in mouse heart and aorta and that striatin and MR are present in the human endothelial cell line, (EA.hy926), and in mouse aortic endothelial cells (MAEC). Further, we show that MR co-precipitates with striatin in vascular tissue. Incubation of EA.hy926 cells with ALDO (10(-8) mol/l for 5-24 h) increases striatin protein and mRNA expression, an effect that was inhibited by canrenoic acid, an MR antagonist. Consistent with these observations, incubation of MAEC with ALDO increased striatin levels that were likewise blocked by canrenoic acid. To test the in vivo relevance of these findings, we studied two previously described mouse models of increased ALDO levels. Intraperitoneal ALDO administration augmented the abundance of striatin protein in mouse heart. We also observed that in a murine model of chronic ALDO-mediated cardiovascular damage following treatment with N(G)-nitro-L-arginine methyl ester plus angiotensin II an increased abundance of striatin protein in heart and kidney tissue. CONCLUSION: Our results provide evidence that increased striatin levels is a component of MR activation in the vasculature and suggest that regulation of striatin by ALDO may modulate estrogen's nongenomic effects.

Histone demethylase LSD1 deficiency during high-salt diet is associated with enhanced vascular contraction, altered NO-cGMP relaxation pathway, and hypertension.

Histone methylation, a determinant of chromatin structure and gene transcription, was thought to be irreversible, but recent evidence suggests that lysine-specific demethylase-1 (LSD1, Kdm1a) induces demethylation of histone H3 lysine 4 (H3K4) or H3K9 and thereby alters gene transcription. We previously demonstrated a human LSD1 phenotype associated with salt-sensitive hypertension. To test the hypothesis that LSD1 plays a role in the regulation of blood pressure (BP) via vascular mechanisms and gene transcription, we measured BP and examined vascular function and endothelial nitric oxide (NO) synthase (eNOS) expression in thoracic aorta of male wild-type (WT) and heterozygous LSD1 knockout mice (LSD1(+/-)) fed either a liberal salt (HS; 4% NaCl) or restricted salt diet (LS; 0.08% NaCl). BP was higher in LSD1(+/-) than WT mice on the HS diet but not different between LSD1(+/-) and WT mice on the LS diet. Further examination of the mechanisms of this salt-sensitive hypertension in LSD1(+/-) mice on the HS diet demonstrated that plasma renin activity and plasma levels and urinary excretion of aldosterone were less in LSD1(+/-) than WT, suggesting suppressed renin-angiotensin-aldosterone system. In contrast, phenylephrine (Phe)-induced aortic contraction was greater in LSD1(+/-) than WT mice on the HS diet. Treatment of aortic rings with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; a blocker of guanylate cyclase) enhanced Phe contraction in LSD1(+/-) compared with WT mice on the HS diet. Acetylcholine (Ach)-induced relaxation was less in LSD1(+/-) than WT mice on the HS diet. Endothelium removal or pretreatment with N(ω)-nitro-L-arginine methyl ester (blocker of NOS) or ODQ abolished Ach-induced relaxation in aorta of WT but had minimal effect in LSD1(+/-). Vascular relaxation to sodium nitroprusside, an exogenous NO donor and guanylate cyclase activator, was decreased in LSD1(+/-) vs. WT mice on the HS diet. RT-PCR and Western blots revealed decreased eNOS mRNA expression and eNOS and guanylate cyclase protein in the heart and aorta of LSD1(+/-) compared with WT mice on HS diet. Thus, during the HS diet, LSD1 deficiency is associated with hypertension, enhanced vascular contraction, and reduced relaxation via NO-cGMP pathway. The data support a role for LSD1-mediated histone demethylation in the regulation of NOS/guanylate cyclase gene expression, vascular function, and BP during the HS diet.

Caveolin-1 ablation reduces the adverse cardiovascular effects of N-omega-nitro-L-arginine methyl ester and angiotensin II.

Caveolae are the major cellular membrane structure through which extracellular mediators transmit information to intracellular signaling pathways. In vascular tissue (but not ventricular myocardium), caveolin-1 (cav-1) is the main component of caveolae; cav-1 modulates enzymes and receptors, such as the endothelial nitric oxide synthase and the angiotensin II (AngII) type 1 receptor. Evidence suggests that AngII and aldosterone (ALDO) are important mediators of ventricular injury. We have described a model of biventricular damage in rodents that relies on treatment with N-omega-nitro-l-arginine methyl ester (L-NAME (nitric oxide synthase inhibitor)) and AngII. This damage initiated at the vascular level and was observed only in the presence of ALDO and an activated mineralocorticoid receptor (MR). We hypothesize that cav-1 modulates the adverse cardiac effects mediated by ALDO in this animal model. To test this hypothesis, we assessed the ventricular damage and measures of inflammation, in wild-type (WT) and cav-1 knockout (KO) mice randomized to either placebo or L-NAME/AngII treatment. Despite displaying cardiac hypertrophy at baseline and higher blood pressure responses to L-NAME/AngII, cav-1 KO mice displayed, as compared with WT, decreased treatment-induced biventricular damage as well as decreased transcript levels of the proinflammatory marker plasminogen activator inhibitor-1. Additionally, L-NAME/AngII induced an increase in cardiac MR levels in WT but not cav-1-ablated mice. Moreover and despite similar circulating ALDO levels in both genotypes, the myocardial damage (as determined histologically and by plasminogen activator inhibitor-1 mRNA levels) was less sensitive to ALDO levels in cav-1 KO vs. WT mice, consistent with decreased MR signaling in the cav-1 KO. Thus, we conclude that the L-NAME/AngII-induced biventricular damage is mediated by a mechanism partially dependent on cav-1 and signaling via MR/ALDO.

Bovine subclinical mastitis caused by different types of coagulase-negative staphylococci.

Subclinical mastitis caused by intramammary infections (IMI) with coagulase-negative staphylococci (CNS) is common in dairy cows and may cause herd problems. Control of CNS mastitis is complicated by the fact that CNS contain a large number of different species. The aim of the study was to investigate the epidemiology of different CNS species in dairy herds with problems caused by subclinical CNS mastitis. In 11 herds, udder quarter samples were taken twice 1 mo apart, and CNS isolates were identified to the species level by biochemical methods. The ability of different CNS species to induce a persistent infection, and their associations with milk production, cow milk somatic cell count, lactation number, and month of lactation in cows with subclinical mastitis were studied. Persistent IMI were common in quarters infected with Staphylococcus chromogenes, Staphylococcus epidermidis, and Staphylococcus simulans. The results did not indicate differences between these CNS species in their association with daily milk production, cow milk somatic cell count, and month of lactation in cows with subclinical mastitis. In cows with subclinical mastitis, S. epidermidis IMI were mainly found in multiparous cows, whereas S. chromogenes IMI were mainly found in primiparous cows.

Modality of physical exercise and cognitive function in Hong Kong older Chinese community.

OBJECTIVE: We reported the association between modality of Physical Exercise and cognitive function in 782 older Chinese adults assessed in the second phase of a population survey for dementia in Hong Kong. METHODS: Profiles of physical exercise was measured by a questionnaire (no exercise, stretching, aerobic and mind-body exercise). Cognitive Assessments included the CMMSE, ADAS-Cog, and Category Verbal Fluency Test (CVFT). RESULTS: The aerobic and mind body exercise groups with longer exercise habits (>5 years) had higher scores in most cognitive tests (Kruskal Wallis tests, p < 0.01). Beneficial effects were more significant in the young old group from 65- 75 years. CONCLUSIONS: Possible age related specific effects of aerobic and mind body exercise on cognitive reserve are worthy of further exploration.

Mineralocorticoid receptor blockade reverses obesity-related changes in expression of adiponectin, peroxisome proliferator-activated receptor-gamma, and proinflammatory adipokines.

BACKGROUND: In obesity, decreases in adiponectin and increases in proinflammatory adipokines are associated with heart disease. Because adipocytes express mineralocorticoid receptor (MR) and MR blockade reduces cardiovascular inflammation and injury, we tested the hypothesis that MR blockade reduces inflammation and expression of proinflammatory cytokines in adipose tissue and increases adiponectin expression in adipose tissue and hearts of obese mice. METHODS AND RESULTS: We determined the effect of MR blockade (eplerenone, 100 mg/kg per day for 16 weeks) on gene expression in retroperitoneal adipose and heart tissue from obese, diabetic db/db mice (n=8) compared with untreated obese, diabetic db/db mice (n=10) and lean, nondiabetic db/+ littermates (n=11). Expression of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, plasminogen activator inhibitor type 1, and macrophage protein CD68 increased, and expression of adiponectin and peroxisome proliferator-activated receptor-gamma decreased in retroperitoneal adipose tissue from obese versus lean mice. In addition, adiponectin expression in heart was reduced in obese versus lean mice. MR blockade prevented these obesity-related changes in gene expression. Furthermore, treatment of undifferentiated preadipocytes with aldosterone (10(-8) mol/L for 24 hours) increased mRNA levels of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 and reduced mRNA and protein levels of peroxisome proliferator-activated receptor-gamma and adiponectin, supporting a direct aldosterone effect on gene expression. CONCLUSIONS: MR blockade reduced expression of proinflammatory and prothrombotic factors in adipose tissue and increased expression of adiponectin in heart and adipose tissue of obese, diabetic mice. These effects on adiponectin and adipokine gene expression may represent a novel mechanism for the cardioprotective effects of MR blockade.

Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice.

Changes in dietary sodium intake are associated with changes in vascular volume and reactivity that may be mediated, in part, by alterations in endothelial nitric oxide synthase (eNOS) activity. Caveolin-1 (Cav-1), a transmembrane anchoring protein in the plasma membrane caveolae, binds eNOS and limits its translocation and activation. To test the hypothesis that endothelial Cav-1 participates in the dietary sodium-mediated effects on vascular function, we assessed vascular responses and nitric oxide (NO)-mediated mechanisms of vascular relaxation in Cav-1 knockout mice (Cav-1-/-) and wild-type control mice (WT; Cav-1+/+) placed on a high-salt (HS; 4% NaCl) or low-salt (LS; 0.08% NaCl) diet for 16 days. After the systolic blood pressure was measured, the thoracic aorta was isolated for measurement of vascular reactivity and NO production, and the heart was used for measurement of eNOS expression and/or activity. The blood pressure was elevated in HS mice treated with NG-nitro-l-arginine methyl ester and more so in Cav-1-/- than WT mice and was significantly reduced during the LS diet. Phenylephrine caused vascular contraction that was significantly reduced in Cav-1-/- (maximum 0.25 +/- 0.06 g/mg) compared with WT (0.75 +/- 0.22 g/mg) on the HS diet, and the differences were eliminated with the LS diet. Also, vascular contraction in response to membrane depolarization by high KCl (96 mM) was reduced in Cav-1-/- (0.27 +/- 0.05 g/mg) compared with WT mice (0.53 +/- 0.12 g/mg) on the HS diet, suggesting that the reduced vascular contraction is not limited to a particular receptor. Acetylcholine (10(-5) M) caused aortic relaxation in WT mice on HS (23.6 +/- 3.5%) and LS (23.7 +/- 5.5%) that was enhanced in Cav-1-/- HS (72.6 +/- 6.1%) and more so in Cav-1-/- LS mice (93.6 +/- 3.5%). RT-PCR analysis indicated increased eNOS mRNA expression in the aorta and heart, and Western blots indicated increased total eNOS and phosphorylated eNOS in the heart of Cav-1-/- compared with WT mice on the HS diet, and the genotypic differences were less apparent during the LS diet. Thus Cav-1 deficiency during the HS diet is associated with decreased vasoconstriction, increased vascular relaxation, and increased eNOS expression and activity, and these effects are altered during the LS diet. The data support the hypothesis that endothelial Cav-1, likely through an effect on eNOS activity, plays a prominent role in the regulation of vascular function during substantial changes in dietary sodium intake.

Screening of mild cognitive impairment in Chinese older adults--a multistage validation of the Chinese abbreviated mild cognitive impairment test.

OBJECTIVE: To develop a short cognitive test for screening mild cognitive impairment (MCI) in Hong Kong Chinese older adults. METHODS: The Chinese Abbreviated MCI (CAMCI) test was developed with a multistage process. In phase 1, a short version of the cognitive test comprising a 1-min animal fluency test and a 10-min delayed word list recall was developed and tested in 578 volunteers (community-dwelling active elderly persons). In phase 2, the CAMCI test was validated in an independent and randomly recruited sample of 459 participants in a community survey. Additionally, the predictive significance of the CAMCI test was evaluated in a group of 196 subjects assessed in phase 1 for conversion to clinical dementia at 20 months' follow-up. The discriminating power of the CAMCI test in differentiating MCI from normal control (NC) and mildly demented subjects was compared with Mini Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) subscales. RESULTS: The CAMCI test was found to have high discriminating power in differentiating NC from MCI and mildly demented subjects in the phase 1 volunteer sample. The receiver operating characteristics (ROC) revealed an area under the curve (AUC) of 0.91. The ROC were further validated in the phase 2 sample. The AUC of the CAMCI test was compared with MMSE and ADAS-Cog subscales. The short MCI test was comparable to the ADAS-Cog subscale in discriminating NC from MCI and demented subjects (chi(2) test, p = n.s.). Logistic regression analysis was carried out to determine significant baseline predictors for conversion to dementia at phase 3 follow-up. Both ADAS-Cog total [Exp(B) = 1.115, p = 0.028] and CAMCI [Exp(B) = 0.88, p = 0.045] scores were significant predictors for dementia status at follow-up. CONCLUSION: The CAMCI test is able to discriminate NC from MCI and mild dementia in Hong Kong Chinese older adults. Its potential for large-scale community screening for early detection of cognitive impairment in late life should be emphasized and explored.

Prevalence of very mild and mild dementia in community-dwelling older Chinese people in Hong Kong.

INTRODUCTION: In this report, the results of a household survey were used to examine the prevalence of very mild and mild dementia in Chinese older persons in Hong Kong. METHODS: The study adopted a two-phase design. At Phase 1, 6100 subjects were screened using the Cantonese version of the Mini-mental State Examination (MMSE) and a short memory inventory. At Phase 2, 2073 subjects were screened positive and 737 were evaluated by psychiatrists. Clinical Dementia Rating (CDR) and cognitive assessment were used for diagnosis of dementia. Very mild dementia (VMD) was defined as a global CDR of 0.5, with memory and non-memory subscale scores of 0.5 or more. Mild dementia was classified for subjects with a CDR of 1. RESULTS: The overall prevalence of VMD and mild dementia for persons aged 70 years or above was 8.5% (95%CI: 7.4-9.6) and 8.9% (95%CI: 7.8-10.0) respectively. Among subjects with clinical dementia, 84.6% had mild (CDR1) dementia. Logistic regression analyses revealed that older age, lower educational level and significant cerebrovascular risk factors were risk factors for dementia, while regular physical exercise was a protective factor for dementia. CONCLUSIONS: A sizable proportion of community-living subjects suffered from milder forms of dementia. They represent a high risk for early intervention to reduce potential physical and psychiatric morbidity.

Prevalence of clinically significant depressive symptoms in an epidemiologic sample of community-dwelling elders with milder forms of cognitive impairment in Hong Kong SAR.

BACKGROUND: Depression and cognitive impairment in later-life have great bearings on public health. The two conditions often co-occur and have mutual implications on short-term risk and long-term prognosis. METHOD: A two-phase epidemiologic survey on the prevalence of dementia in elders aged 60 and over was conducted in Hong Kong in 2005-2006. In the first phase, 6,100 randomly selected community dwelling elders were assessed with Cantonese version of Mini-Mental State Examination (C-MMSE) and Abbreviated Memory Inventory for Chinese (AMIC). Two thousand and seventy-three subjects were screened positive and invited for second phase cognitive and psychiatric assessment. 35.5% of screen-positive subjects participated in Phase 2 assessment conducted by psychiatrists for diagnosis of dementia. Severity of dementia was determined using Clinical Dementia Rating Scale (CDR). Cornell Scale for Depression in Dementia (CSDD) and a structured bedside cognitive battery were also administered to each subject. RESULTS: 1.7% of subjects with CDR 0.5 and 5.9% of subjects with CDR 1 had clinically significant depressive symptoms (>or= 8 on CSDD). Score on CSDD correlated positively with duration of cognitive symptoms, scores on CIRS and CMMSE in linear regression model. In a logistic regression model, male gender, duration of cognitive symptoms, CIRS and CMMSE was associated with increased risk for clinically significant depressive symptoms. CONCLUSIONS: In our sample, milder forms of cognitive impairment were associated with increased risk for depression in the presence of other risk factors such as male gender, higher physical illness burden and longer duration of cognitive symptoms.