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Decreased brain sigma-1 receptor contributes to the relationship between heart failure and depression
Aims Depression often coexists with cardiovascular disease, such as hypertension and heart failure, in which sympathetic hyperactivation is critically involved. Reduction in the brain sigma-1 receptor (S1R) functions in depression pathogenesis via neuronal activity modulation. We hypothesized that reduced brain S1R exacerbates heart failure, especially with pressure overload via sympathetic hyperactivation and worsening depression.
Methods and results Male Institute of Cancer Research mice were treated with aortic banding and, 4 weeks thereafter, fed a high-salt diet for an additional 4 weeks to accelerate cardiac dysfunction (AB-H). Compared with sham-operated controls (Sham), AB-H showed augmented sympathetic activity, decreased per cent fractional shortening, increased left ventricular dimensions, and significantly lower brain S1R expression. Intracerebroventricular (ICV) infusion of S1R agonist PRE084 increased brain S1R expression, lowered sympathetic activity, and improved cardiac function in AB-H. ICV infusion of S1R antagonist BD1063 increased sympathetic activity and decreased cardiac function in Sham. Tail suspension test was used to evaluate the index of depression-like behaviour, with immobility time and strain amplitude recorded as markers of struggle activity using a force transducer. Immobility time increased and strain amplitude decreased in AB-H compared with Sham, and these changes were attenuated by ICV infusion of PRE084.
Conclusion These results indicate that decreased brain S1R contributes to the relationship between heart failure and depression in a mouse model of pressure overload.
- Sympathetic nervous system
- Heart failure
- Depression
- Brain sigma-1 receptor
- Pressure overload
1. Introduction
Numerous studies have demonstrated that heart failure and depression often coexist, and that depression is linked to the severity of heart failure symptoms.1,2 Heart failure and depression are both individually associated with poor health outcomes, and depression also adversely affects heart failure outcomes.3,4 Importantly, depression is associated with the risk of heart failure among patients with hypertension.5 Furthermore, hypertensive heart disease is well recognized as the major cause of heart failure.6 One of the physiological mechanisms involved in both depression and heart failure is high sympathetic tone caused by cardiovascular autonomic dysregulation.7,8 The central nervous system contributes to the worsening of both heart failure9 and hypertension.10 The detailed mechanisms involved in this process remain unclear, but these findings suggest the presence of a common pathway for heart failure and depression in the brain.
Recently, a reduction in brain sigma-1 receptor (S1R) expression has been shown to play a key role in the pathogenesis of depression.11 S1R ligands have been reported to have antidepressant activity in behavioural models of depression.12 The S1R has been shown to modulate neuronal intracellular calcium levels13 and N-methyl-d-aspartate-mediated response.14,15 The results of these studies strongly suggest that the S1R contributes to the regulation of neuronal activity. Neurosteroids such as dehydroepiandrosterone (DHEA) and its sulfate conjugate (DHEAS) are recognized as endogenous S1R agonists,16 and DHEAS was reported to decrease in heart failure.17 Therefore, we hypothesized that expression of brain S1R is reduced in heart failure via decreased DHEAS, and that this reduced expression contributes to the exacerbation of heart failure via enhanced sympathetic activity and worsening of depression. Therefore, the aim of the present study was to assess the role of the brain S1R in the relationship between heart failure and depression.
Recently, we found that a pressure overload model with salt loading is a model of hypertensive heart disease leading to heart failure.18 The relationship between hypertension and depression has been well recognized, and depression is associated with the risk of heart failure among patients with hypertension.5 In addition, the pressure overload model was reported to decrease S1R expression in the left ventricle.16,19 Therefore, the pressure overload model was used in the present study. Aortic banding (AB) was performed in mice then fed a high-salt (HS) diet to accelerate cardiac dysfunction.18 We investigated (i) sympathetic activity by 24-h urinary norepinephrine (U-NE) excretion18,20 and cardiac function by echocardiography18,20; (ii) brain S1R expression; (iii) the index of depression-like behaviour; (iv) the effects of intracerebroventricular (ICV) infusion of PRE084, a selective S1R agonist,24,25 and BD1063, a selective S1R antagonist,21,22 on sympathetic activity, cardiac function, brain S1R expression, and the index of depression-like behaviour and (v) the concentration of serum and brain DHEAS.
2. Methods
2.1 Animals
The study was reviewed and approved by the Committee on Ethics of Animal Experiments, Kyushu University Graduate School of Medical Sciences, and conducted according to the Guidelines for Animal Experiments of Kyushu University and the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised 1996). Male Institute of Cancer Research (ICR) mice (10 weeks old; SLC, Fukuoka, Japan) were used. Sodium pentobarbital was used as anaesthetic, and the adequacy of anaesthesia was confirmed by the absence of a withdrawal response to hindpaw nociceptive stimulation.
2.2 Mouse heart failure model
Mice under sodium pentobarbital [25–40 mg/kg intraperitoneal (ip)] anaesthesia were treated with AB at the suprarenal abdominal aorta18,20 with 5–0 silk sutures guided by a blunted 27-gauge needle, which was withdrawn as quickly as possible. Sham-operated mice (Sham) served as controls. Four weeks later, both AB mice and Sham mice were fed a HS (8% NaCl) diet for 4 weeks (Sham-H or AB-H).18,20 The survival rates after heart failure model preparation were as follows: 4 weeks after AB, 97%; 8 weeks after AB with HS diet (AB-H), 83%.
2.3 Evaluation of cardiac function
Cardiac function was evaluated by echocardiography18,20 under light sodium pentobarbital anaesthesia with spontaneous respiration. An echocardiography system (SSD5000; Aloka, Tokyo, Japan) with a dynamically focused 7.5-MHz linear array transducer was used, and M-mode tracings from the short-axis view at the level of the papillary muscle were recorded. Left ventricle (LV) end-diastolic diameter (LVDD), LV end-systolic diameter (LVSD), and LV wall thickness (LVWT), calculated as the mean thickness of the interventricular septum and the posterior LV wall, were measured, and per cent fractional shortening (%FS) was calculated as follows:
2.4 Evaluation of blood pressure, heart rate, and sympathetic activity
In acute experiments, sympathetic activity was evaluated by power spectral analysis.24,25 Blood pressure (BP) and the heart rate were measured by right carotid artery cannulation with a stretched polyethylene tube (PE50). Data were recorded using the Powerlab system and Chart 5 software (AD Instruments), and the power spectrum of the beat-by-beat systolic blood pressure (SBP) time series and the beat-by-beat pulse interval time series was calculated using the maximum entropy method with MemCalc software (Suwa Trust Co, Ltd).24 Two zones of interest for autonomic control of BP and the heart rate were observed. The first zone, covering the 0.15–0.6 Hz range of the SBP spectrum, was used as a low-frequency zone reflecting sympathetic control in mice. The second zone, covering the 2.5–5.0 Hz range of the pulse interval spectrum, was used as a high-frequency zone reflecting vagal control in mice.25 In chronic experiments, sympathetic activity was evaluated by measuring 24-h U-NE excretion using high-performance liquid chromatography.18,20
2.5 ICV infusion
Under sodium pentobarbital anaesthesia (25–40 mg/kg, i.p.), mice were placed in a stereotaxic frame, and the skin overlying the midline of the skull was incised. A small hole was made with a dental drill at 0.3 mm posterior and 1 mm lateral to bregma.18,20 An infusion cannula (Alzet® brain infusion kit 3; DURECT Corporation, CA, USA) was inserted and fixed to the skull surface with tissue adhesive (the tip of the cannula located 3 mm below the skull surface).18,20 In acute experiments, the infusion cannula was connected to a syringe filled with PRE084, a specific S1R agonist (1 mM), and the agent was infused using a microsyringe pump (infusion rate 1.0 μL/min for 10 min) while measuring BP and the heart rate. In chronic experiments, the infusion cannula was connected to an osmotic minipump (Alzet model 1004; DURECT) inserted subcutaneously into the back for infusion of PRE084 into AB-H (2 mM; infusion rate 0.11 μL/h for 4 weeks initiated concomitantly with HS intake) or BD1063, a specific S1R antagonist, into Sham (2 mM; infusion rate 0.11 μL/h for 4 weeks initiated from 4 weeks after sham operation).
2.6 Oral drug administration
Fluvoxamine maleate (Sigma Aldrich Co., St Louis, MO, USA) mixed in powdered chow was administered orally to AB-H for 4 weeks initiated concomitantly with HS intake for an estimated oral administered fluvoxamine dose of ∼1.0 mg/kg/day.19
2.7 Measurement of organ weight
After completion of the experiments, mice were killed with an overdose of sodium pentobarbital, the heart and lungs were removed, and organ weight was measured.
2.8 Evaluation of S1R expression in the brain
2.8.1 Western blot analysis
Animals were killed with an overdose of sodium pentobarbital. Tissues obtained from the circumventricular tissues including the hypothalamus were homogenized in lysis buffer containing 40 mmol/L HEPES (4-[2-hydroxyethyl]-1-piperazineethanesulfonic acid), 1% Triton® X-100, 10% glycerol, 1 mmol/L sodium orthovanadate, and 1 mmol/L phenylmethylsulfonyl fluoride. Protein concentration was determined with a bicinchoninic acid protein assay kit (Pierce Chemical Co., Rockford, IL, USA). A 15 μg protein aliquot from each sample was separated on a polyacrylamide gel with 10% sodium dodecyl sulfate. The proteins were subsequently transferred onto polyvinylidene difluoride membranes (Immobilon®-P membranes; Millipore, Billerica, MA, USA). A rabbit immunoglobulin G (IgG) polyclonal antibody against S1R (1:1000; Santa Cruz Biotechnology, Santa Cruz, CA, USA) was used as primary antibody.26 Membranes were then incubated with horseradish peroxidase-conjugated horse anti-rabbit IgG antibody (1:10 000). Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as an internal control for the brain tissues. Immunoreactivity was detected by enhanced chemiluminescence autoradiography (ECLTM western blotting detection kit; Amersham Pharmacia Biotech, Uppsala, Sweden), and the film was analysed using the public domain software NIH Image (developed at the US National Institutes of Health and available on the Internet at http://rsb.info.nih.gov/nih-image/).
2.8.2 Reverse transcriptase PCR
Total RNA was prepared from the circumventricular tissues including hypothalamus using RNAlater solution (Ambion, Austin, TX, USA). Complementary DNAs were synthesized by standard techniques using a ReverTra Ace qPCR RT Kit (TOYOBO, Osaka, Japan). Real-time PCR was performed, recorded, and analysed using a thermal cycler dice real-time system (Takara Bio, Shiga, Japan) with SYBR Green I detection. cDNA was amplified using a SYBR Premix Ex Taq (Perfect Real Time) PCR kit (Takara Bio) with specific primers (Sigma R1, forward: 5′-CTC GCT GTC TGA GTA CGT G-3′; reverse: 5′-AAG AAA GTG TCG GCT AGT GCA A-3′; HPRT1, forward: 5′-GCG TCG TGA TTA GCG ATG ATG AAC-3′; reverse: 5′-CCT CCC ATC TCC TCC ATG ACA TCT-3′). HPRT1 was used as a reference to normalize the amount of total RNA amplified in each reaction. Relative gene expression data were analysed using the 2 (−▵▵CT) method.27
2.9 Evaluation of the depression-like behaviour index
Depression was evaluated by the tail suspension test, which uses increased immobility time as an index of depression-like behaviour in mice.28 Tail suspension was conducted in a force transducer, and strain amplitude data were also recorded using the Powerlab system as a marker of struggle activity. The test was performed in the afternoon, and immobility time and struggle activity were determined during 6-min recordings. Additionally, locomotor activity was evaluated by a digital actophotometer.29 Two mice were placed in the actophotometer apparatus cage, and the total number of ambulatory movements was scored over 24 h. The daily variation of locomotor activity was also evaluated by the ratio of movement scores from night to day.
2.10 Measurement of serum and brain DHEAS
Under anaesthesia with an overdose of sodium pentobarbital, a blood sample was collected from the right ventricle, and the mice were perfused with distilled H2O. After adequate perfusion to remove blood, the brain circumventricular tissues and hypothalamus were dissected out. The tissues (0.10 g) were homogenized in 200 μL distilled H2O, rapidly centrifuged, and the supernatant was collected.18 DHEAS concentration was measured by enzyme-linked immunosorbent assay (ELISA).
2.11 Statistical analysis
All values are expressed as mean ± SE. Analysis of variance was used to compare U-NE, organ weight, LVDD, LVSD, LVWT, %FS, immobility time, strain amplitude, DHEAS concentration, mRNA levels, and protein levels between groups. An unpaired t-test was used to compare locomotor activity between Sham and AB-H and changes in protein levels between mice treated with and without S1R ligands. Differences were considered significant at P < 0.05.
3. Results
3.1 Characteristics of AB-H
Both relative heart weight (heart weight/body weight) and absolute heart weight were greater in AB-H than Sham (relative heart weight: Sham, 4.87 ± 0.05 mg/g; AB-H, 6.45 ± 0.08 mg/g, absolute heart weight: Sham, 0.23 ± 0.02 g; AB-H, 0.26 ± 0.05 g; P < 0.05, n = 8 per group). Relative lung weight (lung weight/body weight) tended to increase in AB-H compared with Sham (Sham, 5.81 ± 0.15mg/g; AB-H, 6.20 ± 0.09 mg/g; n = 8 per group). The body weight of AB-H was significantly lower than that of Sham (Sham, 47.4 ± 0.8 g; AB-H, 40.6 ± 1.1 g; P < 0.05, n = 8 per group). Echocardiography revealed that LV dimensions and LVWT were greater in AB-H than Sham, and %FS was significantly lower in AB-H than Sham (Figure 1). Sympathetic activity evaluated by U-NE excretion was increased in AB-H compared with Sham (Sham, 350 ± 44 ng/day; AB-H, 731 ± 26 ng/day; P < 0.05, n = 8 per group). In Sham, HS intake did not alter body weight, organ weight, cardiac function, or sympathetic activity (Sham vs. Sham-H). Mean BP was lower and the heart rate was higher in AB-H than Sham (mean BP: Sham, 90 ± 2 mmHg; AB-H, 78 ± 1 mmHg, heart rate: Sham, 422 ± 16 b.p.m.; AB-H, 477 ± 14 b.p.m.; P < 0.05, n = 5 per group). Tail suspension test revealed increased immobility time and decreased strain amplitude in AB-H compared with Sham (Figure 2A–C). Locomotor activity (24 h) was lower in AB-H than Sham (Sham, 7387 ± 459 counts; AB-H, 3877 ± 864 counts; P < 0.05, n = 6 per group), and the ratio of locomotor activity during night to day, a marker of daily variation, was smaller in AB-H than Sham (Sham, 3.2 ± 0.6; AB-H, 1.6 ± 0.1; P < 0.05, n = 6 per group).
3.2 S1R expression in the brain
The protein levels of brain S1R were decreased in AB-H compared with Sham. In Sham, HS intake did not alter those levels (Figure 3). The mRNA levels of brain S1R did not significantly alter between Sham and AB-H (Sham, 1.2 ± 0.1; AB-H, 0.9 ± 0.1; n = 5 per group).
3.3 Effects of acute PRE084 ICV infusion on cardiovascular regulation
ICV infusion of PRE084 lowered heart rate in both AB-H and Sham. However, changes in the heart rate were significantly smaller in AB-H than in Sham (Figure 4A). Furthermore, sympathetic activity evaluated by power spectral analysis of SBP was decreased significantly only in Sham (Figure 4B).
3.4 Effects of chronic PRE084 ICV infusion
Chronic ICV infusion of PRE084 (PRE) increased protein levels of brain S1R in AB-H compared with no treatment (Figure 5A). mRNA levels of brain S1R slightly increased after chronic PRE084 ICV infusion (AB-H, 0.9 ± 0.1; AB-H with PRE, 1.3 ± 0.1; P < 0.05, n = 5 per group). Chronic PRE084 ICV infusion lowered the enhanced sympathetic activity (AB-H, 731 ± 26 ng/day; AB-H with PRE, 571 ± 43 ng/day; P < 0.05, n = 8 and 5, respectively) and improved cardiac function in AB-H compared with no treatment (Figure 5B). Furthermore, PRE084 also decreased both relative heart weight (heart weight/body weight) and absolute heart weight compared with no treatment (relative heart weight: AB-H, 6.45 ± 0.08 mg/g; AB-H with PRE, 4.50 ± 0.15 mg/g, absolute heart weight: AB-H, 0.26 ± 0.05 g; AB-H with PRE, 0.19 ± 0.07 g; P < 0.05, n = 8 and 5, respectively). Chronic ICV infusion of PRE084 decreased immobility time and increased strain amplitude in AB-H compared with no treatment (Figure 5C).
3.5 Effects of chronic oral administration of fluvoxamine
Chronic oral administration of fluvoxamine lowered enhanced sympathetic activity (AB-H, 731 ± 26 ng/day; AB-H with fluvoxamine, 561 ± 20 ng/day; P < 0.05, n = 8 and 5, respectively) and improved cardiac function compared with no treatment (%FS: AB-H, 27 ± 2%; AB-H with fluvoxamine 37 ± 3%; P < 0.05, n = 8 and 5, respectively). Chronic oral administration of fluvoxamine decreased immobility time and increased strain amplitude compared with no treatment (immobility time: AB-H, 162 ± 9 s; AB-H with fluvoxamine, 93 ± 10 s; strain amplitude: AB-H, 0.12 ± 0.01; AB-H with fluvoxamine, 0.19 ± 0.02; both P < 0.05, n = 15 and 5, respectively).
3.6 Effects of chronic BD1063 ICV infusion on characteristics of Sham mice
Chronic ICV infusion of BD1063 (BD)-enhanced sympathetic activity (24-h U-NE excretion: Sham, 350 ± 44 ng/day; Sham with BD, 576 ± 25 ng/day; P < 0.05, n = 8 and 5, respectively) and tended to impair cardiac function compared with no treatment (%FS: Sham, 47 ± 2%; Sham with BD, 40 ± 3%; P < 0.05, n = 8 and 5, respectively).
3.7 DHEAS concentration
Serum DHEAS concentrations were lower in AB-H compared with Sham or Sham-H (Sham, 0.039 ± 0.009 μg/mL; Sham-H, 0.040 ± 0.006 μg/mL; AB-H, 0.013 ± 0.008 μg/mL; P < 0.05, n = 5 per group). Brain DHEAS concentrations were also lower in AB-H compared with Sham or Sham-H (Sham, 0.047 ± 0.001 μg/mL; Sham-H, 0.046 ± 0.002 μg/mL; AB-H, 0.033 ± 0.005 μg/mL; P < 0.05, n = 5 per group).
4. Discussion
The present study demonstrates that in AB-H (i) cardiac function decreased with enhanced sympathetic activity; (ii) brain S1R expression decreased; (iii) the index of depression-like behaviour was higher compared with Sham; (iv) the decrease in sympathetic activity and the heart rate in response to acute ICV infusion of PRE084, a selective S1R agonist, was smaller compared with Sham; and (v) chronic ICV infusion of PRE084 increased brain S1R expression, lowered enhanced sympathetic activity, and improved cardiac function and the index of depression-like behaviour. These findings indicate that the reduction in brain S1R expression in AB-H contributed to both the exacerbation of cardiac dysfunction via enhanced sympathetic activity and the worsening of depression.
4.1 Reduction of brain S1R in AB-H mice
We demonstrated that the expression of brain S1R was decreased in AB-H and that this reduction was involved in the enhanced sympathetic activity. In AB-H, LV dimensions and LVWT increased, and %FS decreased with the enhanced sympathetic activity. We have previously confirmed the elevated LV end-diastolic pressure observed in this model.18 Therefore, AB-H was used as a model for pressure-overload-induced heart failure. The protein levels of brain S1R were significantly decreased in AB-H, and ICV infusion of PRE084 decreased sympathetic activity and the heart rate to a greater extent in Sham than in AB-H. These results indicate that the protein levels of brain S1R and the S1R response to the receptor agonist were decreased in AB-H. The mRNA levels of brain S1R were also examined in the present study and found not to differ between Sham and AB-H, suggesting a higher turnover rate of S1R in AB-H.30
4.2 Depressive status in AB-H
We demonstrated that immobility time was increased in AB-H compared with Sham. In addition, a decrease in strain amplitude was confirmed as a marker of struggle activity in AB-H. AB-H had lower cardiac function compared with Sham, and the results of the tail suspension test may reflect exercise intolerance caused by cardiac dysfunction. However, short-term momentum in the home cage measured immediately after the test did not differ between AB-H and Sham (data not shown), suggesting that the results of the tail suspension test reflect the greater depressive status in AB-H, rather than exercise intolerance caused by cardiac dysfunction. Furthermore, the decreased 24-h locomotor activity and disappearance of daily variation of locomotor activity were confirmed in AB-H.
4.3 Effects of brain S1R stimulation
To clarify the importance of the reduction in brain S1R expression in this heart failure model, chronic ICV infusion of PRE084 in AB-H and BD1063 in Sham was performed. Chronic PRE084 ICV infusion increased brain S1R expression in AB-H. Our findings are compatible with those of previous studies, in which expression of the S1R was reported to increase in response to chronic agonist stimulation.16 In addition, chronic PRE084 ICV infusion attenuated the enhanced sympathetic activity and improved cardiac function in AB-H. In contrast, chronic BD1063 ICV infusion enhanced sympathetic activity and tended to decrease cardiac function in Sham. ICV infusion of PRE084 also improved the index of depression-like behaviour in AB-H.
To our knowledge, no previous studies have reported chronic PRE084 or BD1063 infusion into the cerebrospinal fluid (CSF). PRE084 has an IC50 of 44 nM in the S1R and IC50 > 10 000 nM in a variety of other receptors.21 BD1063 has nanomolar affinity for S1R and is 30-fold more selective for S1R than the sigma-2 receptor.23 In the present study, the estimated concentration of both chemicals in the CSF was considered to be in the nanomolar range.31 Therefore, the doses of both chemicals in the present study were adequate for use as specific S1R ligands. Using these doses, we were able to successfully show that the brain S1R plays an important role in modulating sympathetic activity and depressive status.
To clarify the effects of systemic treatment with S1R agonist, fluvoxamine, a potent agonist of S1R in addition to its function as a selective serotonin reuptake inhibitor, was orally administered.19 The dose of fluvoxamine was determined according to a previous report.19 Systemic administration of S1R agonist also attenuated the sympathetic hyperactivation in addition to improving depression-like behaviour.
The mechanisms involved in the modulation of sympathetic activity via the brain S1R remain unclear. The S1R is known to modulate neuronal intracellular calcium levels13 and N-methyl-d-aspartate-mediated response.14,15 Furthermore, S1R was reported to enhance brain plasticity and functional recovery after stroke.32 These results suggest that the brain S1R affects neuronal activity and that the S1R in the central cardiovascular control region contributes to the regulation of sympathetic activity. Western blotting for brain S1R detection in circumventricular brain tissue including hypothalamus was performed. Wide distribution of the S1R has been reported in the brain, most abundantly in the hippocampus, facial nucleus, thalamus, and hypothalamus.33 Therefore, the hypothalamus, one of the central cardiovascular control regions, is a promising candidate for the target nucleus involved in modulating sympathetic activity via the S1R. However, the S1R has also been reported in the brainstem, where the other cardiovascular control centre is located. ICV infusion of PRE084 or BD1063 possibly affected the S1R in the brainstem.
In addition, microglia releasing pro-inflammatory mediators such as cytokines and reactive oxygen species34 also expresses high levels of S1R, and S1R suppresses microglial activation.35 Such pro-inflammatory mediators in the brain were reported to cause sympathetic hyperactivation in models of heart failure.36 Therefore, both neuronal and microglial S1R may be involved in the modulation of sympathetic activity.
4.4 Involvement of DHEAS in brain S1R reduction
The mechanisms involved in the reduction in brain S1R expression in this heart failure model also remain unclear. Neurosteroids, such as DHEA and its sulfate conjugate DHEAS, are recognized as endogenous S1R agonists.14,16 DHEAS is produced mainly in adrenal tissues,37 and its serum concentration was reported to decrease in heart failure patients.17 In the present study confirmed that both serum and brain DHEAS concentrations decreased in AB-H compared with Sham mice. Furthermore, a recent study demonstrated that DHEAS deficiencies predicted the severity of depression in heart failure.38 Therefore, a decrease in serum DHEAS concentration may have been responsible for the reduction in brain S1R expression observed in this heart failure model.
4.5 Limitations
The present study revealed that brain S1R expression decreased in AB-H, and the reduction in brain S1R may be involved in depression-like behaviour in this model. However, depression is a clinical syndrome that may have multi-pathogenetic causes. Therefore, other mechanisms may contribute to depression-like behaviour in this model. In fact, brain angiotensin type 1 receptor (AT1R) was reported to be a novel therapeutic approach for treatment of mood disorders via anti-inflammatory effects.39 In previous studies, we confirmed that the brain AT1R increased in AB-H.18 Further studies are needed to clarify the contribution of AT1R to depression-like behaviour and the interaction between AT1R and S1R.
A strong association with depression has been well known in both heart failure and hypertension. Therefore, the pressure overload model, a mimic of hypertensive heart disease, was used as the experimental heart disease model in the present study. Other experimental heart failure models, such as that induced by myocardial ischaemia, have also been used widely. Recently, patients with coronary disease who screened as positive on depression screening test had a greater risk for adverse cardiovascular outcomes.40 Therefore, the experimental heart failure model induced by myocardial ischaemia should also be used to test our hypothesis in the future.
4.6 Conclusion
In conclusion, these findings indicate that brain S1R expression was decreased in AB-H, and that this reduction in brain S1R expression contributed to both the exacerbation of cardiac dysfunction via enhanced sympathetic activity and the worsening of depression.
This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (19890148, 23220013), Kaibara Morikazu Medical Science Promotion Foundation, Kyushu University Interdisciplinary Programmes in Education and Projects in Research Development, and the Salt Science Research Foundation (1136).
We express our sincere thanks to Naomi Shirouzu for help with the western blot analysis.
Conflict of interest: none declared.
- Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2011. For permissions please email: firstname.lastname@example.com.


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DTA's mission is to assist low-income individuals and families to meet their basic needs, increase their incomes and improve their quality of life. Located within the Executive Office of Health and Human Services, the Department ensures that the emergency and transitional needs of the individuals and families of the Commonwealth are met through a combination of federal- and state-funded programs. Massachusetts has a comprehensive system of programs and supports to provide to individuals and families in need in order to achieve greater economic self-sufficiency.
Our primary objective is to provide the right resources to the right people at the right time, with the highest level of programmatic integrity. DTA uses creative outreach efforts and flexible service delivery models to ensure that resources are accessible to, and work effectively for, our clients.
Our three main goals are to:
- Increase the personal and economic well-being of our clients and provide necessary benefits
- Reduce homelessness
- Improve customer service.
Mission Statement
The mission of the Department of Transitional Assistance is to assist low-income individuals and families to meet their basic needs, increase their incomes and improve their quality of life.
DTA Transitional Assistance Offices (TAO):
The front door to the Department's many programs is through its' more than 20 local Transitional Assistance Offices (TAO) throughout Massachusetts. TAO's are responsible for managing and monitoring the delivery of support services for individuals and their families who live in the towns covered by the respective TAO. Functions performed at an area office include case management and information and referral.
DTA Central Office:
Located in Boston at 600 Washington Street, the DTA Central Office oversees all DTA functions and operations throughout the state and establishes statewide policies and procedures. The Department is organized into four functional areas:
- Field Operations
The Field Operations division oversees and supports those responsible for the delivery of services to clients – namely the local offices and program management staff. They work to ensure that DTA clients receive high quality service in a timely manner.
- Change Management
As an agency we are required to be flexible and embrace change frequently. With this in mind, a Change Management division was established to provide strategic planning of all change based initiatives.
- Administration & Finance
As any government agency or private business, DTA must be able to operate effectively and efficiently. In order to ensure exemplary stewardship and support our program objectives, our administrative functions have been consolidated within our ANF division.
- Research, Planning and Evaluation
The Research, Planning, and Evaluation division is tasked with analyzing data, ensuring reports are on track, and looking to the future. RP&E staff work to think outside the box and come up with bold ideas to improve the way that DTA does business.
DTA Organization Chart
A diagram of the organizational structure of the Department.
This information is provided by the Department of Transitional Assistance.


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Lazard Ltd operates as a financial advisory and asset management company worldwide. The company operates from 43 cities in key business and financial centers across 27 countries throughout North America, Europe, Asia, Australia, the Middle East, and Central and South America. Principal Business Lines Segments The company operates in two segments, Financial Advisory and Asset Management. Financial Advisory segment This segment offers corporate, partnership, institutional, government, sovereign and individual clients worldwide a range of financial advisory services regarding mergers and acquisitions (M&A) and other strategic matters, restructurings, capital structure, capital raising, corporate preparedness and various other financial matters. The company focuses on solving its clients' complex issues, providing advice to key decision-makers, senior management, boards of directors and business owners, as well as governments and governmental agencies, in transactions that are of strategic and financial importance to them. The company maintains a major local presence in the United States (U.S.), the United Kingdom, and France, including a network of regional branch offices in the U.S., as well as a presence in Argentina, Australia, Belgium, Brazil, Chile, China, Colombia, Germany, Hong Kong, India, Italy, Japan, Korea, the Netherlands, Panama, Peru, Singapore, Spain, Sweden, Switzerland, and the Middle East region. Services Offered The company advises clients on a range of strategic and financial issues. When the company advises clients on the potential acquisition of another company, business or certain assets, its services include evaluating potential acquisition targets, providing valuation analyses, evaluating and proposing financial and structural alternatives, and rendering, if appropriate, fairness opinions. The company might also advise as to the timing, financing and pricing of a proposed acquisition and assist in negotiating and closing the acquisition. In addition, the company might assist in executing an acquisition by acting as a dealer-manager in transactions structured as a tender or exchange offer. When the company advises clients that are contemplating the sale of certain businesses, assets or an entire company, the company's services include advising on the sale process for the situation, providing valuation analyses, assisting in preparing an offering circular or other appropriate sale materials and rendering, if appropriate, fairness opinions. The company also identifies and contacts selected qualified acquirors and assists in negotiating and closing the proposed sale. As appropriate, the company also advises its clients regarding potential financial and strategic alternatives to a sale, including recapitalizations, spin-offs, carve-outs and split-offs. The company frequently provides advice with respect to the structure, timing and pricing of these alternatives. For companies in financial distress, the company's services might include reviewing and analyzing the business, operations, properties, financial condition and prospects of the company, evaluating debt capacity, assisting in the determination of an appropriate capital structure, and evaluating financial and strategic alternatives. If appropriate, the company might provide financial advice and assistance in developing and seeking approval of a restructuring or reorganization plan, which might include a plan of reorganization under Chapter 11 of the U.S. Bankruptcy Code or other similar court administered processes in non-U.S. jurisdictions. In such cases, the company might assist in certain aspects of the implementation of such a plan, including advising and assisting in structuring and effecting the financial aspects of a sale or recapitalization, structuring new securities, exchange offers, other consideration or other inducements to be offered or issued, as well as assisting and participating in negotiations with affected entities or groups. When the company assists clients in connection with their capital structure, it reviews and analyzes structural alternatives, assists in long-term capital planning, and a
lazard ltd-cl a (LAZ:New York)
Contact Info
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Deliver Rolf and Malakai's Medallions to Guard Thomas at the eastern Elwynn bridge.
|Rolf and Malakai's Medallions (Provided)
DescriptionNow that you have both medallions, deliver them to Guard Thomas at the bridge so that he might know the fate of his murdered guards.
Hello, <name>. Have you discovered the fates of Rolf and Malakai?
You have confirmed my fears, <name>. The murlocs are a threat we cannot ignore.
GainsUpon completion of this quest you will gain:
- 390 experience
- 25 reputation with Stormwind
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Some publishers consider it their business to save friendly local game stores (FLGS), claiming that these locations are the points where new players enter the hobby. The big threat to these stores is online retailers who, owing to less overhead and fewer license requirements, can offer big discounts on publishers' products to cash-strapped consumers. Mayfair Games famously threatens to blacklist any retailer that sells their products at less…
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Cryptozoic and Green Ronin Try to Save Local Game Stores
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The actress still seems crazy about her ex. Read More
It seems the actress' daughter, 'Fifty Shades of Grey' star Dakota Johnson, may have learned a thing or two about confidence from her mother. Read More
The actress donned a purple bikini while vacationing in Mexico for Eva Longoria's wedding.Read More
The 'Fifty Shades of Grey' star's famous parents, Melanie Griffith and Don Johnson, left quite the impression on her.Read More
Kate Hudson definitely knows how to have a good time.Read More
Melanie, Goldie, Kate and Dakota got into the holiday spirit for a cheerful family (swapping) photo, celebrating the snowy season.Read More
Nobody messes with this working girl!Read More
Find out how the two plan to split up all that movie money.Read More
It's the 20th anniversary of the Christina Ricci and Rosie O'Donnell movie.Read More
Antonio Banderas and Melanie Griffith are making their divorce official.Read More
The actors keep the peace to celebrate their daughter Stella.Read More
Dakota Johnson, Melanie Griffith and Kris Jenner go on a girls only trip to Mexico.Read More
Who knew these families were friends?!Read More


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NFL Rush Zone Flyerz Starter Packs allows football fans to engage with their favorite NFL teams in a new way. To play with these collectible figures, hold them on the thumb and pull back–a kind of slingshot action. Kids can create their own games, such as seeing who can launch theirs the farthest or who can knock down the most targets. Each Starter Pack comes with two NFL Rush Zone Flyerz Rusherz. Both have an NFL team logo on them, but one is a mystery Rusherz, so you don't know what the second team is until you open the package. You can collect all 32 NFL teams. The Starter Packs also come with four targets with four football stands.
The NFL Rush Zone Flyerz launch very well, and kids (and adults) will have fun playing different games by launching them. This is a fun collectible toy for NFL fans.
NFL Rush Zone Flyerz Starter Packs are for footballs fans ages 6 and up.
These are available at select Walmart stores.
Sky Viper S670 Stunt Drone
from Skyrocket Toys
Air Hogs Altitude Video Drone
from Spin Master
Meccano MeccaNoid G15KS Personal Robot
from Spin Master
Air Hogs Helix Video Drone
from Spin Master
Nerf N-Strike Modulus Flip Clip Upgrade Kit
from Hasbro
Imaginext DC Super Friends Captain Cold & Ice Cannon
from Fisher-Price
Imaginext Ultra T-Rex
from Fisher-Price
Jurassic World Stomp and Strike Tyrannosaurus Rex Figure
from Hasbro
Imaginext T-Rex
from Fisher-Price
Matchbox Jurassic World Desert 5 Pack
from Mattel


text:
Michael Jackson HIStory Tribute: King of Pop Thrills Again
Arlene Schnitzer Concert Hall, Portland'5 Centers for the Arts 1037 SW Broadway Portland, OR 97205
Our Price
$36 - $41.50*
Full Price
$72 - $83
If the sequined glove fits, wear it ... and no one is a better fit for taking the King of Pop's place than Las Vegas performer Kenny Wizz. He has the moves, he has the voice and, most important, he has the special spirit that made Michael Jackson the ultimate pop superstar even after his untimely death. Now Wizz brings his musical biography Michael Jackson HIStory Show: Thriller to Portland's Arlene Schnitzer Concert Hall. Songs like "ABC," "Ben," "Smooth Criminal," "Beat It" and many more make up the set list of this career-spanning concert. Wizz has drawn on his decades-long experience as "MJ" to create an all-out spectacular show, complete with a live band of talented musicians, fully choreographed dancers and authentic costumes. Find out just how thrilling the Thriller was -- and is -- during this exciting tribute.
* Additional fees apply. No coupon or promo codes necessary to enjoy the displayed discount price.
All offers for Michael Jackson HIStory Show: Thriller have expired.
The last date listed for Michael Jackson HIStory Show: Thriller was Tuesday July 15, 2014 / 8:00pm.
Most Popular Music Event Nearby
Broadway Songstress Shoshana Bean (Wicked) Shares Stories & Songs
- Full Price:
- $40
- Our Price:
- $25
Broadway baby Shoshana Bean first gained fame from her acclaimed roles in Wicked and Hairspray, then… More
Venue Details
Keep expectations lowstar this tip starred
Get there early because parking on theater night is difficult. There is an inside lot a couple blocks up the street.star this tip starred
Reviews & Ratings
"Michael Jackson HIStory Show: Thriller"
Featured review from Shirley Marie
view more less of this review
What an amazing show! A MUST for any MJ fans.
More Information
This show is recommended for ages 6 and older.


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Members of the Washington State Civil War Association, dressed in fashions of the day, joined other passengers for a ride on the Mt. Rainier Scenic Railroad. (Courtesy photo)
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Colin Farrell has revealed that the break-down of his marriage has made himwary of relationships.The Irish hell-raiser was married to actress Amelia Warner for four monthsin 2001 and hasn't been in a ...
Read the Fazed interview with the director and star Franka Potente
Young Brit director Chris Smith sets his feature length debut on the London underground where nasty things appear to go on down in ...
http://www.fazed.com/movies/Enduring Love.html
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Love—the real-life kind, not the kind in the movies—is messy. Writer/director Wes Anderson likes to take on messy themes. They're messy because they are things we think we pretty much already understa...
Dear Joe,
You've been with Beth for awhile, and I think it's great that you guys are able to work through your problems together - that's a definite sign of a stable foundation to a healthy relation...
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If everything else about this guy – and your relationship – is so amazing, than why not let the "calling issue" go?
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He told the committee the world is moving fast ... But laws and policies in America are not keeping up.
He also said if terrorists are able to launch cyber attacks against U.S. cities or the U.S. military ... there could be devastating consequences.
"Our military is more dependent upon cyberspace than any military in the world. And as a matter of fact, we're at the point where we would have a hard time operating as a military if the use of cyberspace were denied to us. And our adversaries know that, so they're looking for vulnerabilities. And it is a potential vulnerability that we've got to pay a lot of attention to."
Representative Thornberry said terrorists could use cyber attacks to give viruses to unmaned aerial vehicles, or to disrupt electric grids, water plants, or worse.
He said lives could be lost if terrorists launched severe cyber attacks.
Copyright 2016 Nexstar Broadcasting, Inc. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.


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I am not anorexic - Anushka Sharma
November 7, 2011 smitag 114508 reads 25 comments
Since this discussion of Anushka Sharma being too thin started here at Pinkvilla, I thought let me post this interview of Anushka Sharma from Mumbai Mirror where she refuted this topic.
Here is the bit where she talks about it. Read the whole interview at MM
People believe that you have become anorexic...
Rubbish. I am very tall. 5' 9" to be precise. This means that if I really put on weight, I shall start looking like a giant. I don't have the tendency to put on weight. (Pauses)
Go on…
After seeing me in Rab Ne Bana Di Jodi, people got the wrong impression. In the film, they made me look bigger. I have always been a lean girl. And for heaven's sake, I am not anorexic. Anorexics eat so little. Watch me eat and you shall know (laughs)!
Another interesting interview about the same topic was published in DNA where Anushka Sharma said that she wears a size 8.Read the DNA interview here
What about you being sub-size zero?
That is the most ridiculous thing I have ever heard. There is nothing known as size zero. I am a size 8, UK. To call me sub zero is ridiculous. 8 is a very healthy size. Being skinny is not a compliment for someone who wants to put on weight, it's frustrating. The world is obsessed with being overweight. If you are happy the way you are its fine.


text:
realmagick.com The shrine of knowledge.
Empress Min Of Korea
A selection of articles related to empress min of korea.
Original articles from our library related to the Empress Min Of Korea. See Table of Contents for further available material (downloadable resources) on Empress Min Of Korea.
- Aviary at the Gates of Heaven: Examining the Bird Symbolism in the Thoth Empress Card
- "This card, summed up, may be called the Gate of Heaven." Book of Thoth, p. 77. Eight birds adorn the fourth card of the Thoth Deck Major Arcana, The Empress. These eight birds, their variant symbology united, point at one overarching meaning -- as...
Tarot Cards >> The Major Arcana
- 3 - The Empress
- The Empress belongs to the young adultness. She symbolizes fertility, femininity, the Great Mother, nature. Meaning: fertility, growth, progress, procreation, love, beauty,delight, the feminine part in both genders, businesswoman. Reverse: infertility,...
Tarot Cards >> The Major Arcana
- The Empress
- Beautiful Mother Divine Creator of the highest and noble Beauty builder of raw creation Project of wonder to finishing She is love to inspire in nature Born of the elements to complete Finesse and delicate maker of Tiny and wonderous design. She comes to form...
Poetry >> Tarot
- Min/Menew
- His earliest form was a fetish resembling a barbed arrow. Later the written form of his name was recognizable in the sign of the ninth nome of Upper Egypt. Min developed from a fertility god for animals to a god of vegetation. Among his attributes were a bed...
Deities & Heros >> Egyptian
- Humor: Major Arcana Road Jokes...
- How did the Fool cross the road? Walking softly and carrying a big stick. Why did the Fool cross the road? To get that yappy little dog off his heels. Why did the Magician cross the road? To manifest his desires into reality. How did the Magician cross the...
Divination >> Tarot Cards
- Angelic Correspondences: Numerology and Major Arcana
- "An angel can illumine the thought and mind of man by strengthening the power of vision, and by bringing within his reach some truth which the angel himself contemplates." St. Thomas Aquinas "Music is well said to be the speech of angels."...
Tarot Cards >> The Major Arcana
Empress Min Of Korea is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, Empress Min Of Korea books and related discussion.
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- Other side to Empress Myeongseong
- Empress Myeongseong (1851-1895) is one of the most intriguing figures in Korea's modern history. Also known as Queen Min in her time, she is the wife of King Gojong, the 26th king of Joseon Kingdom (1392-1910) and the first emperor of the Korean Empire ...
- The Sobering Truth of Empress Myeongseong's Killing
- As a result, most Japanese people today are unaware that their government conspired with a group of civilians and broke into the Korean royal palace, assassinated the empress and desecrated her body. Most Japanese school texts avoid any mention of the ...
- A Carved Jewel of an Apartment in Vienna
- The master bedroom's coffered ceiling, inset with hand-embroidered green silk and velvet panels, is a duplicate of the one Ludwig installed in Empress Elisabeth's imperial train car in 1873.
- Say Hi to Cool New Korean Brand Gentle Monster
- The Korean eyewear brand has already amassed a huge following in Asia, and now it's ready to make a huge push in the U.S. It's already off to a great start, collaborating with the likes of cool-kid brands like Opening Ceremony, Tome, and Hood by Air on ...
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Alamo Rent a Car Naples Intl. Airport Deals
Convenience is essential when it comes to arranging your travel plans. When you're flying to Naples, don't waste time at the airport by waiting in long lines for cabs or trying to figure out bewildering bus routes. Instead, reserve your Alamo car rental at NAP airport today and be on the road as soon as you have your rental car keys in hand. Meaning once you've hit the tarmac, you can head to the Alamo rental counter and pick up your Alamo car rental from Naples Intl..
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Massiosare El Hostel
Real Reviews
Real reviews from fellow travellers
These are trusted reviews from guests who have actually stayed here. We hope you find them helpful.
Note: we only give a property a rating once it has received a minimum of 3 reviews.
- Page:1/1
- " We kept on getting locked out of the hostel when we came back at night. There was supposed to be a security guard but he was not always there. Two nights we had to wait about 20 minutes outside. "
- 09 Jul 2016 Joseph USA
- " It is the cheapest hostel I could find near the centro ciudad de mexico. Hosts were excellent and were very helpful. It is also located near several metro stations (~3min walking distance). Hot showers were available too. The only drawback is that there were quite a few mosquitoes buzzing around while I was sleeping. "
- 13 May 2016 Weichen Singapore
- " Needs more hooks or racks in showers for clothes. "
- 18 Mar 2016 Anonymous Mexico
- " Had one of the single rooms on the top of the building. True, many stairs but you get repaid by a great view and being out of the loud hustle of mexico city. Very nice atmosphere and super helpful staff! Even let me store part of my luggage (for a wedding latr in the trip) for a week when i was traveling elsewhere. I liked the whole setup a lot. My favorite hostel in Mexico city (and i stayed in 5-6 different ones over different trips). "
- 22 Nov 2015 Anonymous Germany


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A triathlon will be held at Taylorsville State Park Sunday beginning at 8 a.m. Spectators are welcome to watch competitors swim 1500 meters, bike 40 kilometers and run 10 kilometers. The swim is the first leg of the triathlon, and the slowest, and will last approximately 50 minutes. The race will be over by noon.
There's now official confirmation of what opposing football teams have known all along about Spencer County's Erico Smith – He's fast!
Smith became Spencer County's first ever track and field state champion last week as he took first place in the KHSAA 2A 100 meter dash with a time of 10.98 seconds, finishing two one-hundreths of a second ahead of 2nd place finisher Rashad Brown of Paducah Tilghman.
Three events came our way last week that touched our hearts in personal ways. Each transported us away from oil spill calamity, a perfect game that wasn't, and other forgettables.
First, Simon Kenton High School
Tragedy testing the human spirit, merging with (basketball) success, and we get must see – "Rebound: A Basketball Story".
The Kentucky Fish and Wildlife will be hosting a fishing derby Saturday, June 12, from 9 a.m. until 12 p.m. at the Taylorsville Lake Tailwaters.
Typically, this event is held during Kentucky's free fishing weekend, but was rescheduled so that it would not coincide with the Family Fun Day held last Saturday.
Following the derby, children are invited to enjoy lunch and free activities, including trap shooting, archery, provided by the Spencer County Fish and Game Club and the Spencer County 4-H Shooting Sports.
Spencer County Middle School Grizzly Football's 7th grade team competed Saturday in the Capital City Classic 7 on 7 in Frankfort, KY. The team went undefeated in pool play and took the #1 seed. They were able to finish second to Elkhorn Middle School in the championship game that came down to several close plays. It was a great day of competition in the 7th grade squad's first ever try in a 7 on 7 tournament.
The Spencer County Chapter of the Family, Career, and Community Leaders of America held its annual Membership Awards Banquet on May 4th. Awards were given to students who competed in STAR Events and who completed their Power of One degrees. Other awards included:
Officer of the Year-Leah Spears
Member of the Year – Lauren Polston
New Member of the Year – Lauren Leichty
Honorary Member – Toby Lewis
Submitted to The Spencer Magnet
Two Spencer County athletes, Leigh Ellen Thomas and Mackenzie Myers, and The Heartland Rage, a traveling 14u softball team based out of Elizabethtown, went undefeated this past Memorial Day weekend in the USFA Blowout tournament in Brandenburg to win the championship in their season opener! Thomas will be an 8th grader at SCMS and Myers will be a freshman at SCHS.
Spending a relaxing day on the golf course is a dream for many golfers, but for nearly 100 golfers who will be participating in the annual Habitat Golf Scramble this weekend at Tanglewood Golf Course, it's also a chance to make the dreams of others possible.
The fifth annual event benefits the Spencer County Habitat for Humanity, an organization that helps to provide adequate housing for those who might otherwise be unable to obtain it through more conventional methods.
It's the first of June and the Cincinnati Reds are tied for first place in the NL Central with St. Louis.
In recent years June is the month when reality sets in for most Cincinnati fans, even the most optimistic of us. The Reds have teased us many times since 1990, the year they swept the World Series in four games against the favored A's, completing a surprising wire-to-wire first place run in their division. Since that title run, success and winning records have been few and far between.
The Eric Bledsoe flap. Lemme get this straight ...
• Linking John Calipari to Bledsoe's high school shenanigans is a grassy knoll stretch.
• Interesting, the quickness a New York Times story moved metro media in Kentucky to remind readers of Calipari's two vacated Final Fours, Derrick Rose slickery getting into Memphis U, then Cal's jump to Kentucky ahead of the NCAA police.
Copyright © 2016
The Spencer Magnet is your source for local news, sports, events, and information in Spencer County, KY and the surrounding area.


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Fair ~
High: 80°F ~ Low: 55°F
Thursday, Oct. 27, 2016
Here is an eBay 'for what it is worth'.Posted Monday, May 16, 2011, at 9:11 AM
eBay completed a survey on gift givers last November to see if they could help seller massage their listings to better attract this category of buyers.
Some interesting observations but I am not sure it will change the way we market our items. However, some of you might be able to us this for the upcoming season, so....
I know it sounds a little early to think about the major Christmas season, but it takes time to make plans, get product and initiate the listing so don't be lulled into complacency because it is just May. Besides, this cool snap has me thinking.
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while thinking about Christmas maybe a little early use your coupons to save even more. Find extra coupons at www.extremeclippers.com
-- Posted by extremeclippers on Mon, May 16, 2011, at 3:21 PM
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Steve Mills and his wife have one daughter. They previously owned two coffee/ice cream shops, currently operate an internet sales company and teach classes, but his primary job involves the paper industry worldwide. Hobbies and interests lie in gardening, photography, recorded music and of course, their pets.
Hot topicsHow does everyone feel about the new medical landscape since Obamacare?
(8 ~ 1:56 PM, Oct 27)
A non-political question, brought up by today's politics.
Fall Harvest Social for Weed'em and Reap Garden club. ALL INVITED.
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Summer Knight (The Dresden Files, Book 4) (edition 2002)
by Jim Butcher
Work details
Summer Knight by Jim Butcher
No current Talk conversations about this book.
Summer Knight more than makes up for the previous entry in this series, [b: Grave Peril|91476|Grave Peril (The Dresden Files, #3)|Jim Butcher|https://d.gr-assets.com/books/1266470209s/91476.jpg|803205]. The story line is all around tighter, the supporting characters better developed, and there's just enough dry wit and banter to keep things fun.
Just like all the other books in this series so far, I enjoyed Summer Knight. Butcher creates a compelling world with ever-expanding complexities that add, rather than detract, from the story. Pair that with characters I've fallen in love with and you've got the makings of a great series. I'm looking forward to continuing with these and plan on picking up the next one as soon as whoever has it from my library returns it.
That being said, I do have some beef with the series.
Harry's compulsive chivalry is driving me insane. He helps every woman that gets near him with any kind of problem, regardless of how dangerous it is for him or how much other stuff he has going on. While he does get brownie points for admitting that this is a problem, he doesn't fight it. His desire to help women just because they're women has gotten him in trouble multiple times, but he doesn't seem to learn.
I'm hoping that he begins to work past this. He keeps bringing it up and contemplating it, so maybe he'll begin to change himself.
Summer Knight
3.5 Stars
An definite improvement on Grave Peril.
The world building in this installment focuses on the Fae, and more specifically, on the conflict between the Summer and Winter courts. The political machinations and allegiances of the various Fae are complex and it is difficult at times to keep track of the different characters and the factions they belong to. Nevertheless, it all comes together at the end, and the climax and resolution are exciting and satisfying.
The plot revolving around the murder of the Summer Knight and the theft of his Mantle of Magic has potential but is poorly executed. There are numerous suspects, however, their motives are never quite clear and Harry's investigation is overshadowed by unrelated plot points, such as the return of an old girlfriend, his problems with the White Council, the wizards war with the vampires, etc.
Harry is an amalgamation of opposites. On the one hand, he is strong-willed, resourceful, has a good heart and good intentions. On the other, he is sardonic, self-absorbed and not a little chauvinistic. He is also a mediocre wizard despite indications that there is something special about him, and he barely manages to survive his encounters with the various villains and monsters in the book.
The secondary cast are wonderful and contribute to making this a fun read. Harry's friend and police contact, the sharp-witted and kick-ass Karrin Murphy, plays a slight larger role although she still doesn't get enough page time. Bob the Skull, Toot the Fairy and his warrior pixies, as well as Billy and the Alphas, all return to flesh out the character pool alongside some new additions, such as the Changelings and the Gatekeeper, a particularly intriguing wizard on the White Council.
Finally, James Marsters narration improves with each book and his voices for the minor characters are truly excellent. He also manages to convey Harry's sarcastic wit so well and there are many laugh-out-loud moments - so beware when listening in public.
Not quite as good as the last one but I still really enjoyed it! Harry is just such a fun character. Not really into the Sidhe I just don't find them very interesting. Can't wait for the next book though!
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Amazon.com Product Description (ISBN 0451458923, Mass Market Paperback)
Private detective/wizard-for-hire Harry Dresden is suckered into tangling in the affairs of Faerie, where the fate of the entire world-and his soul-are at stake.
(retrieved from Amazon Thu, 12 Mar 2015 18:06:33 -0400)
Now that his girlfriend has left him, professional wizard Harry Dresden can't pay his rent and alienates his friends. He's soon approached by the Winter Queen of Faerie with an offer he can't refuse--all he has to do is find out who murdered the Summer Queen's right-hand man, the Summer Knight, and clear the Winter Queen's name. Soon, Harry finds out that the fate of the entire world rests on his solving this case.… (more)
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Glen Johnson must focus on Stoke recovery rather than Barcelona dream
Saturday's 2-0 win over Hull City marked the first time in 11 months that Stoke City had managed to secure back to back wins with clean sheets in what has been an otherwise miserable 2016 for manager Mark Hughes and his players.
It's perhaps even more of an achievement that it was accomplished without the considerable talents of Jack Butland and Glen Johnson; two mainstays of the Potters' back five currently out through injury.
With Butland back in training, his prospects for a swift return look...


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Hotel Villa Medici - Naples
Along with free buffet breakfast, this hotel offers free self parking and dry cleaning/laundry. Relax in the seasonal outdoor pool and enjoy the sun loungers. There is also a poolside bar and a bar/lounge so guests can sip a refreshing drink by the pool or indoors.
Multilingual staff at the 24-hour front desk can provide tour/ticket assistance, express check-in and express check-out. Free WiFi and high-speed (wired) Internet access is provided.
Hotel Villa Medici - Naples
Hotel Info: 1-877-214-4288from $39
- Double Room Classic Not Refundable
- Classic Double Room
- Triple Room
- Quadruple Room
- Junior Suite
- Double Single Use
- Superior Double Room
- Classic Room
Also popular with travelers from the USA
At a glance
Key facts
Hotel size
- This hotel has 15 rooms
- This hotel is arranged over 3 floors
- 24-hour check-in
- Check-out time is 11 AM
- Express check-in/out
Required at check in
- Credit card or cash deposit required
- Government-issued photo ID required
- Minimum check-in age is 16
Travelling with others
- One child (12 years old and younger) stays free when occupying the parent or guardian's room, using existing bedding
- Babysitting/childcare *
- Pets stay free
- Specific rooms only, restrictions apply *
- 1 per room
- Free WiFi and wired Internet access in public areas
- Free WiFi and wired Internet access in rooms
- Free self parking (limited)
In the hotel
- In-room childcare (surcharge)
- Free buffet breakfast daily
- Bar/lounge
- Coffee shop/café
- Snack bar/deli
- Poolside bar
- Room service (during limited hours)
- Coffee/tea in a common area
- Outdoor seasonal pool
- Outdoor pool
- Pool sun loungers
- Pool umbrellas
- Arcade/game room
- Computer station
- 24-hour front desk
- Concierge services
- Tours/ticket assistance
- Dry cleaning/laundry service
- Laundry facilities
- Free newspapers in lobby
- Luggage storage
- Multilingual staff
- Number of buildings/towers - 1
- Year Built 1994
- Elevator/lift
- Safe-deposit box at front desk
- Designated smoking areas (fines apply)
- Garden
- Terrace
- Library
- Fireplace in lobby
- Television in common areas
- Accessible bathroom
- In-room accessibility
- Roll-in shower
In the room
- In-room climate control (air conditioning)
- Air conditioning
- Ceiling fan
- Minibar
- Bathrobes
- Iron/ironing board (on request)
- Washer/dryer
- Blackout drapes/curtains
- Turndown service
- Sofa bed size double
- Sleep Number by Select Comfort mattress
- Yard
- Separate sitting area
- Furnished balcony
- Private bathroom
- Shower only
- Bidet
- Free toiletries
- Hair dryer
- 32-inch flat-screen TV
- Satellite TV channels
- Desk
- Free WiFi
- Phone
- Refrigerator
- Microwave (on request)
- Daily housekeeping
- In-room safe
Special features
- Bicycle rentals nearby
- Ecotours nearby
- Hiking/biking trails nearby
- Kayaking nearby
- Scooter/moped rentals nearby
- Scuba diving nearby
- Snorkeling nearby
- Surfing/boogie boarding nearby
- Windsurfing nearby
Hotel Villa Medici - Naples's small print
Also known as
- Medici Hotel Naples
- Hotel Villa Medici Naples
- Villa Medici Naples
All guests, including children, must be present at check-in and show their government-issued photo ID card or passport.
Cash transactions at this property cannot exceed EUR 2999.99, due to national regulations. For further details, please contact the property using information in the booking confirmation.
Pet-friendly rooms can be requested by contacting the property at the number on the booking confirmation.
Only registered guests are allowed in the guestrooms.
Children under 12 years old are not allowed in the swimming pool without adult supervision.
The name on the credit card used at check-in to pay for incidentals must be the primary name on the guestroom reservation.
Mandatory fees
You'll be asked to pay the following charges at check in or check out:
- A tax is imposed by the city: EUR 2 per person, per night, up to 10 nights. This tax does not apply to children under 18 years of age.
Optional extras
Late check-out can be arranged for an extra charge of EUR 35
Parking is available nearby and costs EUR 20 per 24 hours
Kitchen/kitchenette use costs EUR 15 per day
Rollaway beds are available for EUR 10 per day
Babysitting/childcare is available for an extra charge
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.
Recent reviews
Good 3.7 /5 from 55 reviews
Use the local bars and restaurant. The hotel meet my needs and was off a exceptable standard.