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- Research
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Bazedoxifene, a selective estrogen receptor modulator, reduces cerebral aneurysm rupture in Ovariectomized rats
Journal of Neuroinflammation volume 14, Article number: 197 (2017)
1238 Accesses
11 Citations
Estrogen deficiency is thought to be responsible for the higher frequency of aneurysmal subarachnoid hemorrhage in post- than premenopausal women. Estrogen replacement therapy appears to reduce this risk but is associated with significant side effects. We tested our hypothesis that bazedoxifene, a clinically used selective estrogen receptor (ER) modulator with fewer estrogenic side effects, reduces cerebral aneurysm rupture in a new model of ovariectomized rats.
Ten-week-old female Sprague-Dawley rats were subjected to ovariectomy, hemodynamic changes, and hypertension to induce aneurysms (ovariectomized aneurysm rats) and treated with vehicle or with 0.3 or 1.0 mg/kg/day bazedoxifene. They were compared with sham-ovariectomized rats subjected to hypertension and hemodynamic changes (HT rats). The vasoprotective effects of bazedoxifene and the mechanisms underlying its efficacy were analyzed.
During 12 weeks of observation, the incidence of aneurysm rupture was 52% in ovariectomized rats. With no effect on the blood pressure, treatment with 0.3 or 1.0 mg/kg/day bazedoxifene lowered this rate to 11 and 17%, almost the same as in HT rats (17%). In ovariectomized rats, the mRNA level of ERα, ERβ, and the tissue inhibitor of metalloproteinase-2 was downregulated in the cerebral artery prone to rupture at 5 weeks after aneurysm induction; the mRNA level of interleukin-1β and the matrix metalloproteinase-9 was upregulated. In HT rats, bazedoxifene restored the mRNA level of ERα and ERβ and decreased the level of interleukin-1β and matrix metalloproteinase-9. These findings suggest that bazedoxifene was protective against aneurysmal rupture by alleviating the vascular inflammation and degradation exacerbated by the decrease in ERα and ERβ.
Our observation that bazedoxifene decreased the incidence of aneurysmal rupture in ovariectomized rats warrants further studies to validate this response in humans.
The rupture of cerebral aneurysms elicits devastating subarachnoid hemorrhage (SAH). Surgical and endovascular treatments can be preventive but are associated with inherent risks and complications [1]. Therefore, medical therapy with lower risks for complications is needed to prevent SAH.
The incidence of cerebral aneurysms and SAH is higher in post- than premenopausal women [2, 3]. Post-menopausal estrogen deficiency is thought to play a key role in the pathophysiology of cerebral aneurysms. Our group established a cerebral aneurysm model in ovariectomized rats subjected to hemodynamic stress and hypertension [4]. The model mimics human postmenopausal hormonal conditions. Estrogen-deficient model rats had a higher incidence of cerebral aneurysms than male rats, and estrogen deficiency promoted endothelial damage and vascular inflammation [5,6,7,8]. Estrogen (17β-estradiol) and an estrogen receptor β (ERβ)-, but not an ERα agonist, reduced the incidence of cerebral aneurysm rupture in ovariectomized mice [9]. These findings suggest that ER-related drugs may help to prevent SAH. In humans, postmenopausal estrogen replacement therapy reduced the risk of SAH [10,11,12] but increased the risk for breast and endometrial cancer, stroke, and venous thromboembolism [9, 13,14,15].
Bazedoxifene (BZA), a selective estrogen receptor modulator (SERM), is used to prevent postmenopausal osteoporosis. It has fewer estrogenic side effects than conjugated estrogen. SERM is a ligand of ERα and ERβ; its characteristics are different from pure ER agonists and ER-antagonists because, depending on the target tissue, it exerts agonistic or antagonistic effects [16]. Its tissue-specific effects are thought to be attributable to its distinct affinity for each ER, a unique conformational change in ERs upon binding to SERM, and the distinct distribution of ERα and ERβ in the tissue [16, 17]. Therefore, we used our rat model to investigate whether BZA may represent a potential and safer prophylactic agent against cerebral aneurysm rupture in postmenopausal women.
We established a novel rat model of aneurysm rupture by modifying the carotid ligation procedure used in our original model in which ovariectomized rats were subjected to hemodynamic changes and hypertension without pharmacologically elicited degeneration of the arterial wall [18]. The pathological features of the experimental aneurysms in our ovariectomized hypertensive rats were those of human aneurysms. In the posterior cerebral artery (PCA) where ruptured aneurysms formed most frequently, the mRNA level of interleukin (IL)-1β was higher and the imbalance of matrix metalloproteinase (MMP)-9 and the level of the tissue inhibitor of metalloproteinase-2 (TIMP-2) were greater than at the bifurcation of the anterior cerebral artery-olfactory artery (ACA-OA) where no ruptured aneurysms were observed. We suggested that these molecules associated with inflammation and vascular degradation are at least partly responsible for aneurysmal rupture [18]. Here, we used our modified rat aneurysm model to test the hypothesis that BZA exerts protective effects against vascular inflammation and aneurysm rupture.
We now demonstrate that BZA reduced the incidence of aneurysmal rupture without affecting the blood pressure in ovariectomized aneurysm-model rats. Its restoration of the decreased expression of both ERs in the aneurysm-prone cerebral artery was associated with the reduction of pro-inflammatory cytokines and vascular degradation molecules. We also show that BZA attenuated the body weight gain seen under conditions of estrogen deficiency and hypertension. Our findings suggest BZA as a potential therapeutic agent for the prevention of SAH in postmenopausal women.
Sexually mature (10-week-old) [19] female Sprague-Dawley rats (220–250 g, n = 137; Charles River Laboratories Japan Inc., Yokohama, Japan) were housed under specific-pathogen-free conditions and controlled temperatures (23 ± 2 °C), humidity (55 ± 10%), and light (12-h light/dark cycle, 8 am–8 pm). Food and water were ad libitum.
Cerebral aneurysm induction
Cerebral aneurysms were induced by hypertension (renal artery ligation and a high-salt diet), increased hemodynamic changes (carotid artery ligation), and estrogen deficiency (bilateral ovariectomy) as described elsewhere [18]. We ligated the right external carotid and the pterygopalatine artery and the left common carotid artery. The rats were bilaterally ovariectomized immediately after carotid ligation and then fed a high-salt diet (8% sodium chloride). Two weeks later, the bilateral posterior renal arteries were ligated.
Experimental study 1
To assess whether ovariectomy increases and BZA treatment reduces the incidence of cerebral aneurysm rupture in hypertensive ovariectomized rats, 84 rats were randomly assigned to three groups (each group n = 28). One group was treated with vehicle (HT+OVX); the other two groups received 0.3 or 1.0 mg/kg/day BZA (BZA0.3, BZA1, respectively). Another set of 28 rats was sham-ovariectomized, subjected to hypertension, exposed to hemodynamic changes, and treated with vehicle (HT rats). BZA was kindly provided by Pfizer Inc. (New York, NY, USA). The BZA dose, determined based on an earlier study [20], was suspended in 5% Arabic gum solution (BZA0.3 rats: 0.06 mg/ml, BZA1 rats: 0.2 mg/ml) and perorally administered once a day (5 ml/kg for all solutions) for 12 weeks by blinded investigators. The 5% Arabic gum solution was also the vehicle. In our previous study, cerebral aneurysms started to rupture approximately 30 days after their induction [18]. The administration of BZA and of vehicle was started 2 weeks after renal artery ligation so that BZA would affect the rupture rather than the formation of aneurysms.
Aneurysm rupture was suspected when the rats exhibited neurologically abnormal behavior [21], developed a significant weight loss (> 30 g/day, approximately 10% of their body weight), or died. Rats with these findings were sacrificed immediately, and their brains were inspected to confirm SAH due to rupture of a cerebral aneurysm. Blinded investigators recorded the body weight daily to detect a sudden weight loss possibly indicative of aneurysmal rupture, assessed the clinical signs, and evaluated the brains. A representative ruptured aneurysm at the left PCA is shown in Additional file 1: Figure S1. All surviving rats were euthanized 12 weeks after aneurysm induction, and their brains were inspected for the presence of ruptured aneurysms. Data collection and analysis were performed in blinded fashion.
Of the 112 rats, we excluded 14 (5 HT+OVX, 1 BZA0.3, 4 BZA1, and 4 HT rats) because there was no evidence of rupture, although aneurysmal rupture was suspected.
Blood pressure measurements
To measure the blood pressure, the rats were placed on a 37 °C hot plate (Nissin, Tokyo, Japan) and covered with a blanket. After they adapted to the environment, their systolic blood pressure was measured twice, and the mean value was recorded. Blood pressure measurements were obtained immediately before and 2 and 12 weeks after renal artery ligation by the tail-cuff, auto-pickup method (Softron, Tokyo, Japan).
Experimental study 2
To analyze the molecular mechanisms underlying the effects of ovariectomy and BZA on rat cerebral aneurysms, we performed quantitative real-time PCR (qRT-PCR) to assess the gene expression level and immunohistochemical staining to determine the protein expression level in the cerebral artery.
qRT-PCR assay
Another set of 21 rats was randomly divided into three equal groups of HT+OVX, BZA1, and HT rats. Bazedoxifene or vehicle was administered as in the "Experimental study 1" section. We did not prepare a BZA0.3 group because experimental study 1 had shown that the incidence of cerebral aneurysm rupture was not significantly different between BZA0.3 and BZA1 rats. To avoid excluding rats that would develop aneurysmal rupture, we euthanized these rats at 5 weeks after renal ligation before their experimentally induced aneurysms had begun to rupture in experimental study 1. We collected tissue samples from these 21 rats from the left proximal PCA (between the basilar bifurcation and the posterior communicating artery) where ruptured cerebral aneurysms had formed most frequently in HT+OVX rats in experimental study 1.
After transcardial perfusion with normal saline, we removed the left PCA. Total RNA was extracted with the MagNA Pure RNA isolation kit (Roche, Tokyo, Japan) and placed in a MagNA lyser (Roche). We used Transcriptor Universal cDNA Master (Roche) for the reverse transcription of total RNA to cDNA and a LightCycler 2.0 (Roche Diagnostics, Tokyo, Japan) for qRT-PCR. LightCycler FastStart DNA Master and SYBR Green I (Roche) were used for glyceraldehyde 3-phosphate dehydrogenase (GAPDH), ERα, ERβ, IL-1β, IL-6, tumor necrosis factor-α (TNF-α), MMP-9, and TIMP-2. The primers were as follows: for GAPDH, forward (F), 5′-TAC ACT GAG GAC CAG GTT G-3′, reverse (R), 5′-CCC TGT TGC TGT AGC CAT A-3′; for ERα, F, 5′-TGC ACC ATC GAT AAG AAC C-3′, R, 5′-GTC TCC TGA AGT GCC CAT T-3′; for ERβ, F, 5′-CTG CAT GGC TGA GCG ACA A-3′, R, 5′-AGA GAC TCA TGG GAC TCA GAT-3′; for IL-1β, F, 5′-TGC AGG CTT CGA GAT GAA C-3′, R, 5′-AGC TCA TGG AGA ATA CCA CTT G-3′; for IL-6, F, 5′-TCT CAG GGA GAT CTT GGA AAT G-3′, R, 5′-TAG AAA CGG AAC TCC AGA C-3′; for TNF-α, F, 5′-CCC AAC AAG GAG AAG T-3′, R, 5′-CGC TTG GTG GTT TGC TAC-3′; for MMP-9, F, 5′-CCT GGA ACT CAC ACA ACG-3′, R, 5′-GAG GTC ATA GGT CAC GTA GG -3′; and for TIMP-2, F, 5′-CCC TCT GTG ACT TTA TTG TGC-3′, R, 5′-TGA TGC TCT CTG TGA CC-3′. The PCR conditions were 95 °C for 10 min followed by 40 cycles at 95 °C for 10 s, 60 °C for 10 s, and 72 °C for 8 s. We subjected samples from each group to two independent qRT-PCR assays to determine the gene expression level. The results were quantified after normalization to the expression of GAPDH mRNA. To assess the effect of BZA on the uterus, we collected the uterus and measured its weight.
Immunohistochemical staining
The left proximal PCA from two HT+OVX and two BZA1 rats was collected 5 weeks after renal ligation to confirm ER protein expression in the arterial wall. After perfusion with 4% paraformaldehyde, the left PCA was harvested, immersed in 4% paraformaldehyde (24 h at 4 °C), and successively dehydrated in 10, 20, and 30% sucrose. The arteries were rinsed with phosphate-buffered saline, embedded in OCT compound (Tissue-Tek Inc.), and cut into 5-μm thick serial sections with a cryotome (CM 1850; Leica). After 30-min serum-free protein blockade (Dako, Carpinteria, CA, USA), primary antibodies against ERα and ERβ (Santa Cruz Biotechnology, CA, USA) diluted 1:100 with Canget signal immunostain (Toyobo, Osaka, Japan) were added for overnight incubation at 4 °C. Sections not treated with the primary antibodies were the negative control. All sections were then incubated for 1 h at room temperature with fluorescein-conjugated secondary antibodies Alexa Fluor 594 (Molecular Probes, CA, USA) in Canget signal immunostain (1:800 dilution, Toyobo), mounted with Vectashield (Vector Laboratories, CA, USA), and examined under a fluorescence microscope (KEYENCE, BZ-X710, Osaka, Japan).
Statistical analysis
For sample-size calculation, we implemented α = 0.05 and 1-β = 0.8 with an effect size of 0.4 (literature-based) [9] using G*Power 3.1 (University of Düsseldorf, Düsseldorf, Germany), indicating that 25 samples per group were required. Expecting a loss of 10–15% of the rats, we used 28 animals per group in experimental study 1. Statistical analyses were performed with SPSS 22 (IBM Armonk, NY). Fisher's exact test was used to analyze the incidence of cerebral aneurysm rupture. Sequentially, obtained data (mean ± SD) were analyzed with analysis of variance (ANOVA) followed by Scheffe's test for multiple group comparisons of the mRNA level. Differences were considered statistically significant at p < 0.05.
BZA prevents aneurysmal rupture in rats
To determine whether estrogen deficiency increases while BZA decreases the incidence of cerebral aneurysm rupture in estrogen-deficient rats, we compared the incidence of rupture during 12 weeks of observation in hypertensive ovariectomized aneurysm rats treated with vehicle (HT+OVX), 0.3 mg/kg BZA (BZA0.3), or 1 mg/kg BZA (BZA1) and in hypertensive sham-ovariectomized rats (HT rats) (for their preparation see the "Experimental study 1" section). The treatments were started 2 weeks after bilateral renal ligation and continued throughout the 12-week observation period.
As shown in Fig. 1a, HT+OVX rats manifested a significantly higher incidence of cerebral aneurysm rupture than HT rats (52 vs 17%, p < 0.05). BZA treatment decreased the incidence of rupture (BZA0.3, 11%; BZA1, 17%; each p < 0.05 vs HT+OVX rats). Notably, the rate of aneurysmal rupture in BZA0.3 and BZA1 rats was similar to that in HT rats, suggesting that the effect of BZA was not dose-dependent. BZA did not affect the systolic blood pressure, which was elevated after renal ligation (Fig. 1b). These results suggest that estrogen deficiency promoted aneurysm rupture in the presence of hypertension, while BZA inhibited its effect in a blood pressure-independent manner. Most ruptured aneurysms had arisen in the PCA (64%); 14% each were found in the internal carotid or the anterior cerebral artery (14%), and 9% in the middle cerebral artery.
Although there was no significant difference in the body weight at the time of randomization [HT, 251.8 ± 16.2 g; HT+OVX, 260.9 ± 22.7 g; BZA0.3, 261.0 ± 16.4 g; BZA1, 263.7 ± 12.7 g (mean ± SD)], 12 weeks after aneurysm induction, the body weight of HT+OVX rats was significantly greater than that of HT rats (381.4 ± 27.6 vs 300.2 ± 18.8 g, p < 0.05). The body weight of BZA1 was significantly lower than that of HT+OVX rats (263.7 ± 12.7 g vs 335.3 ± 17.3 g); treatment with 0.3 mg/kg BZA did not affect the body weight (375.8 ± 24.4 g) (Fig. 1c). In addition, 5 weeks after aneurysm induction, the wet uterine weight of HT+OVX rats was significantly lower than that of HT rats; it was similar in BZA1 and HT+OVX rats (HT, 440.5 ± 48.1 mg; HT + OVX, 145.5 ± 21.1 mg; BZA0.3, 261.0 ± 16.4 mg; BZA1, 134.7 ± 13.1 mg; mean ± SD; see Additional file 2: Figure S2]) The incidence of aneurysmal rupture and the body weight in BZA1 and HT rats were similar, suggesting that 1 mg/kg BZA revoked the effect of estrogen deficiency on the vasculature and the body weight without increasing the uterine weight.
BZA upregulates ERα and ERβ expression in the cerebral artery
As BZA is a SERM acting on ERs, we next investigated how treatment with BZA affected the ER expression in the cerebral artery of estrogen-deficient rats. Five weeks after bilateral renal ligation, we assessed the mRNA level and the protein expression of ERs in the left PCA where ruptured aneurysms had formed most frequently in experimental study 1.
HT+OVX rats exhibited significantly lower mRNA levels of ERα and ERβ than did HT rats with intact ovaries. In BZA1 rats, the mRNA level of both ERα and ERβ was significantly elevated and was similar to the level in HT rats (Fig. 2a). In agreement with the mRNA level of ERs, ERα, and ERβ, protein expression was low in the cerebral arteries of HT+OVX rats. In BZA1 rats, the expression of both ERα and ERβ was greater than in HT+OVX rats (Fig. 2b). These findings indicate that BZA restored the gene and protein expression of both ERα and ERβ that was decreased by estrogen deficiency.
BZA downregulates IL-1β and decreases the MMP-9/TIMP-2 ratio in the cerebral artery
Elsewhere, we demonstrated that aneurysmal rupture in ovariectomized hypertensive rats was associated with the increase in the mRNA level of IL-1β and the MMP-9/TIMP-2 ratio in the aneurysmal wall [18, 22]. Here, we examined the mRNA level of IL-1β, IL-6, TNF-α, MMP-9, and TIMP-2 to explore the mechanisms underlying the protective effects of BZA against aneurysmal rupture.
The IL-1β mRNA level was significantly higher in HT+OVX than HT rats. In BZA1 rats, the level of IL-1β was significantly decreased and similar to the level in HT rats (Fig. 3a). The mRNA level of IL-6 was similar among HT, HT+OVX, and BZA1 rats (Fig. 3b). On the other hand, the mRNA level of TNF-α was significantly increased in HT+OVX rats, and while it was lower in BZA1 rats, the difference did not reach statistical significance (Fig. 3c). These findings suggest that the gene expression of IL-1β and TNF-α, but not of IL-6, is regulated at least partly by ERs.
The mRNA level of MMP-9 was significantly higher in HT+OVX than HT rats. In contrast, the mRNA level of TIMP-2 was lower in HT+OVX than HT rats. The mRNA level of MMP-9 in BZA1 rats was significantly lower, and TIMP-2 was higher than in HT+OVX rats (Fig. 4a, b). Consequently, the MMP-9/TIMP-2 ratio was reduced in BZA1 rats (Fig. 4c). These observations suggest that elevated MMP-9 mRNA- and attenuated TIMP-2 mRNA expression are associated with the downregulation of ERs. The downregulation of IL-1β and the amelioration of the MMP/TIMP2 ratio via the modulation of ERs by BZA may have contributed to the prevention of aneurysmal rupture in our estrogen-deficient hypertensive rats.
We demonstrate that ovariectomy promoted aneurysmal rupture in hypertensive rats subjected to hemodynamic stress. We first document that in our hypertensive, ovariectomized aneurysm-model rats, the downregulation of ERs and the upregulation of pro-inflammatory molecules in the rupture-prone cerebral artery were associated with an increase in the aneurysmal rupture rate and that BZA ameliorated the downregulation of ERs, restored their gene and protein expression, decreased the incidence of aneurysmal rupture, and lowered the level of pro-inflammatory- and vascular degradation molecules. The incidence of ruptured aneurysms and the mRNA level of ERs and pro-inflammatory and vascular degradation molecules were similar to those in HT rats with intact ovaries. These findings suggest that BZA prevented aneurysmal rupture associated with inflammation and vascular degradation via the downregulation of ERs in our ovariectomized aneurysm-model rats.
Estrogen exerts diverse vascular effects mediated mainly by ERα and ERβ [23]. The treatment of ovariectomized rats with estradiol reversed the decrease in ERα and ERβ expression in the cerebral vessel wall [19]. Using our original aneurysm model, we demonstrated that estrogen deficiency elicited by ovariectomy reduced the expression of ERα while the expression of ERβ was retained at the bifurcation of the ACA-OA where unruptured aneurysms were highly and reproducibly induced [6]. The present study showed that the expression of ERα and ERβ in the PCA prone to aneurysmal rupture was reduced in our ovariectomized aneurysm rats and that BZA upregulated both ERα and ERβ in the PCA. Elsewhere, our group documented that in ovariectomized aneurysm mice, treatment with estrogen or an ERβ-, but not an ERα agonist, reduced the incidence of cerebral aneurysm rupture [9]. The downregulation of ERβ is thought to be associated with inflammation [24]. We suggest now that in our current rat aneurysm model, BZA exerted protective effects against rupture through ERβ stimulation.
IL-1β promotes extracellular matrix degradation by increasing the production of MMPs and decreasing the production of TIMPs [25, 26]. TNF-α and IL-6 also stimulate the expression of MMP-9 [27, 28]. In our current and earlier studies [18, 22], the increase in IL-1β and TNF-α and the imbalance between MMP-9 and TIMP-2 were associated with aneurysm rupture in ovariectomized aneurysm rats. BZA abated the increase in IL-1β and the imbalance between MMP-9 and TIMP-2 and resulted in a moderate inhibition of TNF-α. ERβ stimulation decreased cellular inflammasome activity and IL-1β expression after global cerebral ischemia in ovariectomized rats [24]. Selective ERβ agonists repress the transcription of pro-inflammatory genes including TNF-α [29]. The ERβ agonistic effects of BZA may be responsible for the downregulation of pro-inflammatory cytokines, resulting in the inhibition of vascular degradation.
Others reported that TNF-α modulates cerebral aneurysm formation and rupture. The TNF-α inhibitor 3,6'dithiothalidomide resulted in aneurysmal stabilization and a significant decrease in the rupture rate [30]. In contrast, a meta-analysis reiterated that IL-6 was not associated with the pathogenesis of intracranial aneurysms [31]. These studies support our present findings.
In women, ERα activation in the brain stimulated physical activity and reduced their food intake and body weight gain [32, 33]. Therefore, the effect of BZA at 1 mg/kg, but not 0.3 mg/kg, on the body weight of our rats may have involved the upregulation of ERα. On the other hand, since ERβ is thought to be associated with vasoprotection, the effect of BZA on the body weight via the upregulation of ERα may be smaller than the vasoprotective effects elicited by ERβ. Estradiol and a selective ERα agonist increased the uterine weight in mice [15]. However, BZA had no such effects in the current and an earlier study [20], indicating that its effects are tissue-specific.
Use of our original rat aneurysm model resulted in a high incidence (more than 80%) of unruptured aneurysms at the ACA-OA bifurcation; at most, 10% of these aneurysms ruptured during the 12-week observation period. For the current study, we modified the hemodynamics of our original model and produced a novel model in which approximately 50% of the experimentally induced aneurysms spontaneously ruptured [18]. With this new model, we demonstrated the protective effect of BZA, a selective ER modulator, on cerebral aneurysm rupture. The efficacy for prevention of aneurysm rupture may provide a new therapeutic option in the clinical setting.
Our study has some limitations. First, we assessed the changes in the mRNA level and the protein expression of the ERs elicited by ovariectomy and BZA. For a better understanding of the effects of individual ERs, studies using specific ER agonists or inhibitors and knockout animal are needed. Second, we started the administration of BZA 2 weeks after aneurysm induction without confirming the presence of cerebral aneurysms, and we did not confirm the presence of unruptured aneurysm in rupture-prone arteries at 12 weeks. Therefore, it is unclear whether BZA prevented their formation or their rupture. Third, the rodent age may affect their vascular response to estrogen [34], and menopause simulated by ovariectomy in our rats may be different from natural menopause in aged rats. Further studies are underway to address these questions.
This is the first study to show that BZA exerted protective effects against aneurysmal rupture in hypertensive ovariectomized aneurysm rats without affecting their blood pressure. It ameliorated the downregulation of ERs, the upregulation of IL-1β, and the MMP-9/TIMP-2 imbalance in the cerebral artery. Since BZA has fewer estrogenic side effects than estrogen and is clinically used to address osteoporosis, it may help to prevent SAH in postmenopausal women.
Anterior cerebral artery-ophthalmic artery
Estrogen receptor
Glyceraldehyde 3-phosphate dehydrogenase
Matrix metalloproteinase
Posterior cerebral artery
- qRT-PCR:
Quantitative real-time PCR
Subarachnoid hemorrhage
Selective estrogen receptor modulator
Tissue inhibitor of metalloproteinase-2
Tumor necrosis factor
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de Rivero Vaccari JP, Patel HH, Brand FJ 3rd, Perez-Pinzon MA, Bramlett HM, Raval AP. Estrogen receptor beta signaling alters cellular inflammasomes activity after global cerebral ischemia in reproductively senescence female rats. J Neurochem. 2016;136:492–6.
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Eberhardt W, Huwiler A, Beck KF, Walpen S, Pfeilschifter J. Amplification of IL-1 beta-induced matrix metalloproteinase-9 expression by superoxide in rat glomerular mesangial cells is mediated by increased activities of NF-kappa B and activating protein-1 and involves activation of the mitogen-activated protein kinase pathways. J Immunol. 2000;165:5788–97.
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Poljak M, Lim R, Barker G, Lappas M. Class I to III histone deacetylases differentially regulate inflammation-induced matrix metalloproteinase 9 expression in primary amnion cells. Reprod Sci. 2014;21:804–13.
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Yao JS, Zhai W, Fan Y, Lawton MT, Barbaro NM, Young WL, Yang GY. Interleukin-6 upregulates expression of KDR and stimulates proliferation of human cerebrovascular smooth muscle cells. J Cereb Blood Flow Metab. 2007;27:510–20.
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Moon SK, Cha BY, Kim CH. ERK1/2 mediates TNF-alpha-induced matrix metalloproteinase-9 expression in human vascular smooth muscle cells via the regulation of NF-kappaB and AP-1: involvement of the ras dependent pathway. J Cell Physiol. 2004;198:417–27.
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Cvoro A, Tatomer D, Tee MK, Zogovic T, Harris HA, Leitman DC. Selective estrogen receptor-beta agonists repress transcription of proinflammatory genes. J Immunol. 2008;180:630–6.
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Starke RM, Chalouhi N, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, Wada K, Shimada K, Hasan DM, Greig NH, et al. Critical role of TNF-alpha in cerebral aneurysm formation and progression to rupture. J Neuroinflammation. 2014;11:77.
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Sathyan S, Koshy LV, Srinivas L, Easwer HV, Premkumar S, Nair S, Bhattacharya RN, Alapatt JP, Banerjee M. Pathogenesis of intracranial aneurysm is mediated by proinflammatory cytokine TNFA and IFNG and through stochastic regulation of IL10 and TGFB1 by comorbid factors. J Neuroinflammation. 2015;12:135.
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Xu P, Cao X, He Y, Zhu L, Yang Y, Saito K, Wang C, Yan X, Hinton AO Jr, Zou F, et al. Estrogen receptor-alpha in medial amygdala neurons regulates body weight. J Clin Invest. 2015;125:2861–76.
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Tarhouni K, Guihot AL, Vessieres E, Toutain B, Procaccio V, Grimaud L, Loufrani L, Lenfant F, Arnal JF, Henrion D. Determinants of flow-mediated outward remodeling in female rodents: respective roles of age, estrogens, and timing. Arterioscler Thromb Vasc Biol. 2014;34:1281–9.
Not applicable.
This work was supported by a Grant-in-Aid for Scientific Research [JSPS KAKENHI Grant Number JP15H04950], a Grant-in-Aid for Young Scientists (B) [JSPS KAKENHI Grant Number JP15K19972], and a Grant-in-Aid for the Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation from the Japan Society for the Promotion of Science [JSPS KAKENHI Grant Number JPS2407].
Availability of data and materials
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
Ethics declarations
Ethics approval
All experiments and protocols were approved by the Ethics Committee of the Institute of Biomedical Sciences, Tokushima University Graduate School and conducted in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Experiments were reported according to the ARRIVE guidelines. Before all surgical procedures, the rats were anesthetized with isoflurane inhalation (induction 4%, maintenance 2–2.5% in room air) and a local subcutaneous bupivacaine (0.25%) injection. Euthanasia was performed with an anesthetic overdose (4% isoflurane inhalation).
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Additional files
Additional file 1: Figure S1.
A ruptured aneurysm in the left posterior cerebral artery (PCA) of an OVX/VC rat (arrowhead). (TIFF 4425 kb)
Additional file 2: Figure S2.
Wet uterine weight 5 weeks after aneurysm induction. *p < 0.05 (Scheffe's test). Data represent the mean ± SD. n = 7 per group. (TIFF 2286 kb)
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
About this article
Cite this article
Maekawa, H., Tada, Y., Yagi, K. et al. Bazedoxifene, a selective estrogen receptor modulator, reduces cerebral aneurysm rupture in Ovariectomized rats. J Neuroinflammation 14, 197 (2017). https://doi.org/10.1186/s12974-017-0966-7
- Estrogen
- Estrogen receptor
- Intracranial aneurysm
- Selective estrogen receptor modulator
- Subarachnoid hemorrhage

subset: commoncrawl


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Medication Technician CNA-M at Eastern Maine Healthcare Systems
Waterville, ME
About the Job
Regular Part-time
Various Shifts Available
This posting is for part-time Medicaton Technician CNA-M positions in the Skilled Unit - Various shifts available.
Our mission is to enhance the lives of our residents and their families. Such care recognizes the importance of quality service to residents and co-workers. Each employee has the following responsibilities as an individual:
·Responsible - works independently, in a safe and appropriate manner.
·Sensitive - displays sensitivity and empathy to the needs of residents and co-workers.
·Timely - recognizes time as a most valuable resource andresponds promptly to residents' and co-workers' needs.
·Accurate - works carefully and precisely, with attention to detail.
·Coordinated - organizes and delivers service in the proper order. Displays good organizational skills and utilizes resources wisely.
·Thorough - meets all requirements of the position.Is able to evaluate and follow-up services.
Summary of Major Functions
The Medication Technician– C.N.A.-M is responsible for the administration of certain medications to residents as prescribed for them by their licensed care providers under the direction of the Licensed Nurse, in accordance with State and Federal regulations and facility policy.This position may also entail functioning as a C.N.A, which would include other nursing directed activities, including provision of personal care services, assistance, support and supervision for residents and other designated duties assigned by their supervisor.
Essential Functions and Work Role Responsibilities
Primary responsibility includes the preparation, administration and documentation ofmedication administered to individual residents, ensuring accuracy of person receiving medication, preparation, route, dosage, form and time of delivery of medication as well as timely documentation of all of the above.
1.Ensures that medication is verified three times prior to its administration.Ensures label on medication contains all documentation required by federal and state legislation and that label agrees with current order.
2.Observes each resident as they take their medication.Ensures medication is
Never left unattended or left with the resident at the bedside.
3.Documents administration of medication in the Medication AdministrationRecord () as soon as resident is observed taking medication.Documents any instance when medication is not taken or is refused, as well as the reason for omission and/or refusal and reports these instances to supervisor.
4.Observes, records and reports unusual signs, symptoms or reactions to the nurseReports all medication errors to supervisor as required by facility policies andprocedures.
5.Takes and records appropriate vital signs whether required before, during orafter administration of medication.These may include temperature, pulse,respirations, blood pressure, oxygen saturation, blood glucose , or level ofdiscomfort, in accordance to medication orders or parameters, and in accordancewith facility policies and procedures.
6.Consults appropriate drug references to verify proper drug indication, dosage,route, purpose, storage and administration guidelines and precautions as well asinteractions and possible side effects of each medication.
7. Demonstrates knowledge of common terms, abbreviations and symbols relatedto medications and
their administration.
8Stores medications in accordance with current federal and state regulations and policies and procedures of the facility.Maintains the security of all drug storage areas at all times.Separates internal vs. external preparations.Maintains separation of individual resident's medications.
9.Observes residents' rights related to medication administration, recognizing the following.
·The right to be informed of the purpose for the medication
·The right to refuse any or all medication
·The right to select their own pharmacy provider
·The right to treatment with dignity and respect at all times.
·Maintains confidentiality of all information in accordance with HIPAA and facility guidelines
·Immediately reports any violations of resident rights, complaints or grievances made by residents or their families to the supervisor.
10.Utilizes appropriate aseptic techniques in the preparation, administration andstorage of medication.
·Disinfects hands after administering medication to each resident
·Washes hands with antibacterial soap and water utilizing proper hand washing techniques after the administration of eye preparations
·Utilizes personal protective equipment when there is risk of exposure to blood or body fluids.
11.Assists residents with activities of daily living (bathing, dressing, grooming,etc.) and instrumental activities of daily living, ( housekeeping, minor mealpreparation, meal service, laundry, and transportation) as assigned bysupervisor.
12.Monitors health, safety and well-being of the residents.Accurately measuresresident's blood pressure, temperature, pulse respirations, weight and other appropriate vital signs and records them accordingly.Reports concerns about residents to supervisor and co-workers on a need-to-know basis, maintaining confidentiality at all times.
13.Identifies supplies needed to perform tasks; communicates these needs to supervisor.
14.Practices safe working habits while utilizing all equipment, chemicals, tools and utensils.Reports any equipment malfunctions and or safety concerns.
15.Assists in keeping the environment safe for residents; follows safe working practices and encourages others to do so as well.
·Immediately reports all accidents/incidents and injuries to shift supervisor/administrator and accurately completes incident report and/or workman's compensation report.
·Follows all safety policies and procedures and reports all hazardous or malfunctioning equipment, as well as missing or illegible MSDS chemical labels to person in charge or the administrator.
·Follows established policies and procedures related to infection control and exposure to blood and body fluids.Immediately reports occupational exposures to person in charge and or administrator.
·Uses appropriate personal protective equipment when there is a risk of exposure to blood borne or other potentially infectious material.
16.Provides care for residents within scope of practice of a C.N.A.Documents all provision of care.
17.Attends continuing education programs and facility in-services when required to ensure current, relevant knowledge of issues affecting the elderly, as well as facility policies and procedures.
18.Leaves work area for breaks only as assigned and as expressly authorized by the person in charge.
19.Maintains a positive work atmosphere by behaving and communicating in a manner which promotes teamwork.
20.Provides supervision and assists residents to maintain personal hygiene by:
·Giving complete bed baths, showers, or whirlpool baths
·Caring for teeth or dentures and providing special mouth care as needed
·Combing hair, shaving, trimming nails and applying make-up when desired by resident
·Dressing in appropriate clothing
21.Assures that residents receive adequate nutritional care by:
·Positioning resident so that independent feeding is facilitated
·Feeding residents when necessary
·Encouraging poor eaters and assisting those with marginal food intake to get the maximum benefit from meals and snacks.
22. Assists residents with functions of elimination by:
·Helping and/or reminding the resident to go to the bathroom at appropriate times
·Providing bedpans or urinal as requested or at regular intervals as required
·Participating in bowel and bladder rehabilitation programs as stated in the care plans
·Making proper use of incontinence products and protective pads
23. Assists residents to maintain or improve their level of mobility and prevent problems of immobility by:
·Repositioning residents for their comfort and to prevent pressure sores frequently and at least every two hours
·Assisting with range of motion of all extremities by exercises or activities
·Using good body mechanics to assist a resident who can support his own weight to transfer into a chair or bed and with another staff member to transfer a resident who requires lifting
·Using mechanical life and turning sheets as aids in moving heavy or difficult residents
·Assisting residents with the safe use of walkers, canes and crutches when walking
·Encourage participation in activities and transport of residents to activities of their choice.
24.Maintains a safe, clean environment for the resident by:
·Keeping bed neat, clean and made up with fresh linens as required
·Using physical restraints only when absolutely necessary and demonstrating proper application of vest, belt, geri-chair and specialized restraints
·Disposing of soiled linen and trash in proper receptacle.
25. Provides emotional support on a day to day basis by:
·Using listening techniques, allow residents to verbalize their concerns without being judgmental
·Encouraging participation in recreational programs
·Keeping furniture and personal articles neat and orderly in order to prevent falls and other accidents
·Practicing good infection control practices of frequent hand washing and use of universal precautions when dealing with body fluids.
26. Provides information about the resident's condition and any significant changes by:
·Taking, recording and reporting temperature, pulse, respiration, blood pressure and weights at regular intervals and when indicated by a change in condition
·Reporting anything different or unusual about the resident – rashes, bruises, complaints of pain, vomiting, diarrhea, fever, etc.
·Documenting as required on ADL sheets – special foods and fluids, intake/output, mobility, bladder and bladder restraints, etc.
27. Functions as a member of the facility resident care team by:
·Adhering to dress code and maintaining good standard of personal hygiene and grooming
·Participating in staff development and in-service education programs according to State/Federal regulations
·Sharing/helping with work load and cooperating with other staff members regardless of individual assignments
·Following facility personnel policies and procedures
28.Performs other essential duties as necessary or required
29.Ensures proper use and handling of equipment and supplies
Working Behaviors
1.Adheres to and carries out all policies and procedures
2.Reports on-the-job injuries and or grievances to the supervisor before the end of the shift on the day the injury occurs.
3.Establishes and maintains constructive working relationships with co-workers, residents, families and visitors.
4.Maintains confidentiality of verbal and written information
5.Promotes in a positive way
6.Promotes teamwork in the provision of services for residents
Physical Environment
Exposed to all resident elements, including exposure to blood and body fluids and other unpleasant elements.At times, long and irregular hours are necessary.Exposure to hazardous substances is, at times, unavoidable.Frequent multiple tasks and resident needs will be assigned in a rapid fashion.
Physical Criteria/Effort
Work involves standing and/or walking over 70% of the time.There is moderate physical effort in positioning, lifting, or moving residents of various weights and body shapes, with or without assistance.Vision and hearing acuteness is required at all times.Repeated bending, squatting, and stooping is necessary.The incumbent is subject to frustration and fatigue.Manual dexterity to perform all aspects of care and prescribed treatments for residents, including but not limited to preparation of different forms of medication as well as the ability to administer them; also involves manual dexterity to administer personal care and other therapies as prescribed for residents.
Occupational Risks
Occupational injuries may occur from not following policies and procedures regarding exposure to hazardous materials including blood and body fluids and potential injuries from sharp objects, violent individuals, and physical environment.Working with cleaning chemicals and other medicinal/pharmaceutical preparations which may require personal protective equipment.
Probability And Consequences of Errors
Errors in practice can result in negative resident outcome.Probability is contingent upon individual practice.Poor performance will be addressed according to established progressive disciplinary policies and procedures of the facility and the State of .
Minimum Requirements For The Job
·Currently certified and registered with the Maine Registry
·Certification in the State of as a -M
·Training/Experience as a Certified Nursing assistant
Completion of a state approved program.Previous clinical experience in acute care of long-term care is desirable.
·Certified medication training as outlined by the state
·Experience or interest in working with older adults
·Maturity, friendliness and enjoyment in working with people
·High school diploma or GED, with reading, comprehension and writing ability at 12th grade level or higher


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|By Dwip
|June 19, 2012, 3:29 pm
|Comments (8)
This is a thing which just happened.
Me: Ah yes, the Civilization 5 xpack, Gods and Kings came out today. I'd best go get that.
*drives to Gamestop*
Me: Hey, so, uh, Gods and Kings. Any copies?
Gamestop: Sorry, pre-orders only.
Me: I see. Any idea when you'll get more?
Gamestop: Not really.
Me: I see. Well, thanks.
*drives home*
Me: Hey Steam, I bet you can solve this.
Steam: Yes, but you need to click three buttons and a checkbox.
Me: This seems reasonable. *does so*
Steam: Install will probably take about 10-15 minutes.
Me: Great. Just enough time for a shower. Perfect.
And here we are. Because, you know, as much fun as scheduling my life around somebody else's shipping schedule is, I'll take a pass.
|Computer Games - Civilization Series, Random and Ravings
|Comments (8)
|Comment by prettyfly
|June 19, 2012 at 11:21 pm
I'm tempted to get stroppy about the fact they've delayed the release for two days in Australia. But in my case it actually means it won't unlock until Friday (in my country's time zone), which coincidentally means that I won't be able to play it until the afternoon after my History project is finished and handed in.
And since that project is worth 90% of my mark in that topic its probably actually a good thing that I don't have Civ distracting me.
Still, I can't wait to name my religion 'Syphilis'.
|Comment by prettyfly
|June 20, 2012 at 2:11 am
So I take it they haven't really solved the AI's still seem to be problematic?
Also, exactly how much of a buff does religion tend to give you?
You must be logged in to post a comment.


text:
Discography Updated
- Piet Botha
- Piet Botha & Jack Hammer
- Jack Hammer
- Wildebeest
- Various Artists
- Raven
This was when I first met Piet Botha and Johnathan Martin (that is the correct spelling for Johnathan, I found out years later!). Piet often used to say that I put them on the internet before they even knew what the internet was!
— Brian Currin, 10th July 2020
from SA Rock Digest, Issue #39, 21st November 1999
Piet Botha's famed blues-rock band is releasing a retrospective of their 4 albums on a new compilation CD early in December. Titled simply "Anthology" this CD will include 4 or 5 new songs plus a new re-recording of the classic 'Fort Lauderdale' alongside tracks from all 4 previous albums.
Those of you who were lucky enough to see Piet Botha on his recent "Skopgraaf" tour would have heard a couple of the new tracks, including 'April'.
Piet Botha, Jonathan Martin and Tertius du Plessis wowed the enthusiastic audience at the Whammy Bar in Cape Town recently. Their set included Piet Botha solo songs, Jack Hammer tracks and some covers including a stunning version of Zeppelin's 'Tangerine' and Bob Dylan's 'All Along The Watchtower'.
Please see the Original post
Please also see: South African Rock Legends: Piet Botha and Jack Hammer
"Kyk nou die langpadRoep my nou maar weerDaar is genade en liefdeEn nog baie meerKyk nog 'n somer alweer weggegaanEn al wat jy doen, ek sê maar niksLaat dit met jou goed gaanSien jou weer" – Sien jou Weer (JP Botha)
Today marks one whole year without you. We miss your wisdom, the way you laughed, the smell of your pipe, the solos that only you could play… Your Fender is silent now, but your music can still be heard in the houses of all who loved you dearly. Thank you to everyone for your love and support over the past year. The Hammer lives on in the memories you share.
"Bury me when the starsShine bright over ZanzibarThe moon can be the preacherAnd the tide can do the restYou don't have to be perfectJust do your best" – Bury Me When (JP Botha)
Release Information:
2LP: 2019 Wolmer Records, 199753E
CD: not unreleased on CD
Buy at PietBotha.bio
See separate album releases
Songs were recorded at various studios across the country between 1985 – 2011
Limited edition, double LP, uniquely numbered, mixed specially for vinyl by Lanie van der Walt / Wolmer Records
It's taken me a long time to truly assimilate this release. Ironically enough I know all the music on this compilation, but allow me to explain the importance of this particular release. Piet Botha passed away this year but left us with some of the grittiest, down-to-earth, soul searching music. The renegade son of a principled and extremely well-liked politician, Piet was one of the most amazingly talented local musicians ever to grace us with his presence, persona and was liked by all. His blues and pure rock in Jack Hammer was the mainstay and result of a life on the road, touring incessantly but always giving a piece of his heart away to fans, friends, roadies and music junkies and the music sung in English, and would not be out of place anywhere in the world. This is a double album with one record dedicated to material by Jack Hammer, and the other to his solo work. His solo work was generally performed in Afrikaans (his native tongue), but was equally rewarding and he regularly delivered the most incredible albums. He was a rocker, a husband, a father, a maverick, a beautiful soul with a powerful gravel-laden voice, a entertainer and the epitome of what humans can achieve when they channel all their creativity into their music. A belated tribute to our fallen son, not to be forgotten. Wolmer Records, 2019. Limited edition. Sleeves notes judiciously acknowledge all members of both incarnations. Even Billy Bob Thornton.
Wayne Roux, 2019
In light of the recent passing of a great father and teacher Piet Botha, some of his closest comrades got together to not only show their respect and admiration for this legend but also to honour an old friend in the only manner they knew how, by giving him a song.
Composed and arranged by Andre Kriel the track features the Jack Hammer band Johno, Tertius and Paul, together with Andre and Kobus from The Black Cat Bones, Arthur and Rudolph Dennis, Gareth Wilson and finally the Van Der Walt Brothers Lanie, Chris and Heine aka 'The Wolmers'.
The Gauteng chapter of the collaboration was tracked and engineered in June 2019 by Lanie van der Walt at the famed 'Wolmer Records' in Pretoria North where Piet recorded most of his albums in both the Jack Hammer band as well as his solo offerings. Arthur and Rudi Dennis laid down their voices and guitar in Strand, Western Cape at Riku Lätti's 'Wasgoedlyn' studios and the entire process was documented and edited into a live studio music video by the acclaimed Image Engineer's Fred van Leeuwen.
Old Friend
Seems it's time for us to part
But it's not the end
Although it truly breaks my heart
Now the memories left behind
Are all that remains
So long for now
Till I see you again
Old Friend
Seems the world is moving on
But our time is spent
I can tell it won't be long
And the road we travelled on
I now walk alone
But I'll keep going till
It leads me home
We can't live forever
No one ever will
But don't you ever say never
Just keep pushing up that hill
Old Friend
I look back on all those years
And I try to pretend
I try to hold back all my tears
You have showed me many ways
Now you're gone and I'm turning grey
You know it's hard for me to say
I miss you today
We can't live forever
No one ever will
But don't you ever say never
Just keep pushing up that hill
You know we're only passing by
We come and we go
Are we living on borrowed time?
Nobody really knows
Old Friend
The Jack Hammer line-up featuring on Handful Of Rain has endured over the years, with Piet Botha (guitars, keys, harmonica, vocals), Johnathan Martin (guitars, vocals), Tertius du Plessis (bass) and Paul van de Waal (drums). The album also features guest artists Arthur Dennis (guitars, vocals) and Rudolph Dennis (drums, guest vocals) from Akkedis/Lyzyrd Kyngs. Piet Botha's harmonica is present throughout the album, and the style is familiar, lingering long after, like a renegade's signature tune in an old western.
The timbre in Piet Botha's singing is full of longing and resistance. In the title track, he sings "Here I go again on a lonesome highway / A handful of rain and empty heart", with Johnathan Martin, 'The Kid', by his side, harmonising, singing the same words. Cut from the same cloth. "That's How We Roll" echoes Neil Young, "me, I got nothing / just this old guitar"; a song about this brotherhood of musicians defying the Man, choosing the road over the rat race with its fitting rock 'n roll chorus.The haunting cover of Four Jacks and Jill's "Master Jack", a song about choosing solitude over society, flows into the album's theme: "no hard feelings if I never come back." Delving into the songwriting is a melancholy joy, and each listen reveals new meanings and interpretations. Is a song like "When the Moon Was Young" a love song first, a protest song second? Piet Botha gently contends,"They think they can own her / but even a fool knows / the moon belongs to lovers…"
The hair-raising harmonies of "Emily" and "Where Is the Clown" remind us why Jack Hammer are at their best when Piet Botha and Johnathan Martin come together. Not only do they whistle the same tune when it comes to existing and creating outside of the mainstream, but their musical accord completes Jack Hammer. Handful of Rain can best be summed up in "Sweet Soul Music", Piet Botha's collaboration with the Soweto String Quartet: violins, harmonica and electric guitars join on a song about rivers turning into seas, about songs turning our solitude into a universe of connected souls: "Keep the music in your heart / You will never walk alone."
Released January 2016
Track Listing:
Moonshine productions in association with STRAB presents:
Otterlake Easter Festival 2015
3–5 April
Gauteng's premier music festival The Otterlake Easter festival is back and bigger than ever this coming Easter!
Enjoy 3 days of live music, performed by South-Africa's top artists, in the serene bush-veld surroundings of Kameelfontein, north east of Roodeplaat Dam, less than 40kms from Pretoria's center. Come and swim in our lake or pool, fish, camp, laugh and experience the magic for the long-weekend! The festival is 'kiddie friendly'- children's play area with jumping castles etc. and swimming pool. Free entrance for children under 12 (bring ID's). Not only will you enjoy an experience of a lifetime; you'll be contributing to a very worthy cause, as proceeds of ticket sales will be donated to Unite Against Poaching and help protect our country's precious rhinos.
For the thirsty the festival has two main bars and a beer garden, for the hungry there will be a variety of tasty food stalls. Weekend Camping, clean toilets and hot shower facilities available. Other facilities include a mobile ATM, curio stalls and wood for sale.
An extra highlight on Saturday eve will be Otterlake's Easter Fire Celebration – a 10 meter high bonfire, an old European tradition, which symbolizes the bringing of people in from the darkness and into the light.
Weekend Tickets are only R370 on-line (includes camping), limited weekend tickets will be available at the gate at R400. Day passes available at R150.
Live music starts daily from 12h00 until 24h00 Friday to Sunday.
Gates for the event will open daily from 10h00.
Day visitors also welcome.
This year's lineup includes:
Piet Botha, Francois van Coke, The Black Cat Bones, Akkedis (CPT), Tidal Waves, Jaco vd Merwe (Bittereinder), Naming James, The Fake Leather Blues Band, Gareth Wilson, Meesh-Mash, Avade (KZN), Feed The Wolf, Bacchus Nel, Crystal Park, Hoot 'n Anny Band, Pedro Barbosa, Mountain Thief, The Pirates, Hardball, Monkeys in Boots, Yaki Naude, Tuin, Donovan Bourne, Franco Jamneck…more to be announced!
♬ Strictly No Cooler-boxes in music arena area
♬ No glasses or bottles in music arena
♬ No Drugs
♬ No Weapons
♬ No Pets
♬ No Bad Attitudes
♬ Right of Admission Reserved


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Your draft
This was deleted because there was no official source given. Generation V has been announced, as well as the first two games, which makes it less than likely that Crystal will be remade as a third version to HGSS. Please, when writing news articles (even rumors) supply a source so we can affirm its legitimacy. —darklordtrom 02:39, 12 April 2010 (UTC)


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Nestle India Ltd follows January-December fiscal. Net sales of the company rose to Rs 2,348.3 crore for the third quarter, up 11% compared to Rs 2,115.5 crore in the same period of previous year.
Nestle India MD Etienne Benet said: We will continue to focus on reinforcing the fundamentals of our growth drivers, further improve our operational efficiencies and keep rationalising our stock keeping units.
Overall expenses during the quarter were at Rs 1,950.1 crore, up 11.21%, against Rs 1,753.5 crore in the corresponding period a year ago. Nestle India has declared second interim dividend of Rs 18 per equity share for 2013.


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the hopelessness of Soviet stores.
So, friends — today will be an interesting post about Soviet shops. I don't know why — but still in the environment of fans of the Soviet Union very popular is the myth that the scoop of people were fed with high-quality products that were natural, and they are always in any quantity you could buy in any store. Supposedly compared to modern products in the USSR, it was natural, and the shelves were full of goods — this was a good choice.
Of course, it is not. There is no "good selection of products" In the USSR was not all the years of its existence, and in order to buy something more or less tolerable — people were forced to defend the huge queues. This, incidentally, puts an end to all the fantasies about what is supposedly "the Soviet Union was a country of justice and of happiness" — once again still in the USSR in the literal sense of the words "survival of the fittest", which could in queues fighting to get themselves and their family products.
So in today's post we will look at what looked like the trade of products in the USSR and compare it with today. Make sure you check out the article below, write your opinion in the comments, and of friends added do not forget. And telegram channel also subscribe)
02. First, let's take a look at this picture of a small provincial Soviet store in the sixties — according to many fans of the USSR, this time it was the"Golden age" of the Union — consequences of the war have already overcome, and "cursed restructuring" has not yet begun.
However, as you can see in the photo, there is no "commodity abundance" store — on the shelves you can see the same sour bread "brick" and several types of simple canned — in the sixties of fresh fruit and vegetables was not really to buy, but canned like "Breakfast tourist" on the shelves had quite a lot — the feeling that the whole country went on a big hike during communism)
03. Where Soviet citizens to buy fresh fruits and vegetables? In addition to the vegetable stores (which also rarely normal range), there were also markets and vserazlichnymi point of exit trade. This picture was taken in the seventies, long before "the damned perestroika" — a store near the cinema sells some plain apples, and they immediately queue. I think in a modern supermarket you didn't even looked in the direction of these apples, and in the USSR it was a running scarce commodity that was rarely in a normal shop for normal vegetables and fruits needed to "run".
04. And this is a very important thing that you need to understand throughout the Soviet trade — you can't just come into the store and out in half an hour with a complete set of products (as is happening now), it was impossible in principle. Yes, hunger you wouldn't be dead — bread, yogurt and some cereals have been in every store, but if desired such as normal meat or vegetables — had to stand in a long queue (often for hours), or run on the markets, where the choice of vegetables/fruit were better than in stores.
05. As, for example, the trade took place in the meat Department of the Soviet stores? Delivery time normal sausage or a decent meat became known to customers, and often even before the opening of the store next to it stood a considerable part.
06. Fans of the USSR write — "but in the Union no one starved!". Yes, indeed — the bread and yogurt you could buy always, but how long can you stretch out on one bread, yogurt and pasta grey? And in order to buy something other than bread and yogurt, often had to defend the huge queues at the queue stretches outside the shop, and in the foreground you can see the product that you can take without waiting — huge bottles of sugared water with addition of citric acid under the name "birch SAP".
07. Themselves meat departments of the stores looked like this. That meat was packaged and freely lying in the refrigerator showcase (as is happening now) and the speech could not be — it would grind in two minutes. Meat stood in long queues, and the best pieces have got either "thieves" (friends of the shop staff), or just those who got there first. Sold meat often along with heavy bones (to increase sales weight) and all the meat Department in the USSR was a scheme of butchering pigs or cows standing in the line, Soviet citizens wondering which piece to take.
08. Those who for some reason didn't manage to bring valuable product was in the queue for meat last got one skin, bones and pieces of fat called "soup mix". This is the question of "care of the weak" in the USSR…
09. Sausage was about the same situation — time delivery of sausages became known in advance, and it was sorted very quickly, plus the considerable part of employees of shops "shove its" — sausage (especially of scarce dry-cured) was great payment for the services familiar to hairdressers, plumbers, and dentist.
10. More or less freely in the sausage Department, you could buy it — cooked sausage grayish color, with bacon ("Amateur") or no fat ("doctor"). No natural raw smoked and dry cured sausages, no good sausages, wieners and sausages to beer, not to mention clippings, fillets, etc. And also pay attention to the price — pounds even so homely sausage worth as much as 3 rubles and 60 kopecks — that is, for the average Soviet salary could buy only 40-50 pounds of sausage.
11. The situation with the sale of poultry was the same, you are no showcases, refrigerators with a free sale — chickens were released strictly in order, often no more than 1-2 pieces per person (depending on situation). Even in the photo below you can see an interesting detail — in addition to the normal lever weights on the counter are still e — apparently, they were added in order to make it less "frauds on the deficit," leverage and weights could come up with a lot of tricks.
By the way, the photo is some very good and rare broiler chickens, usually of Soviet chickens looked a bit different — was spifflicate, knackered, skinny, bluish and often sold with the remnants of feathers — feathers had to scorch over the burner of a gas stove.
12. Similar scales were massively introduced in the late eighties, that already says a lot about the Soviet trade — apparently rukovodstvo many shops tired of the constant machinations of sellers, in which the balance spring is stretched, then the weight will enclose — the balance shown is more than the product weighs really, and the difference of the gain was placed in his pocket.
13. The fish Department. Here is the same situation as with the meat, and sausages, who had first — dismantled the best, the rest got the leftovers. Pictured left — some nondescript frozen Alaska Pollock tails.
14. In the last years of the Soviet Union in the shops and all were completely empty shelves. This is not a metaphor, see for yourself — here is a Moscow grocery store, photographed in January 1990.
15. But the January 1991, it is also Moscow, the capital of the USSR.
16. A very characteristic photo of the last years of the Soviet Union — two of the storefront is completely empty, the window on the left are those cans of sugared water with addition of citric acid under the name "juice", in the background you can see the scales, and in the right corner — the scheme of cutting of meat carcasses.
17. To all the above, it should be added that trade in Soviet shops, even from the point of economy of time was organized very inefficient — often the buyer stood in one line to weigh the product, then stood a second queue to the cashier to get the check, and then stood a third place to check is stamped to previously weighed commodity.
Photo: Gettyimages.
Such cases.
Well, you still want the poor in Soviet stores? So you bought)?
© 2019, paradox. All rights reserved.


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Plenum Healer: offering metaphysical healing
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65.22 Questioner: Can you tell me what this chamber did to the entity to create this awareness in him?
Ra: I am Ra. This chamber worked upon the mind and the body. The mind was affected by sensory deprivation and the archetypical reactions to being buried alive with no possibility of extricating the self. The body was affected both by the mind configuration and by the electrical and piezoelectrical properties of the materials which were used in the construction of the resonating chamber.
This will be the last full query of this working. May we ask if there are any brief queries at this time?
3.16 Questioner: Does the shape of the pyramid itself— is that a key function in the initiation process?
Ra: This is a large question. We feel that we shall begin and ask you to re-evaluate and ask further at a later session, this somewhat, shall we say, informative point.
To begin. There are two main functions of the pyramid in relation to the initiatory procedures. One has to do with the body. Before the body can be initiated, the mind must be initiated. This is the point at which most adepts of your present cycle find their mind/body/spirit complexes distorted from. When the character and personality that is the true identity of the mind has been discovered, the body then must be known in each and every way. Thus, the various functions of the body need understanding and control with detachment. The first use of the pyramid, then, is the going down into the pyramid for purposes of deprivation of sensory input so that the body may, in a sense, be dead and another life begin.
We advise, at this time, any necessary questions and a fairly rapid ending of this session. Have you any query at this time/space?
61.12 Questioner: Could you tell me why it is important for the appurtenances and other things to be so carefully aligned with respect to the instrument and why just a small ruffle in the sheet by the instrument causes a problem with the reception of Ra?
Ra: I am Ra. We may attempt an explanation. This contact is narrow-band. The instrument is highly sensitive. Thus we have good entry into it and can use it to an increasingly satisfactory level.
However, the trance condition is, shall we say, not one which is without toll upon this instrument. Therefore, the area above the entrance into the physical complex of this instrument must be kept clear to avoid discomfort to the instrument especially as it re-enters the body complex. The appurtenances give to the instrument sensory input and mental visualization which aid in the trance beginning. The careful alignment of these is important for the energizing group in that it is a reminder to that support group that it is time for a working. The ritualistic behaviors are triggers for many energies of the support group. You may have noticed more energy being used in workings as the number has increased due to the long-term, shall we say, effect of such ritualistic actions.
This would not aid another group as it was designed for this particular system of mind/body/spirit complexes and especially the instrument.
There is enough energy transferred for one more long query. We do not wish to deplete this instrument.
Version (?): Lightly Edited, Ra Contact, Relistened, Original
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text: As I have been on and off with Makeover Monday recently due to me having to prepare for job interviews as that elusive first graduate job comes ever closer. I have found some time today to slip in my Week 32 entry on broken toilets in India. Since the dataset I had worked with came from the … Continue reading Makeover Monday Week 32 – Usable Girls Toilets in India


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Subscriber Login
Country: Ukraine
Organisation: Communal Enterprise "Khersonelectrotrans" of Kherson City Council
Description: Bids are invited to supply low-floor trolleybuses along with tools, spare parts and diagnostic, repair and maintenance equipment as well as undertake works to modernise catenary network and traction sub-stations. Each trolleybus should be 12 metres long. The contract is being financed by a loan by the European Bank for Reconstruction and Development (EBRD). Tendering is expected to commence in the second quarter of 2019. Further details are available at https://www.ebrd.com/work-with-us/procurement/p-pn-190604a.html.
Closing date: June 4, 2020
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Phone: +380 552 354267
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Another gorgeous wedding at Stanbrook Abbey to share with you. This old convent has been converted into a hotel and is part of the Hand Picked Hotels group. It is stunning inside and out. Lots and lots of photo opportunities. The latest of our couples to choose this wonderful Worcestershire wedding venue was Flo and Andy.
The daytime element of the wedding was to be an intimate ceremony and celebration with family and close friends and then more joined them later to party the night away.
I was with Flo in the Rose Suite where Michelle of Michelle G Make up was already busy along with Valerie of The Big Hair Day. Her stunning dress from Wed2b was under wraps so that her bridal party didn't get a sneak peek before she put it on!
Andy used the Groom's Room at the venue to change into his suit from Bill Child Formal Wear in Hereford. Kev was there to make sure that Andy got some preparation photos too.
The decor around the venue was beautifully done by The Secret Garden with flowers by Floral Roundabout. Everywhere looked amazing.
The ceremony was held in the Callow Hall which has the wow factor. I never tire of capturing wedding ceremonies here. Beth Humphreys sang throughout. She has a beautiful voice. After the ceremony we made our way outside for the traditional confetti throw along with a few family photos. We were also able to capture some relaxed photos of guests enjoying the drinks reception.
The wedding breakfast was held in the Callow Hall. We have photographed many many weddings at Stanbrook Abbey but this was the first time we had photographed the hall set up for a wedding breakfast. WOW! It looked amazing.
We had time for a few more couple photos after the meal and then it was over to the marquee for the evening celebrations where Beth was to sing again alongside DJ Rich Palmer. We even got a sunset! Huge thanks to Clyde and Kiley for making sure everyone had a great day.
Enjoy a selection of the photos below. To see more contact the newly weds for the password and discount code for their gallery.
Supplier note: Feel free to share images of your work from our blog but please ensure no changes are made to the photos including social media filters and that you credit us.


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IN MEMES | Fans in their feels as latest season of Somizi's reality show ends
Fans were left in panic mode on Thursday night as the fourth season of Somizi's reality show came to an end.
Last night's episode saw Somizi and Mohale prepare for their wedding day by meeting caterers, planners and designers.
Fans even got the inside story on their meeting with Gert-Johan Coetzee, as they thrashed out outfit ideas with the celebrated designer.
They weren't too impressed with his idea of showing chest in one of the outfits, but were blown away by his other designers.
On top of that, Somizi was planning his mother's 79th birthday, which included Lilian Dube on the guest list.
The show, a hot favourite on social media, trended as fans shared their thoughts on the drama unfolding on screen.
But it soon turned to sadness at news of the season ending.
Somizi moved to console fans and promised the show would go on. He also hinted at "something special" coming real soon.
"Something special is on the cards very soon. And it's also definitely not the last time you will see Living the Dream with Somizi. 2020 is gonna be just super epic."
The streets were a mess.
Stop calling taking care of your parents "black tax". Stop it! #LTDWSomizi pic.twitter.com/au3LMsAc0J— tumelo (@Tumi_Setumu) October 3, 2019
Oooh no this is the last episode #LTDWSOMIZI ?????? pic.twitter.com/U8aC7ZrAQG— ?YANDA?SOBHAYI? (@YandaSobhayi) October 3, 2019
I think I'm cursed. I only caught two episodes of this season. I've been missing the the rest of the episodes as well as repeats on Saturdays ?. I'm even at work rn. Like I'm so clueless #LTDWSomizi pic.twitter.com/tGH4saa4I9— ??Prince Kingsley Lerato Mentor (@princekmentor) October 3, 2019
So ke last episode vele??— Blu (@Miss_Pabi) October 3, 2019
Angikho right!! #LTDWSomizi pic.twitter.com/tafu0IU3DG
Somizi's relationship w his mom . #LTDWSomizi pic.twitter.com/4NvdOt4fGQ— Ntebogang Kobedi (@KobediNtebogang) October 3, 2019
R79000? Bathong Somizi is still going to be blessed hey!!!#ltdwsomizi pic.twitter.com/A5Jaz9Z70R— ✨Ms_Leighrah? (@Lira_Ngubz) October 3, 2019
#LTDWSomizi is the best celebrity reality show in the country ??♀ pic.twitter.com/7BbUjaZIf8— NOMFUSI LENGS (@NomfusiLengs) October 3, 2019


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About Us
St. John's Event Calendar
For upcoming monthly events at St. John's, please view the calendar below. Click on the date (blue bar) to view that day's events, or click on an event to see its details.
To submit a schedule request to the church office, click here.
Events for November 28
- 28 Nov
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Congratulations to Ken Baird , Australian Myths & Legends oldest player , for winning the Confederation of Australian Sport (CAS)/ Sportscover's 2018 Clubbies Award for the Best Masters Performance.
This is a very prestigious award as CAS is the peak national body for sport in Australia.
The sporting bodies affiliated with CAS represent 5.8 million Australians.
I thank all of the Club's members who voted for Ken.
Ken who is a life member of the Club turns 90 later this month is currently not enjoying the best of health.
Ian Farr – President.
More information.