text:
Nitrosative Stress as a Modulator of Inflammatory Change in a Model of Takotsubo Syndrome
Author + information
- Received April 11, 2017
- Revision received October 8, 2017
- Accepted October 10, 2017
- Published online April 30, 2018.
Article Versions
Author Information
- Sven Y. Surikow, BHlthSc (Hons)a,b,
- Thanh H. Nguyen, MD, MMedSci, PhDa,b,
- Irene Stafford, BSca,
- Matthew Chapman, BSc, MClinSci, DMU, CEPIAa,
- Sujith Chacko, MBBSa,
- Kuljit Singh, MBBS, PhDa,b,
- Giovanni Licari, BSc, PhDb,
- Betty Raman, MBBSa,b,
- Darren J. Kelly, PhDc,
- Yuan Zhang, MBBS, PhDc,
- Mark T. Waddingham, BSc (Hons), PhDc,
- Doan T. Ngo, BPharm, PhDa,
- Alexander P. Batea,
- Su Jen Chua, MBBSa,
- Michael P. Frenneaux, MDd and
- John D. Horowitz, MBBS, BMedSci(Hons), PhDa,b,∗ (john.horowitz{at}adelaide.edu.au)
- aThe Queen Elizabeth Hospital, Department of Cardiology, University of Adelaide, South Australia, Australia
- bBasil Hetzel Institute, Adelaide, South Australia, Australia
- cDepartment of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia
- dUniversity of East Anglia, Norfolk, United Kingdom
- ↵∗Address for correspondence:
Dr. John D. Horowitz, Cardiology Unit, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville South, SA 5011, Australia.
Visual Abstract
• Treatment of female rats with a single dose of isoproterenol results in apical hypokinesis mimicking Takotsubo syndrome
• Myocardial inflammation includes increased content of 3-nitrotyrosine and poly(ADP-ribose), indicating nitrosative stress and PARP-1 activation, respectively
• Pretreatment with 3-aminobenzamide (a PARP-1 inhibitor) attenuates negative inotropic changes
• We conclude that the peroxynitrite/PARP-1 cascade contributed to negative inotropy in this model of Takotsubo syndrome, consistent with the limited data available in patients
Previous studies have shown that patients with Takotsubo syndrome (TS) have supranormal nitric oxide signaling, and post-mortem studies of TS heart samples revealed nitrosative stress. Therefore, we first showed in a female rat model that isoproterenol induces TS-like echocardiographic changes, evidence of nitrosative stress, and consequent activation of the energy-depleting enzyme poly(ADP-ribose) polymerase-1. We subsequently showed that pre-treatment with an inhibitor of poly(ADP-ribose) polymerase-1 ameliorated contractile abnormalities. These findings thus add to previous reports of aberrant β-adrenoceptor signaling (coupled with nitric oxide synthase activation) to elucidate mechanisms of impaired cardiac function in TS and point to potential methods of treatment.
Takotsubo syndrome (TS) reflects catecholamine-induced global myocardial inflammation, which predominantly affects the left ventricular (LV) apex. Since its initial description by Japanese investigators (1), the phenomenon of TS has aroused considerable interest among clinicians, as its differentiation from acute myocardial infarction represents a diagnostic challenge (2,3). Even more intriguing is the epidemiology of TS, with its predominant occurrence in aging women, episodes being precipitated both by acute emotional or physical stressors and the presence of neuropsychiatric disorders (4,5). Furthermore, it was originally considered that TS might be a relatively rare disorder, which is not the case: approximately 10% of suspected ST-segment elevation myocardial infarction cases in women aged >50 years are actually TS (6). Finally, TS induces prolonged myocardial inflammation (7), including patchy inflammatory infiltrate on myocardial biopsy samples (8), with persistent LV dysfunction (9), disordered cardiac energetics (10), and associated impairment of quality of life for ≥3 months, with a propensity toward recurrence (11).
To date, the only definitive progress that has been made regarding the pathogenesis of TS is related to the pivotal role of catecholamine release and its interactions with the myocardium: there is extensive evidence that TS can be induced by both endogenous and exogenous catecholamines (12). Furthermore, considerable evidence exists that the effects of this catecholamine "surge" on the myocardium include an initial phase of regional depression of myocardial contractility (with minimal myocardial necrosis) followed by a prolonged phase of slowly resolving intense and essentially global myocardial inflammation and associated edema. Among systemic markers of myocardial inflammatory activation, substantial release of B-type natriuretic peptide/N-terminal pro–B-type natriuretic peptide in the absence of pulmonary edema serves best to delineate the progress of attacks (13). However, the precise cause of this inflammatory activation remains uncertain.
Studies in rodent models of TS have added substantially to the understanding of the impairment of myocardial contractility and associated propensity toward shock in the acute phases of the disorder. Notably, 2 studies have suggested a pivotal role for stimulation of β2-adrenoceptors, with an associated shift from Gs- to Gi-based signal transduction, mediating cardiodepressant (but also cardioprotective) effects (14,15). However, the findings of these investigations do not address the issue of the pathogenesis of the myocardial inflammation that follows the initial catecholamine exposure, nor has any mechanism for inflammatory activation in TS been suggested by other previous experiments.
We made a series of observations which suggest that nitrosative stress may be critical to both inflammation and energetic impairment in TS. We showed that patients with TS differ from age-matched female control subjects with regard to 2 aspects of nitric oxide (NO) signaling (16). Specifically, patients with TS exhibited greater platelet responsiveness to the antiaggregatory effects of NO. Furthermore, plasma concentrations of asymmetric dimethylarginine, a competitive inhibitor of NO generation, were significantly lower in patients with TS than in control subjects. If release and/or effects of NO are increased in patients with TS, this result may be particularly relevant under conditions of β2-adrenoceptor stimulation, given that β2-adrenoceptors are coupled to activation of nitric oxide synthase (NOS) (17). Increased release of NO in the presence of the superoxide (O2–) anion, which is also incrementally produced by the actions of catecholamines on the myocardium (18), potentially induces formation of the peroxynitrite (ONOO–) anion. This action induces associated redox stress, protein nitration (19), and deoxyribonucleic acid damage, resulting in activation of poly(ADP-ribose) polymerase (PARP)-1, which among other effects, acts as an "energy sink" (20); nicotinamide adenine dinucleotide is directly depleted, leading to potential phosphocreatine depletion, with associated inhibition of glycolysis (21).
Pilot immunohistological studies of LV myocardium in patients dying early in the course of TS indeed reported evidence of nitrosative stress: increased myocardial content of the nitrosative stress marker 3-nitrotyrosine (NT) and possibly increased content of poly(ADP-ribose) (PAR), a downstream product of PARP-1 activation (22), which represents a potential mechanism of energetic impairment (20,23).
We therefore sought to evaluate the potential roles of the generation of nitrosative stress, with the precursors of ONOO– (O2– and NO) being incrementally generated by increased β2-adrenoceptor stimulation (coupled to NOS activation [17]) and by oxidative stress induced primarily by catecholamine-triggered β1-adrenoceptor stimulation and/or endothelial NOS "uncoupling," respectively; a rat model of TS was utilized.
We also sought to evaluate the impact of this putative cascade on expression of the pro-inflammatory α-arrestin thioredoxin-interacting protein (TXNIP), which might theoretically be increased either via direct stimulation by ONOO– (24) and/or via withdrawal of NO-mediated suppression (25). Given that PARP-1 may activate nuclear factor kappa B (NFκB) (26) via phosphorylation, myocardial content of phosphorylated and total NFκB were also evaluated. The nature of the cellular component of myocardial inflammatory infiltrate in TS has been document only minimally (8,27) thus far, and we also elected to evaluate those changes. Furthermore, in a subsequent series of experiments, the impact of PARP-1 inhibition was evaluated to determine whether PARP-1 activation was mechanistically critical in this model.
Rat model
The goal of this study was to assess the effects of isoproterenol on the myocardium of aging female rats (n = 17; weight, 210 to 280 g) to most closely mimic the demographic characteristics of TS in humans. Preliminary experiments were conducted to assess the impact of age and dose of isoproterenol on tolerability; the results showed that in Sprague-Dawley rats age >8 months, the mortality rates after injection of isoproterenol were unacceptably high. Therefore, the age of 4 to 5 months and a dose of 5 mg/kg were eventually selected. Under these conditions, short-term mortality (manifest generally between 0.5 and 2 h) was approximately 33%. Baseline echocardiography was followed by a single intraperitoneal injection of isoproterenol for treated rats, with follow-up echocardiography performed 24 h later. Animals were then killed, and the myocardium was harvested for immunohistological and immunoblotting analyses. Control rats (n = 10) were killed after 24 h, without exposure to isoproterenol, to provide immunohistochemical and immunoblotting controls. This study was approved by the relevant institutional ethics committees.
In a subsequent series of experiments, we evaluated the impact of pre-treatment with the PARP-1 inhibitor 3-aminobenzamide (3AB) (50 mg/kg intraperitoneal injection) administered 30 min before isoproterenol administration (ISO/3AB) (n = 17). Comparisons were made with rats treated with isoproterenol alone (ISO) (n = 17), blinded to treatment group. Four rats were treated with 3AB alone.
For baseline and 24-h analysis of the effects of isoproterenol on LV structure and function, rats were initially anesthetized with 2% isoflurane, which was reduced to 0.5% during echocardiography. Animals were placed on their backs on a warming pad, their chest shaved and limb-leads attached for electrocardiogram recording. A Vivid 7 ultrasound system with a 10S 2298589 sector array probe (GE Vingmed Ultrasound AS, Horten, Norway), at a frequency of 4.0 to 10.5 MHz, was used for the acquisition of echocardiographic views. Views of the parasternal long-axis, as well as parasternal short-axis at the level of the base, mid, and apex, were captured for assessment of the left ventricle.
LV wall thickness and fractional area shortening were measured at end-diastole in the parasternal long-axis view, by using two-dimensional echocardiography, at 3 pre-defined levels: 1) basal, measurements were performed at 3 mm below the mitral annulus; 2) mid-ventricle, measurements were recorded at the level of the papillary muscle; and 3) apical, measurements were performed 3 mm from the LV apex. Radial strain was measured from the short-axis view at the level of the apex with image depth set at approximately 2.0 to 2.5 cm with a frame rate of 240 to 260 frames/s.
Echocardiographic images were transferred to an EchoPAC PC workstation with Q analysis software enabled (GE Vingmed Ultrasound AS). Experienced investigators blinded to treatment status and phase of treatment performed all analyses, with measurements made in triplicate. Interobservation coefficient of variability for the measurement of apical strain was 13%.
Preparation of rat myocardium
After 24-h follow-up echocardiography, all rats were killed under anesthesia, and hearts were excised. Hearts were divided into basal and apical LV sections, which were fixed in 4% formaldehyde for paraffin embedding and snap-frozen in liquid nitrogen for immunoblotting analysis.
Immunohistological methods
Myocardial content of the following was determined by immunohistochemistry: 1) 3-NT, as a marker of nitrosative stress; 2) PAR, representing the principal product of PARP-1 action; 3) TXNIP, a pro-inflammatory α-arrestin; 4) CD68, as a marker of macrophage/monocyte infiltration; and 5) CD45, as a marker of leukocyte infiltration.
In all cases, the methods utilized for these studies were analogous, with variation only in the primary and secondary antibodies and dilution used. Thus, the sequence of quantitation involved the following steps. First, 4-μm sections of tissue were cut and mounted onto Menzel Superfrost Ultra Plus (Thermo Fisher Scientific, Waltham, Massachusetts) slides, then allowed to dry overnight in a 37°C oven. Slides were deparaffinized, followed by antigen retrieval in citrate buffer at 100°C. Slides were blocked for endogenous peroxidase utilizing 3% hydrogen peroxide, followed by protein blocking using DAKO serum-free protein block (Agilent Technologies, Santa Clara, California). The primary antibodies were as follows: 3-NT (Upstate #06-284, Merck, Kenilworth, New Jersey), 1:500 dilution; PAR (Trevigen 4335-MC-100-AC, Bio-Techne, Minneapolis, Minnesota), 1:100 dilution; CD68 (ED1, Santa Cruz sc-59103, Dallas, Texas), 1:50 dilution and CD45 (OX30, Santa Cruz sc-53047), 1:25 dilution; and TXNIP (MBL Anti-TXNIP [VDUP1] mAb K0205-3, 1:500 dilution (Woburn, Massachusetts).
All primary antibodies were diluted in DAKO antibody diluent solution. Sections were left to incubate overnight at 4°C. The secondary antibody for 3-NT was DAKO EnVision+ System HRP Labelled Polymer Anti-Rabbit (k4003), 1:100 dilution; for PAR, CD68, CD45, and TXNIP, Santa Cruz Biotechnology goat anti-mouse IgG-HRP (sc-2005), 1:100 dilution. Sections were left to incubate for 40 min at room temperature. For visualization, liquid DAB + Substrate Chromogen System (DAKO, k3467) was applied to each section, before being placed in distilled water to finish the reaction. Slides were incubated in hematoxylin for 10 s followed by 3 dips in Scott's Tap Water for counterstaining. Slides were then dehydrated, and coverslips were applied.
All slides are cleaned before being placed into the NanoZoomer (Hamamatsu Photonics K.K., Shizuoka Prefecture, Japan). Between 8 and 12 focus points were individually selected for each section, depending on the size of the section. NanoZoomer creates high-quality images of each section, allowing for accurate analysis.
All analyses were performed by investigators blinded as to rat treatment group. Reproducibility of estimates was evaluated via determination of the coefficient of variability. The images generated by NanoZoomer were processed by using Aperio ImageScope version 12.3 (Leica Biosystems, Nussloch, Germany), which generates a measure of the proportion of the total slide occupied by the stain.
Immunoblotting studies
Given the central importance of the 3-NT data, a subsidiary assay was performed by using immunoblotting (data on 5 control rates and 5 isoproterenol-treated rats, with blots in triplicate). Apical and basal sections of rat hearts were ground to a fine powder under liquid nitrogen and homogenized in 1X lysis buffer that contained protease and phosphatase inhibitor cocktails. The protein concentrations of supernatant were quantified in triplicate by using the DC Protein Assay (Bio-Rad Laboratories, Hercules, California) based on modification of the Lowry method and prepared in Laemmli sample buffer for separation at 30 μg protein/sample. Proteins were separated by using a 7.6% sodium dodecyl sulfate polyacrylamide gel electrophoresis and transferred onto a nitrocellulose membrane (Sigma). Blots were blocked with 5% nonfat milk in Tris Buffered Saline, 0.01% Tween, at room temperature for 2 h and then probed overnight at 4°C using primary monoclonal antibodies (3-NT, Abcam, Cambridge, United Kingdom; ab61392, 1:4,000 dilution). The same blot was washed and re-probed for β-actin (Abcam, ab8226, 1:5,000 dilution for 3-NT) to determine equal sample to loading and then incubated with a secondary HRP-conjugated antibody (3-NT, Santa Cruz Biotechnology; anti-mouse 1:5,000 dilution). The bands were visualized by using ImageQuant LAS 4000 (GE Healthcare Life Sciences). Band intensities were quantified by using Multi-Gauge Software. Effects on expression of 2 bands of 3-NT relative to β-actin were quantified for all experiments.
For subsequent experiments evaluating pre-treatment with 3AB, immunoblotting was also performed to compare expression of PARP-1 and its product PAR in hearts 24 h post-ISO (n = 10) or ISO/3AB (n = 10) treatment. The methods were as for 3-NT (detailed above) but utilizing the primary antibodies PARP (Cell Signaling Technologies, Danvers, Massachusetts; #9542: 1:1,000 dilution) and PAR (Trevigen; #4335-MC-100-AC: 1:800 dilution). The ratio of PAR generation to PARP-1 expression was used as a measure of PARP-1 activity.
Methods for NFκB were analogous to 3-NT and PARP/PAR, although with primary antibody for NFκB (Phosphorylated NFκB, Cell Signaling Technology; #3033 1:2,000; Total NFκB, Cell Signaling Technology, #8242 1:1,000). A dilution of 1:2,000 for β-actin was used, with secondary antibody at 1:5,000 (Santa Cruz Biotechnology, anti-rabbit). The ratio of phosphorylated NFκB to total NFκB was used as a measure of NFκB activation.
Statistical analysis
All statistical analyses were performed by using GraphPad Prism 7.02 (GraphPad Software, La Jolla, California). Echocardiographic parameters were assessed via paired comparison of baseline and 24-h echocardiograms, with evaluation being performed while blinded as to experimental sequence. Comparisons of parameters were performed by using paired Student's t tests for normally distributed parameters.
Evaluation of differences in content and regional distribution (apical vs. basal myocardium) of 3-NT, TXNIP, and PAR was performed by using 2-way analysis of variance (ANOVA).
For evaluation in subsequent experiments of the impact of 3AB on ISO-induced changes, all statistical comparisons (unpaired) were between subsequently treated ISO rats and ISO/3AB–treated rats. Data involving effects of intervention (ISO or 3AB, respectively) on the difference between parameters at baseline and 24 h were normally distributed and were analyzed by using 2-way ANOVA. All data are expressed as mean ± SEM unless otherwise stated.
Effects of ISO
Echocardiographic findings
After injection of isoproterenol (5 mg/kg intraperitoneally), 11 of 28 rats died suddenly within 2 h; data for the surviving 17 rats were analyzed. Overall appearances of the left ventricle included a variable degree of apical hypokinesis. Major echocardiographic changes induced by isoproterenol are depicted in Table 1. Specifically, there was approximately a 15% increase in heart rate, apical LV wall thickness increased (consistent with the presence of myocardial edema), and apical strain rate decreased markedly (Figure 1), with a smaller, yet significant, decrease in apical fractional shortening and ejection fraction.
The LV myocardium in isoproterenol-treated rats was infiltrated mainly with macrophages/monocytes (CD68+) rather than leukocytes (CD45+), consistent with activation of a cellular component of an inflammatory process (Figure 2).
3-NT accumulated significantly, especially in the apical myocardium (p = 0.0024) (Figures 3A, 4A, and 4B⇓⇓). There was approximately a 4-fold increase in 3-NT content (from 5.7 ± 0.7% to 21.2 ± 6.9%) of the apical myocardium of control rats compared with isoproterenol-treated animals.
PAR content increased significantly (p = 0.014) (Figures 3B, 4E, and 4F), although less markedly than with 3-NT. For example, apical PAR content was 1.9 ± 0.1% in control rats and 2.9 ± 0.2% in isoproterenol-treated animals.
The TXNIP content of myocardium in isoproterenol-treated rats increased approximately 2.5-fold relative to control rats (Figures 3C, 4C, and 4D), with a significant apex-to-base gradient. Although this increase was not dissimilar to that seen with 3-NT, there was no significant correlation between 3-NT and TXNIP content.
3-NT immunoblotting consistently generated 2 bands of molecular weight (47 and 70 kDa, respectively) (Figure 5), as shown in previous studies (28). Changes were quantitated regarding each individual band, rather than averaging data. These revealed (via 2-way ANOVA) a significant increase in the 47-kDa band (p = 0.003) and a borderline increase in the 70-kDa band (p = 0.05) with isoproterenol treatment without obvious regional variability.
Comparisons between ISO and ISO/3AB
Echocardiographic/clinical findings
Mortality with ISO/3AB was approximately 32%, which is not significantly different from ISO alone. Data are presented on the 17 surviving rats. Apical radial strain and fractional shortening remained preserved in the ISO/3AB group at 24 h compared with the ISO alone group (time-treatment interaction values, p = 0.0004 and p = 0.037, respectively) (Table 2, Figure 6). Other echocardiographic measurements, such as apical wall thickness or heart rate, were not significantly different between the ISO alone and ISO/3AB groups.
3AB alone induced no changes in wall motion (data not shown).
CD68 content tended to decrease with ISO/3AB compared with ISO alone (mean 10.0 ± 3.3 to 7.2 ± 3.1), but this finding did not reach statistical significance.
3-NT content was not significantly different between treatment groups at 24 h (treatment p > 0.05) (Figures 7A, 8A, and 8B⇓⇓).
PAR content was increased in the ISO/3AB group compared with the ISO alone group (treatment p = 0.0001) (Figures 7B, 8E, and 8F).
TXNIP content was further elevated in the myocardium of ISO/3AB–treated rats compared with rats receiving ISO alone (treatment p < 0.001) (Figures 7C, 8C, and 8D).
PARP-1 immunoblotting (116-kD fragment) revealed that apical PARP-1 expression did not significantly differ at 24 h between ISO-treated rats and ISO/3AB–treated rats (6.9 ± 2.7 vs. 2.1 ± 0.8; ANOVA, p = 0.16).
PAR formation also did not change significantly (37.9 ± 10.7 for ISO and 32.8 ± 8 for ISO/3AB; p = 0.90).
Phosphorylated:total NFκB ratios were not significantly different between groups after performing a 2-way ANOVA with Dunnett's test for multiple comparisons (p = 0.43).
The current experiments were conducted to evaluate the possible occurrence, and potential pathophysiological impact, of nitrosative stress in an animal model of TS. We showed, in female rats injected with isoproterenol, that precipitation of TS-like echocardiographic changes (29) was associated with intramyocardial accumulation of 3-NT, a conventional marker of nitrosative stress (19), and of PAR, a product of PARP-1 activation and thus a marker and mediator of myocardial energetic impairment (30). Myocardial TXNIP content was also significantly increased after ISO administration, consistent with increased stimuli for its expression, such as withdrawal of NO effect (25) and/or disruption of laminar flow and associated shear stress (31); this process known to be precipitated by glycocalyx shedding, a recently delineated component of TS (32). We also reported the presence of inflammatory infiltrate, with a substantial increase in CD68+ cells, representing predominantly macrophage/monocyte infiltration. Furthermore, as noted on echocardiography, LV wall thickness increased significantly with ISO. In a sequential series of experiments, the PARP-1 inhibitor 3AB substantially limited the severity of systolic functional impairment in the rat model, relative to ISO alone.
These findings are therefore consistent with four observations from our clinical investigations of TS. First, patients with TS usually have increased tissue responsiveness to NO and decreased concentrations of asymmetric dimethylarginine. These fluctuations facilitate ONOO– generation (19). Second, pilot studies in patients dying of TS also revealed increased myocardial 3-NT content (22). Third, myocardial energetic impairment persists for at least 4 months after acute attacks of TS (10). Finally, glycocalyx shedding occurs in the acute stages of TS (32), which increases cellular permeability and may contribute to the prolonged and characteristic accentuation of myocardial edema (33) in this condition. A schematic representation of these findings is provided in Figure 9.
The current findings are also consistent with the fact that myocardial β2-adrenoceptors are linked to NOS (34); β2-adrenoceptor stimulation would be expected to increase NO release in this manner. It has previously been shown that β2-adrenoceptor density relative to that of β1-adrenoceptors is greatest in the LV apical myocardium (15). In the rat ventricle, β-adrenoceptor–stimulated release of NO increases with senescence (35). Indeed, in the current experiments, even in control hearts, there was a trend for apical 3-NT content to exceed basal. In terms of the propensity for increased NO generation to induce nitrosative stress in the presence of oxidative stress, this factor has been previously shown in models of both central neuronal injury (36) and anthracycline-induced cardiac injury (37). Intriguingly, Zhang et al. (38) described the protective effects of hydrogen sulfide in isoproterenol-treated rats, a benefit apparently resulting from reversal of catecholamine-induced reactive oxygen species generation. However, ONOO–-related markers were not assessed in this study.
The finding that the cellular myocardial infiltrate in this model consists primarily of macrophages/monocytes raises issues, including the basis for their presence within the myocardium and their potential contribution to myocardial cell damage. A previous study in an atherosclerotic mouse model (39) found that macrophage/monocyte infiltration may result primarily from glycocalyx shedding, which itself is engendered largely by matrix metalloproteinase activation. Therefore, one potential means of evaluating this cascade of events (Figure 9) in terms of the impact on myocardial function would be to evaluate the effects of matrix metalloproteinase inhibitors (e.g., low-dose doxycycline) (40).
In view of the findings in the rats treated with isoproterenol alone, the question inevitably arises: is nitrosative stress/PARP-1 activation pivotal to the development of the TS-like LV systolic dysfunction in this model?
We chose to address, in a subsequent series of rats, the hypothesis that the PARP-1 inhibitor 3AB might attenuate the contractile abnormalities seen with isoproterenol alone. In the event, 3AB did indeed significantly and markedly attenuate apical systolic dysfunction (Figure 6, Table 2). As expected from our overall construct (Figure 9), this finding was associated with no change in myocardial 3-NT content. In terms of the role of PARP-1 activity and formation of PAR, it must first be stated that in most models of acute cellular injury, PARP-1 activation is relatively transient, peaking within 4 h (41,42). Thus, the cardioprotective impact of 3AB would be exerted primarily during these first few hours. The observed increase in PAR content at 24 h (on immunohistochemical evaluation) suggests restoration of PAR formation after washout of 3AB. Indeed, Zhao et al. (43) have shown that in an acute myocardial infarction model, PARP protein expression level is increased for at least 8 weeks' post- administration of 3AB in association with acute infarction. From our immunoblotting data, it appears that there is little or no residual PARP-1 inhibition after 24 h. Furthermore, Cieslar-Pobuda et al. (41) have also documented evidence of precipitation of "rebound" oxidative stress 12 to 48 h post–pulse therapy with PARP-1 inhibitors. Taken together, these data suggest that reactivation of PARP-1 occurs under these circumstances, without limiting the overall utility of initial therapy.
The current results therefore represent the most definitive evidence to date of a central role for nitrosative stress in a model of TS. However, it remains to be determined in the clinical setting to what extent PARP-1 activation post–β2-adrenoceptor stimulation contributes to the prolonged energetic impairment that has recently been demonstrated clinically in TS (10). For example, it is theoretically possible that increased TXNIP content may have contributed to energetic impairment as well as to overall inflammatory activation (31).
Activation of PARP-1, apart from its role in deoxyribonucleic acid repair, also functions as an "energetic sink," depleting adenosine triphosphate (20) and inhibiting glycolysis (21) during the production of PAR. If this effect is central to the impairment of myocardial contractility, it would be expected that inhibition of either the ONOO– effect (44) or of PARP-1 (23) would ameliorate TS. Both experimentally and clinically based investigations to evaluate this possibility seem appropriate under the current circumstances. In this regard, the finding on meta-analysis that utilization of angiotensin-converting enzyme inhibitors (which limit PARP-1 activation [45]) may limit recurrence of TS (46) is consistent with a known effect on nitrosative stress (47).
Study limitations
There are several limitations to the current study, beginning with those inherent in an animal model. We investigated only single doses of isoproterenol and 3AB, with a single post-intervention time point (while both earlier and later evaluation might well have been useful), and therefore needed only a relatively small sample size. Furthermore, although we detected nitrosative stress, we have not yet determined whether the observed negative inotropic changes might also partially reflect ONOO–-mediated effects, independent of PARP-1 activation (44). We have also not determined to what extent the observed contractile changes in this model are initiated by β-adrenoceptor–triggered NOS activation.
It is important to recognize that 3AB limited, but did not totally abolish, the negative inotropic effects of isoproterenol. Hence, it is possible that other biochemical mediators may contribute to these changes. For example, Willis et al. (48) used a rat model similar to that in the current study but evaluated residual impairment of contractility after 2 weeks. At that stage, both impaired oxidative metabolism and calcium mishandling in both systole and diastole were shown to underlie contractile impairment.
The extent of myocardial edema associated with the acute increase in LV wall thickness was not determined, and therefore it is uncertain to what extent this finding might have been due to swelling of inflamed myocardial cells. Other studies have reported, for example, increased cardiomyocyte diameter (49) and/or increased cardiac weight (50) without specifically investigating the potential role of increased tissue fluid load; further clarification of this issue is therefore a priority. In terms of the potential duration of inflammatory changes post-isoproterenol administration, a number of studies (50,51) have evaluated the impact of prolonged isoproterenol administration in the rat model, documenting a plateau effect early regarding negative inotropy and a diminution of presumptive inflammation/edema after day 1.
Until recently, it might have been considered that TS was relatively rare and generally benign; the lack of an effective treatment was therefore of little importance. With greater understanding of the natural history of this disorder (33,52), and of the role of nitrosative stress in the pathogenesis of TS (Figure 9), it has become necessary to develop appropriate strategies to treat the myocardial inflammatory activation that drives the clinical features of TS.
COMPETENCY IN MEDICAL KNOWLEDGE: Although it is now clear that TS is a relatively common cause of disability and death, especially in aging women, there is no current consensus as to how, in susceptible hearts, catecholamine exposure induces inflammatory activation within the myocardium, with systolic dysfunction and associated energetic impairment. Despite its substantial long-term mortality rate, TS has no established treatment. However, the presence of nitrosative stress, previously reported in post-mortem heart samples, represents a theoretical basis for therapeutic intervention.
TRANSLATIONAL OUTLOOK: We found that in hearts of female rats, exposure to β2-adrenoceptor stimulation induces TS-like ventricular dysfunction, nitrosative stress, and downstream activation of the "energetic sink" enzyme PARP-1. These findings raise a number of potential therapeutic options for both acute management and long-term treatment post-TS, including inhibition of NOS, "scavenging" of ONOO–, PARP-1 inhibition, and use of angiotensin-converting enzyme inhibitors.
The authors thank Cher-Rin Chong and Geraldine Murphy for their invaluable assistance with the immunohistochemical analyses, along with Matthew Smith for his assistance with animal handling. They also thank Professor Danny Liew of the Outcome Research Unit, Monash University, for his invaluable contribution to the statistical analyses.
This work was funded in part by a Project Grant from the National Health and Medical Research Council (Australia). Mr. Surikow, Dr. Raman, and Dr. Singh were recipients of Postgraduate Research Scholarships from the University of Adelaide (Mr. Surikow and Dr. Singh) and from the Cardiac Society of Australia and New Zealand (Dr. Raman). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Abbreviations and Acronyms
- 3-aminobenzamide
- analysis of variance
- isoproterenol
- left ventricular
- NFκB
- nuclear factor kappa B
- nitric oxide
- nitric oxide synthase
- nitrotyrosine
- superoxide
- peroxynitrite
- poly(ADP-ribose)
- poly(ADP-ribose) polymerase
- Takotsubo syndrome
- thioredoxin-interacting protein
- Received April 11, 2017.
- Revision received October 8, 2017.
- Accepted October 10, 2017.
- 2018 The Authors
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- Rogers N.M.,
- Thomson A.W.,
- Isenberg J.S.
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- Nguyen T.H.,
- Liu S.,
- Ong G.J.,
- Stafford I.,
- Frenneaux M.P.,
- Horowitz J.D.
- ↵
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- Zhu W.Z.,
- Zheng M.,
- Koch W.J.,
- Lefkowitz R.J.,
- Kobilka B.K.,
- Xiao R.P.
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- Fogli S.,
- Nieri P.,
- Breschi M.C.
- ↵
- Zhang Z.,
- Jin S.,
- Teng X.,
- Duan X.,
- Chen Y.,
- Wu Y.
- ↵
- Cancel L.M.,
- Ebong E.E.,
- Mensah S.,
- Hirschberg C.,
- Tarbell J.M.
- ↵
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- Uchida K.,
- Takahashi S.,
- Fujiwara K.,
- et al.
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- Mueller K.A.L.,
- Heinzmann D.,
- Klingel K.,
- et al.
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- Linck B.,
- Boknik P.,
- Baba H.A.,
- et al.
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Things were not working out so well and I sought out help. My first OB had me try 4 rounds of Clomid before referring me to a specialist. (I have always know that my body has had issues since I was very young. I just never expected them to be so bad). I was told that I have severely bad Endometriosis, cyst, amongst other issues and that I needed surgery quickly. On January 30th, 2009 I went in for a Laparoscopy to clean out all the endometriosis, which also led to a d&c. After a long road of recovery we started on our journey of IVF.
In October of 2009 we found out that we were pregnant. My husband and I were so excited, but at 5 weeks we went in for the ultrasound and discovered that it was ectopic miscarriage. I was put on meds to clean out my system and sent back in to have another d&c.
We again tried in February 2010 with all the IVF treatments. In March we were on our way in to have the transfer done, but received a call that our embryos did not make it out of the unfreezing process. I refused to give up and we kept on going. That April we found out that we were pregnant and that there was a good chance it was twins. I have never felt so excited in all my life.
At 5 weeks we had the first ultrasound and there they were. You could see both there little hearts beating away. It was so amazing. We continued going in every two weeks for ultrasounds and check ups. My last ultrasound was at 17 weeks and everything looked great. They were growing well and had great heart beats. The doctor told us that we would get to find out at our 20 week appointment what they were. Unfortunately we never made it that far.
On August 3rd, I went into labor with my twin babies at 19 1/2 weeks very unexpectedly. That morning I got up and did my morning routine before leaving to go watch my nephew, I was not expecting to all of a sudden feel pressure and cramping. I quickly called my husband and told him to come home right away, that something was wrong, very wrong. I was taken to the hospital by ambulance and checked right away by the ER doctor. He proceeded to call the on-call OB who checked me and had to break the bad news that I was in labor and there was nothing we could do.
I was admitted to Labor and Deliver where we waited for several hours to deliver our babies. At that time we did not know they were boys. They discovered that I had gone into labor due to infections amongst other things. We tried to save one of the babies who still had a very strong beating heart. We could only do so if I did not run a fever, the fever meaning infection. Unfortunately I ended up with one. My fever jumped so high so fast the doctor told us we could not save him, and now I was getting sicker. It was time to deliver them.
Our sons were born August 4th at 2:37am and 2:48am after 18 hours of labor. Our son Emmett had already passed when he was born, but our son Everett lived for about 15 minutes before he passed in our arms. They are the most precious gifts that my husband and I have ever received and we miss them so much. Not a day has passed without a tear being shed, or a thought of them. We love them truly. There are our little buddies.
I am struggling so much to just get through the days. It hurts more than I can describe. God has our little angels with him, and I know they are safe, but I wish they were still growing in my belly.

subset: commoncrawl


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Top Left: Magazine cover, Top Right: Article title page, Bottom: My section of the article
Sunday, September 4, 2011
SouthwestArt Magazine - 21 Under 31 Competition
My painting, "House Mouse," has been selected for SouthwestArt Magazine's annual competition, 21 Under 31. Every year the magazine selects 21 artists under the age of 31 and recommends that collectors and enthusiasts start watching them. The competition and my painting appear in the current, September issue of this year, so take a look if you find yourself near a newsstand or have a subscription!
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We always knew Karen Gillan — feisty, fire-haired companion Amy Pond on Doctor Who — would be absolutely perfect for the big screen, and today Deadline is reporting that the Scottish beauty has been cast in the new film Romeo and Brittney. Gillan will play "a spiky New Jersey high school teenager who finds herself trapped Alice In Wonderland-style in Shakespeare's Romeo and Juliet." (Karen as a Joisey girl? Will Teresa Guidice of the Real Housewives offer her services as an accent coach?)
In the story, Gillan's character "wakes up in mythical 13th century Verona with all the people she knows from her high school life playing characters in the play. And she wants to get out because she knows how the play ends."
Set to start shooting in May, the comedy will co-star Gillian Anderson in the dual roles of Karen's mother (brilliant casting) and the Nurse, and young star Robert Sheehan (Misfits) will play her geeky Romeo. Comedian David Baddiel will direct. Producer Arvind Ethan David calls the project "Shakespeare In Love meets Clueless."
Could this be Karen's Gwyneth Paltrow/Alicia Silverstone moment?
by Kevin WicksRead More


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In between the sensational Pokemon Go augmented reality gaming app's success, one more app has managed to grab attention of millions of smartphone users – Prisma photo editing app with the painting effect kind of photo filters. The simple yet effective photo filter app has been released on iTunes for Apple iPhone users and it has garnered millions of users quickly.
Now that the popularity of the app has gone high, people started sharing their creative works done using the Prisma app have also gone viral and the people who use smartphones running on Android also began to search for the app in Google Play Store. And you should know that the official Prisma app for Android hasn't yet released by the company.
According to reports, the official Prisma Android app will be launched by the end of July, i.e., this month-end. However, desperate people are trying to find the Prisma app in Android app store and ending up with fake apps with same or similar names. Most of them has got around 1 star rating because of their uselessness. Most of the apps are only submitted to the Play Store to get some click on advertisements and earn some revenue for the spam developers.
Meanwhile, there are sites which also provides (claims to provide) Android APK file for the Prisma app so that any Android users can enjoy over 30 photo filters of the app. Since, we haven't tried the unofficial version of the Prisma app on Android, we recommend our readers to stay away from such APK files, which could install malware on your smartphones. Since, only a few days left for the official launch, why take risks and install fake Prisma apps from either Play Store or unofficial APK packages?
Meanwhile, you can try your hands on similar apps like PicsArt, Photo Lab, Super Photo and Camera 360. Don't install any application those are named as Prisma in the Google Play Store as for now. Those are fake apps and just spams.


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Did you know that regular stretching is just as important as regular exercise? Stretching assists in correct posture by lengthening tight muscles that pull areas of the body away from their intended position. Most of us spend a lot of time at our computers, which creates tight chest muscles. This pulls the shoulders and head forward, leaving us with a hunched shoulder look. So here are some stretches you can do to make sure you are not hunching over your computer today!
Fun Stretches brought to you by Triangle Spine Center
1) Rita's choice: Lazy Stretch. We are not sure what this is called, but it should be called the lazy stretch. There is not much to it, but she swears by it. You lie down on the ground. Stretch your hands high as you can over your head and point your toes as far down as you can. Hold this pose for 20 seconds. Don't forget to breathe! Repeat 5 times.
2) Sam's Choice. Partner Pull. For this one you will need a friend. Stand facing your partner about 6 inches apart. Grab each other's wrists, while both partners lean back. Hold for 20 seconds. Repeat 5 times.
3) Franks Choice: Tennis Ball. Place a tennis ball on the wall. Lean in on the ball in between your shoulder blades. Next, roll on the tennis ball preferable where you're having pain or tension. (Tip: use a tennis ball over other types of balls. The grip on the ball makes it easier to keep it in place)
4) Dr Cinnamon: Foam Roller. With the foam roller placed in the middle of your back, clasp your hands behind your head and bring your elbows together. Slowly begin to roll up to the top of your shoulder blades and down to the bottom of your rib cage. Repeat process 5 times, keeping your neck and lower back from arching.
5) Sully's Choice: The Crossing Guard. Extend your arm out (like you're a crossing guard stopping oncoming traffic) Keeping your arm straight at the elbow, use your opposite hand to pull your fingers back until you feel a gentle stretch in the forearm.
Keep moving! Suffering from back pain lately? Check out our back pain treatment!


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I love summer. I love days in the pool and backyard, but it wreaks havoc on my hair. I get my hair highlighted about every 6 weeks, which damages my hair. If I don't use a quality conditioner after shampooing, my hair gets crazy. Like eighties-Jane Fonda big and fuzzy CRAZY, definitely not the look I'm going for!
Since I usually blow dry my hair after washing, it gets even more damage and needs nourishing products to be soft and sleek without all of the craziness. I've used an expensive salon brand shampoo and conditioner for the past year after my stylist recommended it, but I was happy to try out a much more affordable conditioner, Dove Nourishing Oil Care Daily Treatment Conditioner.
I've been using Dove Nourishing Oil Care Daily Treatment Conditioner for over a week now and am impressed by the results, especially since it costs 80% less than I was paying for my "salon" brand conditioner. I have a ton of wavy, unruly hair and this Dove conditioner manages to tame it without having to add a bunch of product afterwards. I even performed the ultimate conditioner test: washing & conditioning then letting it air dry.
When I let my hair air dry without blowdrying it piece by piece with a round brush, things can get awfully frizzy. I was happily surprised when I used Dove Nourishing Oil Care Daily Treatment Conditioner, let my hair dry naturally and didn't have crazy hair. It looked like I had natural "beachy" waves and my hair was smooth with next to no fly-aways.
I definitely recommend Dove Nourishing Oil Care Daily Treatment Conditioner if you're looking for a great conditioner to nourish your hair for a great price! There is a coupon for $1.50 off at the bottom of this post if you want to try it out.
I would love to know what your favorite beauty treatment for your hair is. Mine is definitely highlights! Follow the link below to answer this question and enter to win a $1,000 Spafinder gift certificate!
Enter to win a $1,000 Spafinder gift certificate!
You may receive (2) total entries by selecting from the following entry methods:
a) Follow this link, and provide your email address and your response to the Promotion prompt
b) Tweet (public message) about this promotion; including exactly the following unique term in your tweet message: "#SweepstakesEntry"; and then visit this link to provide your email address and the URL to that Tweet.
c) Blog about this promotion, including a disclosure that you are receiving a sweepstakes entry in exchange for writing the blog post, and then visit this link to provide your email address and the URL to that post.
This giveaway is open to US Residents age 18 or older. Winners will be selected via random draw, and will be notified by e-mail. Winners will have 72 hours to claim the prize, or an alternative winner will be selected.
The Official Rules are available here.
This sweepstakes runs from 9/4/2012 – 9/30/2012
Be sure to visit Dove®Hair.com to get a coupon for $1.50 off Dove Hair Therapy products.


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Here you'll find extra resources I've created to aid in our homeschooling journey
Preschool Math with Target (pk-k)
20+ pages of counting, sorting, pattern, and number matching activities. Majority of the pages were made to match items from the summer 2018 teacher collection from Target's Bullseye's Playground.
Weather Unit Study (pk-k)
A 3-week themed study about all things weather. Includes supply list and book suggestions, as well as a list of activities to choose from throughout each week.
My African Alphabet (pk-k)
African-centered alphabet tracing pages for preschoolers and early writers.
Homeschool Planning Stickers
Functional stickers for your homeschool planner.
File is a PDF and does not include machine cutting guides.
Vocabulary Index (3-8)
Pages to keep track of vocabulary words
Nile River: An Introduction (5-8)
Notebooking pages and activities that correspond to the second chapter in Molefi Asante's Classical Africa text.
HOD Bible Copywork and character traits (3-4)
Pages for each unit in Bigger Hearts For His Glory NIV bible verses are used.
HOD Poetry Copywork and vocabulary (3-4)
Pages for each unit in Bigger Hearts For His Glory.
Night Before Christmas Unit study (3-5)
A one-day homeschooling lesson based on the popular Christmas poem. This lesson relies on web links.


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Is it October 18th already? Is today really this blog's two year anniversary? Well then, that can only mean it's time for the annual state of the blog address, where I recount the past year and talk about my plans for the future.
Blog-based plans, of course.
(No, I'm not planning to monetize the blog, but this pic almost had you for a sec, huh?)
To start, let's ditch the faux formality of last year's State of the Blog if for no other reason than to fall in line with the let-it-all-hang-out / I'm-a-normal-person-like-you tone that my country's current election seems to have embraced with open arms.
So. The big focus this year was my plan to relocate from New York to California and going through the archives of the past year I can see that my posting schedule was quite spotty. In fact, there were a few months without a single post, due to the fact that behind the scenes, I had a lot going on.
("Can't talk. Drafting. But be a doll and pass the ketchup. Thanks.")
First and foremost I was working really hard with my editor on getting the book I was working on for years in shape for submission. And second was that I was working to set aside money for my move. Those two forces rubbing against one another pushed the posting of this blog a few notches down on my priority list, and while that's no excuse, it is the truth of what happened.
But looking back over some of the posts it was probably better that I wasn't posting that much, because my brain and nervous system was being crushed by all the pressure I was putting myself under. Sure, my second year of posting brought us excellent pieces like 5 Things I Learned Driving Across America (Again) and the revealing Can Goblin. Others went to a very real, very dark place. Notably the posts The Best of Times, the Worst of Times, and to a lesser extent, Nobody Likes Rejection. The tone of said posts may cause you to wonder—why? Why go through all this trouble of doing risky stuff like moving to another state? Why care so much about what happens with your fiction writing? In other words, why have you been compelled to take these risks and stick your neck out?
(Nothing against exposed necks, of course.)
Lately I asked myself the same, and came up with the reason, so I'll spell it out as easily as I can. In summer 2014 I graduated from college, thus ending my formal education. For the next two years, ending in summer 2016, through travel, inner exploration, and assorted risk-taking, I had come to the end of my informal education. Now of course, informal education never truly ends. Many experiences await me in the future, but I'm done taking such extreme measures in search of a great "I-don't-know-what." In other words, I'm over being reckless.
Thus, making this the perfect time for the blog to enter its third year, because its creator no longer has his head (and the rest of his body) all over the place. As of this posting I'm writing a standalone novel, the same one introduced in Let Her Rest, and from the pace at which it's going alone now, I'm looking to submit to some professionals I know in February. I bring this up not to brag or anything like that, but to establish that for me, in order continue writing novels and also keep up with this blog, I have decided to establish a trend where I blog once a month, consistently.
(So from now on, each month will get its very own post, special and unique, like the signs of the zodiac. Make sense?)
Content-wise, I no longer have crazy travels to talk about, such as teaching English in Korea or waking up in Berkeley in a cold sweat. This is good, though. It will allow me to focus a little less on myself, and a little more on stuff that readers would like. Naturally I'm just as experimental as ever, but I'm thinking of more topical stuff and how it relates to my life. I mean, the post Red Rising: My Frustration Abounds has been seeing a lot of traffic lately, so maybe I'll do another book review? Speaking of books, I want to finally get around to my talked-about-but-never executed post, "A Cabin in the Woods" where I shed light on the writing process for all you lay people.
Should be fun.
But then the pendulum swings in the other direction, and I think about if it's worth it to blog for another year, and the year after that. For the sake of being open and honest, I'm going to confess that if I can't get any traction with my writing in the form of a book deal or at the very least representation, we're looking at a 50/50 chance of me ending this blog on this exact date in 2017.
(Kind of like this film, minus the part where a demon commits sexual assault.)
In other words, the blog would shutter its windows after a three year run. That may sound unfortunate at first, but if it really were to end in a years' time it would instill a sense of urgency to talk about other topics I've been thinking about posting but never got around to because something else came up. Like my thoughts on religion or politics.
Maybe. It's all up in the air at this point.
Taking it one day at a time,
J. F. Seegitz
P.S. Be sure to SUBSCRIBE by email if you haven't already and leave a COMMENT below if you've got any ideas for the blog in the coming year. Or if you just feel like saying hello. It's up to you.


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At Niki Jones we specialise in beautiful hand embroidered cushion designs. Traditional craftsmanship combined with our distinctive palette and use of natural materials creates a truly unique and special collection of cushions, perfect to adorn your home. We use two different embroidery techniques across our collection, with each technique employed depending on the design. For example, the fine, crisp detail obtained in our Concentric Cushions is created by machine embroidery in cotton thread. The inimitable, swirling texture of hand crewelwork in wool lends itself beautifully to our Lattice and Harlequin hand embroidered cushion designs amongst many others.
You can see the beautiful texture these different techniques create, which is striking and unique.
Choose from our Berber Collection, which is inspired by traditional Moroccan motifs and vintage embroidery. A fresh interpretation of these classic motifs brings them to the present day.
We are renowned for our crewelwork cushions. This traditional technique originates from Kashmir, Northern India. We remain true to this tradition and have all of our crewel collection made there by highly skilled craftsmen. Niki works closely with these craftsmen developing her hand embroidered cushion designs, emphasising that 'it's all in the detail.'
In breathing new life into this traditional craft, our collections reflect Niki's extensive travels with a nod to modernity and contemporary design, as well as ensuring their survival for future generations.
Our iconic Concentric design is seen across our cushion and rug collections. Ancient geometry and mathematical pattern are a constant source of inspiration and it's easy to see the roots of this in our iconic circular Concentric cushion.
In geometry, two or more objects are said to be concentric, coaxial, or coaxial when they share the same centre or axis. The combination of this concept interlaced with triangles creates a captivating illusionist pattern, which radiates like a sun motif.
This pattern was developed by Niki back in 2010, not long after the brand was first launched, yet it remains a firm favourite and has become a signature of the brand. To create the precision and uniformity required of this decorative optical pattern, we use the technique of machine embroidery on our cushions.
A combination of fill and running stitch in mercerised cotton thread gives each motif its lustrous sheen, which contrasts beautifully with the natural linen or cotton base-cloth. Each cushion is then framed with our handmade cotton pom-poms. Every pom-pom is intricately sewn on by hand as a finishing touch.
As always, the provenance of a technique and a craft is incredibly important to us. We are proud to use traditional techniques from their place of origin to create beautiful pieces for you to treasure at home for generations to come.


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The Wrythe SM5 Expert 24/7 Locksmith Company
Did you lost your keys and you are in desperate need of help getting into your office or home? Call the emergency locksmith service in The Wrythe SM5 right now! Locksmith Earl is the reliable locksmith company in the area. We have an up to 30-minute response to emergency calls. Our locksmiths are police approved and experienced in resolving lock outs, lock picking, lock fitting, repairs and replacement in The Wrythe SM5. When you choose our trusted commercial and domestic locksmith services, you will get:
- Home insurance and security advice
- No hidden prices
- After break-in repairs
- Fast local service
- No callout charges
To hire a professional locksmith, call our 24/7 customer support on 020 3404 1580 or fill our online contact form.
Our key cutting expert services
Our skilled key cutters can make a new key or a duplicate of your home and business keys. We can make the following types of keys:
- Key cutting services, Cylinder keys, Household keys
- Security keys, Window keys, Bump keys
- Keys for Euro cylinders, Restricted key sections keys
- Any replacement key, lockers repairs, patio keys
Why we are the most preferred local locksmith company
All our locksmiths are thoroughly trained and insured. We offer simple solutions for any emergency lockout circumstances in the area. You can hire the services of a local locksmith at any time, 365 days a year.
You can have a specialized safes locksmith, home security locksmith or a UPVC locksmith in 30 minutes of your call. We offer domestic and commercial after burglary repairs. We can provide you with locks that match the latest BS3621-2007 standards and fit them for any door. Contact us if you need professional domestic locks repair or new lock installation.
More about the home security locksmith in The Wrythe SM5
Our company provides its highly professional and efficient locksmith services in The Wrythe SM5. We offer expert burglary repairs, lock picking, lock replacements, safes locksmith, lock installations and damaged lock repairs to commercial and residential customers in the area. Our locksmiths are all certified to deal with a wide variety of locks and keys. You can also call us for expert affordable key cutting services.
Key cutting services
Our trained key cutters have the equipment and skills to make new keys and duplicates for different locks. Our swift locksmith services allow for quick action in case of a home, office or locker lockout. The keys we cut are at affordable prices and of the highest quality because we rely on modern equipment and tools for the key cutting.
Some of the keys we can make:
- Household keys, Patio keys, Window keys
- Mobile key cutting services, Security keys, Cylinder keys
- Keys for restricted key sections, Lockers repairs, Euro cylinders
- Bump keys, any replacement key
Do not hesitate to book one or more of our locksmith services.
How to book our locksmith services
Contact our 24/7 customer support service at 020 3404 1580 or use the online booking form. We do not any deposit. Our pricing is clear cut - the rates are fixed, and we will not ask you to pay any hidden fees. We offer discounts for booking several of our services and give preferential prices to our regular customers. Book our services now!


text: Nitro Pro 9 Serial keys plus Crack Full Version Download. Nitro Pro 9 Serial keys plus Crack Full Version Free Download. Nitro Pro 9 Serial keys plus Crack Full Version is the excellent software fully design with latest features along with comprise fully capability in convert PDF software. This software gives the excellent plans for small businesses along with large corporations. It's the one of the most user-friendly software we revised it. It contain the multiple features along with tools so it's easy to use. This software doesn't include any virtual printer that fully permits you to create PDF's from other files, but it can also fully transfer existing PDFs to files such as Word documents, HTML files, text files, or images. It also comprise the OCR capabilities that making it possible to convert scanned documents directly into PDF files. It also fully permits you to edit the text along with images in a PDF. With the help of this software you can easily convert existing PDFs back into editable documents, preserving the original layout and much more. It also fully supported to Word, Excel and a number of several text formats. It quickly along with easily extract images and text from the PDF files. 1stly download along with Install Nitro PRO 9 Serial Keys along with go to Activation Window. Next Click 'Advanced' button. Then Click 'Manual' button. After Copy the appeared Installation ID there. Further Click Next button twice. Open Keygen along with paste the copied code in the Installation Code field in Nitro Pro 9 Keygen. Next Click Serial button and Copy the serial keygen. Then Paste it into the file of Nitro 9 Activation Window Serial Key. After Click Activation button in the Nitro Pro 9 keygen and again copy an activation code too. Next Paste it into the file of Nitro 9 Activation Certificate. Finally Click Activate. Entire the procedure done. Now you can free use the Nitro 9 PRO Full Version with enjoy. Full Video Tutorial Nitro Pro 9 crack. Nitro Pro 9 Serial keys plus Crack Full Version Download From = Bitlinks. Previous Speccy Professional Crack plus Serial keys Free Download. Next Uniblue System Tweaker 188.8.131.52 Serial Key Full Version. You may also like.PREVIOUS NEXT


text: This winter Patrón has partnered with Pacific Domes for this Event Marketing effort; creating a number of geodesic domes with printed brand messages for this outdoor bar at a Colorado ski resort. The strong structure of our domes are extremely wind resistant, and engineered to withstand a hefty snow load. The igloos are up at Copper Mountain, Aspen/Snowmass, Crested …Read MoreRead more


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Dwarfs are highly gifted creatures. They may be small in stature
and also quite stout but they too are Magical Creatures. They can transform any type of basic metal or stone into precious objects-
These precious objects could range from the finest gemstones layered in pure gold and silver. The gemstones could be sapphire's, ruby's, diamonds, and even blue diamonds. The quality of their weapons and armor were of the highest quality metals and some of the most powerful magic of the Norse Gods. Some of these legendary weapons were the legendary golden spear, golden ring and hammer. This would explain why they inspire such Awe. Dwarfs can choose to pass on some of their magic skills to humans-mortals if they choose to or if they feel the human is shown good qualities that a dwarf. If a Celtic
Smith were to find a dwarf at work on his anvil, he could be compelled to bless him with the secret of the craft or to attend him, when called to completing tasks. Alternatively dwarfs might curse the items they make, much like the other underground metal workers of Norse legend. The Dark Alf's who brings about only misfortune.
festive dress for weddings, which these dwarfs do provide for the mortals when the come, providing that they come before the sunrays that hit the human world. In return for their generous gifts to the mortals, the mortals would give great portions of a great feast to the dwarfs. Although in many of the German tales of this generosity of the dwarfs toward the mortals, dwarfs were mocked by mankind and forced to abandon their glorious underground palaces.
house and field, in kitchens and spinning rooms, willing and ready to lend a helping hand in all sorts of household chores. Sometimes they would even help the very poor with gold and precious stones, raising them up from their poverty-
Sometimes they provided helpful advice and told entertaining tales to the boys and girls, relating poetic mysteries, such as those of Paris.
Here these dwarfs could sit next to a warm stove, they could spend the night on a little bundle of straw or on their own mountain jar of asbestos when the winter cold would push into the deepest parts of their palace halls of the underworld and turn it all to Ice even the underwater springs would be frozen solid ice till spring.
underworld palace halls with the water springs now unfrozen.
I hope you all Enjoy my post on the Tiny & Talented/ The Dwarves
I did most Enjoy doing this post. And I am sorry about the Image being taken off for a bit, but they are on now for Good! I hope
Love you all my dear Friends and Followers! Much love and joy to you all Your Wendy-ooo)


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Lower East Side early in the morning on Rivington St. the familiar 'klink-a-klink-ka-dink' on the pavement has begun. A chorus of four-wheeled shopping carts, a downtown disco beckons me up and out the door with my camera seeking their majesties the Bottle Queens.
Bottle Queens are a force of wonder
My portfolio of transformative photography documenting the untouchable status of woman forays through NYC garbage collecting bottles and cans for the cash redemption value of a nickel.
These renderings reflects my abiding intrigue of her, their lives and their community, a sustainable network for over a period of three years.
The resulting photos of the Bottle Queens is part of 88 piece exhibition and became the overlying deep dive into the eco system of redemption, recycling and redefines Iconic.
Ultimately the focus of my work is to raise awareness the Bottle Queens raise necessity - it's not passion, or preference it's a necessity. (of course I'm quoting Jeff Haden)
Ever wonder what happens to the bottle once it's been it's been redeemed or where it's being recycled and what if it's not redeemed or recycled who collects nickel deposit? Equally paramount what if China stopped importing our cargo containers filled with plastic bottle?
Lower East Side Rivington St., NYC
Lower East Side Spring St., NYC
Lower East Side Delancey St., NYC
West Village W4th NYC
Chinatown Broadway NYC
Soho Bleecker St., NYC
Lower East Side Grand St., NYC
NoHo Astor Place, NYC
Lower East Side Clinton St., NYC
Lower East Side Ludlow St., NYC
redeemed. ever ask yourself what happens after redemption?


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Moderately a new hotel, set on the outskirts of Thimphu, Mingmar Hotel is modest, however offers a very comprehensive facility in comparison with other similar hotels; foremost, being the heated swimming pool. The hotel offer a fusion of Bhutanese and urban design in its deco and architecture, the design being subtle yet elegant and appealing, one can observe use of Bhutanese ideas especially in the interiors, giving it a modern look with a class. The hotel is ideal for one who is not interested in staying in city center however with easy access to it. Managed by well-trained staff, the services are known to be of superior quality. Despite being on the outskirts, places of interest in Thimphu are easily reachable.
The hotel offers one of the most comprehensive facilities in this price range such as swimming pool, Concierge service, In-room dining, Valet, Laundry service, Currency exchange, Steam and Sauna, business center, air-conditioned conference room, a multi cuisine restaurant and a bar.
Trophel Tours & Treks is accredited by Tourism Council of Bhutan (License No: 1030972) and member of Pacific Asia Travel Association (PATA) and Global Sustainable Tourism Council.


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Buses don't necessarily have a reputation as the most innovative transit option around. But thanks to new advances in technology, all that is changing. With features like onboard Wi-Fi, Global Positioning System (GPS), telematics, cameras, enhanced driver support tools, and a greater focus on the passenger experience, next-generation fleets are changing perceptions about bus transit in cities across the country.
Buses don't necessarily have a reputation as the most innovative transit option around. But thanks to new advances in technology, all that is changing. With features like onboard Wi-Fi, Global Positioning System (GPS), telematics, cameras, enhanced driver support tools, and a greater focus on the passenger experience, next-generation fleets are changing perceptions about bus transit in cities across the country.
In many of these cities, a decline in ridership has forced public transit systems to take a closer look at how they operate so that they can be more efficient and better meet passenger expectations in today's connected world. While some of the motivating factors may be different for school transportation directors, you likely have similar goals as you explore ways to enhance your bus systems.
Implementing the Next-Generation School Bus
Across the country, increasing safety and security remains a top priority for school buses, along with other important objectives like improved maintenance and efficiency, optimized bus routes, enhanced driver tracking, and simplified communications with parents. At the same time, more and more school systems are also focused on what's happening on the bus itself. This includes not only managing disruptive behavior but also leveraging students' time on board more productively.
Like your counterparts at mass transit systems, you're probably turning to technology to help solve these challenges. Onboard Wi-Fi, for example, allows districts to "extend the classroom" so that students can get school work done while on the bus. Identification (ID) cards allow parents and administration to track student whereabouts. Stop-arm notifications help identify violators, and cameras provide enhanced security both inside and outside the vehicle, while telematics monitor bus status and help maintain the fleet.
With all of these Internet-enabled options now available—and more always on the horizon—it's beginning to seem like the sky's the limit. Technology is giving us powerful new ways to automate, optimize, and enhance all aspects of school bus operations. But in practice, it's not always so simple. In fact, many school transportation directors now face a new challenge: How do you coordinate and connect all these different technologies, tools, and suppliers, especially when your budgets are anything but unlimited?
You need a centralized device that can bring it all together.
As school buses become well-connected vehicles, with telematics to GPS and everything in between, there needs to be a factor that ties all of the technology together. And that connecting piece is Internet access. With Wi-Fi on the school bus, districts get the access they need to keep moving forward in the connected world while saving money and expanding their capabilities to integrate any Wi-Fi enabled solutions.
Let's take a look at some of the different types of technologies available to the connected school bus, and how you can use them to meet your efficiency, safety, and educational goals.
- Router. A router provides the bus with Wi-Fi connectivity, similar to the setup of any non-mobile Internet network. But specific routers need to be used to work effectively in the unique environment of a passenger vehicle and to meet the specific requirements of a connected school bus
- Student Wi-Fi. As more school districts implement digital learning initiatives requiring students to complete online assignments outside the classroom, millions of students who lack Internet access at home find themselves caught in the Homework Gap. At the same time, it is estimated that U.S. students spend a staggering 520 million school days on buses each year, according to the American School Bus Council. The Kajeet SmartBus™ extends the classroom to the school bus with safe, CIPA-compliant Internet access for students. Kajeet Education Broadband™ equips school buses with 4G LTE connectivity preconfigured with CIPA-compliant, education-only filters, keeping students focused on schoolwork and not on distractions.
- Global Positioning System (GPS) and Routing. GPS technology has become standard equipment in many passenger vehicles today, but it's still relatively new within the school transportation industry. That's quickly changing as districts discover the variety of ways GPS technology can improve bus safety, security, and tracking.
Download the "Connected Bus: 8 Technologies for the Next Generation School Bus" report, which digs further into each of these technologies, including driver tablets, telematics, cameras, student ID cards and general purpose input/output.


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Amtrak test train out of Chicago at 10:15 am CT
update: at Porter 12:15 PM ET 35 leading 4211 on rear end
Wolverine Service Trains 351 and 354: Signal Improvements between Ann Arbor and Pontiac
Effective May 8 - 11, 2017
Signal improvements taking place between Ann Arbor and Pontiac will affect Trains 351 and 354 on the dates shown below:
Train 354: Monday through Wednesday, May 8, 9 and 10, 2017
Train 354, which normally operates between Chicago and Pontiac, will terminate at Ann Arbor. Customers will be provided bus service from Ann Arbor to Dearborn, Detroit, Royal Oak, Troy and Pontiac.
Train 351: Tuesday through Thursday, May 9, 10 and 11, 2017
Train 351, which normally operates between Pontiac and Chicago, will originate in Ann Arbor. Customers will be provided bus service from Pontiac to Troy, Royal Oak, Detroit, Dearborn and Ann Arbor. At Ann Arbor, customers will transfer to Train 351 making all remaining stops on the route.
Bus Departs 45 Minutes Earlier: Please pay close attention to the bus departure time on your ticket. The bus replacing Train 351 will depart Pontiac 45 minutes earlier (at 5:00 am) and depart 45 minutes earlier at all stations through its arrival in Ann Arbor.
Possible Delays
All trains traveling through the work area may encounter delays. You can check the status of your train on Amtrak.com, with our free mobile apps or at 1-800-USA-RAIL (1-800-872-7245). You can also sign up for text or email delay notifications when booking your reservation.
We appreciate your patronage and apologize for any inconvenience.
Thank you for traveling with Amtrak.
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We drive action.
Pyramid is a full-service strategic communications firm
giving voice to good causes for more than 20 years.
We tackle many tough issues, but care most about one: great results.
Pyramid is a certified B Corp
We seek to continually measure and improve our commitment to social responsibility. It's yet another step in our journey of doing good for our world. That's why we became a certified B Corporation.
Let's work together.


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Learn more about Smoky Mtns Tourism Development Authority.
Travel and tourism information for Townsend, Maryville, Alcoa and Blount County.
Smoky Mtns Tourism Development Authority
201 S Washington St
Maryville, TN 37804
Questions? Please Email
Contact Phone Number
Toll-Free Phone Number
Fax Number
Admission Rates
None. Tourist information and brochures.
Dates Closed
Major holidays.
Open 7 days a week - 9 a.m. to 5 p.m. Closed most major holidays.
TripAdvisor Rating


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Pentax has officially unveiled the new K-7 DSLR. After a series of leaks, we now have all the facts on this new 14.6 megapixel shooter. In addition to shooting 720p video, it offers an intriguing HDR mode, which produces one composite image from a series of 3 bracketed exposures. The Pentax K-7 will carry a retail price tag of $1299.95 for the body only and should be available in July 2009.
Check availability at Amazon.com.
In addition to the K-7, Pentax has also introduced two new weather-resistant lenses: the DA 18-55mm at $199.95 and the DA 50-200mm at $249.95.
More details in the press release below. [Read more…]


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Jed York, the San Francisco 49ers CEO and team owner, is someone I really like and enjoy talking to whenever and where-ever I see him: Hala Hizaji's Professionals VIP event of a few years ago, NFL Owners Meetings, The Bay Lights Super Bowl 50 Ceremony last year, The bar at the Waldorf Astoria in New York in 2015 – the list goes on. He's a gracious, thoughtful, smart, and engaging person to talk with. So, it's in that sprit that I write this, rather than the attack-dog, insulting style of a certain SF Bay Area columnist. But I digress. Jed York has a problem. (For more on my take on Jed York, see the Zennie Abraham Zennie62 on YouTube video, above.)
If I were to walk into Mr. York's office, say, next week, and asked to see his five-year to ten-year plan for the San Francisco 49ers, he couldn't present it to me. Not because he didn't want me to see it, but because he does not have one. That, even though he started with the 49ers in their office of strategic planning. As one who's background is in urban planning, and thanks to a number of teachers and authors of great city planning and public administration books, I don't need to see his office to know what is going on. There is no book. No understanding of football business dynamics. And no plan.
How else to explain this: four head coaches in four years? Working backward, as now former San Francisco 49ers Head Coaches we have whoever Jed's going to hire next in 2017 (or his new general manager brings in), Chip Kelly in 2016, Jim Tomsula in 2015, and Jim Harbaugh in 2014. How can anyone claim to build anything that resembles organizational security with a track record like that? The Jed York-run SF 49ers organizationally look like The City of Alameda, California before my good friend John Russo was hired as city manager in 2011.
In order to avoid being one more person going out of a yearly revolving door of city managers, Russo asked for, and was given, a five year contract. While he served four years of that five-year contract, he had enough time to solve a number of key organizational problems and in the process install his own policies and approaches. Russo was able to walk away from that job and go down to Riverside as its new city manager in 2015 having left behind a long list of accomplishments and a better ran city. Russo had a plan; Jed York does not have a plan.
To York's defense, he might defensively say that what he's doing is called "incremental planning" but as one who is not a fan of that approach, my retort is that one needs a long term plan to know why and how they're making a particular change in the organization at any given time.
Because Jed York lacks an overall plan, he and his charges will go into a search for a head coach and a general manager without any really good, robust checklist to find and then evaluate potential candidates. Unlike others in the media, I'm going to provide one. Here's all that Jed York needs to consider not just in hiring a new general manager and a new head coach for the San Francisco 49ers, but for with respect to the future of the place that Bill Walsh built.
For the General Manager role and scored on a scale of 1 to 10:
1. Does the general manager candidate have NFL budget and business operations experience?
2. Does the general manager candidate understand or have experience with the salary cap and capology?
3. Does the general manager candidate have NFL (or managerial) contract negotiation experience?
4. Is the general manager candidate known to NFL players (which helps in drawing free agents and building a roster of players).
5. Is the general manager candidate known to NFL agents (which helps in drawing free agents and building a roster of players).
6. Does the general manager know who's who in coaching and administration at the pro and college level (which helps in hiring coaches)?
7. Can the general manager actually draw-up and discuss a football play and talk about how football strategy has changed?
8. Can the general manager identify and discuss what innovations in football strategy have developed over the last 20 years?
The person that Jed York hires should be given a free-path to seek out and hire the head coach that fits a criteria which includes player relationships, football strategy innovation, game management experience, and roster movement experience. And one other note should be placed in the folder of the new general manager as that person searches for the 49ers next head coach: 'doesn't need to be known by the media or fans.'
That last point is critical if the new GM is expected to really be allowed to go out and get the best person for the job. Jed should also remember that the next GM can just as easily be a woman as a man, and black or Asian or Latino, as well as white – that's right. Talented female NFL professionals like Amy Trask and Katie Blackburn have established that a woman can do the job of general manager, president, or Jed's role, CEO, very well.
Jed York has to use the criteria, and be flexible where he thinks that someone has enough of a strength in one area to overcome a weakness in another – and also be aware that the person being considered knows what their own shortcomings are. Then pull the trigger and bring that person in for a five-year contract, and then work with that person, and the organization, to write an overall plan for the organization – and then stick to it. The Dallas Cowboys first owner, the late Clint Murchison, Jr., did just that – ok, something like that.
Clint Murchison, Jr knew that, in the young, innovative, head coach he hired Tom Landry, he had a person who formed a long term plan for the development of the Dallas Cowboys – he just needed time to make it work. So, when the Cowboys first year under Landry ended without a win, and the next five years without a winning season, in 1964, Murchison gave Landry a 10-year contract, then hired Tex Schramm to run the organization, and stepped out the way.
The rest is history. Your move, Jed. Good luck.


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First up Pepe from RT Read in full at link
In the summertime, people flock to Montreux, Switzerland, to follow the jazz festival. This week, though, the 'performance' is by a positively un-swinging lot, part of the (in theory) very serious Geneva 2 conference on Syria.
What is Geneva 2 for? It has nothing to do with 'peace'. It won't yield an international deal to end the Syrian tragedy. The horrible war facts on the ground will remain facts, and horrible; many perpetrators won't be gathering in Montreux. Syrian civil society has not even been invited.
And then the whole charade degenerated into pitiful parody even before it started.
This past Sunday, it seemed that UN Secretary-General Ban Ki-moon had decided to spring out of his trademark vegetable slumber, inviting Iran to Geneva 2. The invitation lasted less than 24 hours; after the requisite 'pressure' by Washington – instigated by those sterling democrats of the House of Saud – it was duly rescinded.
Thus we had Ban Ki-moon parroting the US State Department....
|UN Secretary General Ban Ki-Moon (C) opens the so-called Geneva II peace talks next to UN-Arab League envoy for Syria Lakhdar Brahimi
Iran out and Ban Ki invites Alf and Mork from Ork. Well not really, but, he may as well have.
Ban Ki-moon also invited the Holy See, as well as Australia, Luxembourg, Mexico and the Republic of Korea, among others, to Montreux; as if these actors had any clue about what's going on in Syria.
Yup, Luxembourg, Mexico and Korea.
But the apex of the farce is that Iran cannot go, while Saudi Arabia and Qatar – who continue to weaponize every Syrian 'rebel' in sight, from young adrenaline seekers to Western-supported Takfiris and beheaders – can. And will.Meet 'good' and 'bad' Al-Qaeda - A theme regular readers here are totally aware is complete and utter rubbish. There are no good or bad hired killers. There are just hired killers.
|FSA brand hired killer
Time to break it down. Washington ruled that Iran cannot be in Montreux because it supports Assad. It's as simple as that.
Washington dictating to the UN is the norm. Washington dictating to the Syrian exiled 'opposition' is also the norm. Everyone is a puppet in this lethal comedy.
As for Western spin doctors, they are dizzier than flies over corpses. As part of the new Western myth that the Saudi Arabia-sponsored Islamic Front – formed last September against the US-backed Supreme Military Council – are nothing but 'good Al-Qaeda', now we have top 'rebels' routinely acknowledging to Western corporate media they are, well, Al-Qaeda.Ah yes, the Islamic Front.. Recall I mentioned them in this post, complete with a whose who chart? The US extends a diplomatic hand to Islamists in Syria. But, not the bad ones.
That's right, not the 'bad' ones.
Tens of thousands of foreign jihadis using Al-Qaeda's network of safe houses in Turkey – well, that's not such a big deal. As the narrative goes, 'our new friends' in the Islamic Front are just 'conservative Salafi Muslims'. What if they are fond of the odd torture binge and will think nothing of slaying the odd Shiite or Christian? Not such a big deal.
As for the 'bad' Al-Qaeda gang – from Al-Nusra Front and Ahrar al-Sham to the Islamic State of Iraq and the Levant (ISIL) – they are on a roll. After all, they are the ones with fighting experience/leverage on the ground. And when push comes to shove, they just run yet another ring around clueless Western necks.( I disagree with "clueless")
Take Ahrar al-Sham. They now lead the Islamic Front – and talk to the Americans. (Please refresh your memory at the relinked post. ) And guess what; they're going to Montreux! The icing on this Takfiri cake is that, ultimately, their "interests" are being defended by no less than US Secretary of State John Kerry. Washington promoting al-Qaeda? Well, we've seen that movie before.Why yes, we have!
|Maalula- NATO's mercs targeted christians here where they speak Aramaic
Second in line- Play the girl power card and score political points- Meaningless, empty but sadly too many of my cohort eat that up- My cohort being women.
CFR Mouthpiece - Mouthpiece from the CFR basically tells us nothing will come from Geneva II, which is correct, because bottom line that is the desired outcome. For the US, Israel, Saudi Arabia, Qatar, Turkey etc. The war mongers. This can go on and on and on.... because, really it is just ordinary Syrians that are being harmed. Patrick from the CFR is so unconcerned with ordinary Syrians he doesn't even mention them. The only hope is a decisive victory on the battlefield on one side. Here is hoping it is not NATO.
"In sum, the most likely diplomatic outcomes of this long awaited "peace conference" are likely to be pretty thin gruel. Even with the Iranian spoilers relegated to the sidelines, "Geneva II" is unlikely to see any major breakthroughs. At best, the summit will mark another phase in a protracted negotiating process that may continue for years, unless circumstances on the battlefield result in a clear victory for one side"
Battlefield victory aside talking head suggests that Kerry play the woman in power card, for maximum PR effect.
"The United States can make a meaningful difference in negotiations between the two sides. This would be to insist on the inclusion of significant numbers of women in both sides' delegations"
Because " peace is too precious to leave to the men with guns"
|Yup, girl power
Absurd. This 'girl power' is as meaningful as Lady Gaga's bullying campaign. It sounds nice. It gives some people the warm and fuzzies. But what real difference does it make? None. It's PR. It's empty. But, it is a dam perfect button to push. Women vs Men. Women as peacemakers.
And last, but certainly not least, Egypt steps up to plate.
Continuing it's western lackey role by inviting the NATO approved opposition to talks in Cairo. Not that this is anything new for Egypt. Mr Morsi played the same game. He hosted the NATO opposition in Cairo, also. Aaah.........The more things 'change' the more they are exactly the same
Egyptian Foreign Minister Nabil Fahmy has invited Syrian opposition groups to Cairo for talks on unifying their disparate positions.
The Syrian opposition should unite their views to create "real policies" that pave the way for a "civil state for all Syrians," Fahmy said.
Egypt- Still doing NATO's bidding.


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Ground-breaking prostate cancer research scanner to be installed
PUBLISHED: 09:16 28 May 2019 | UPDATED: 09:16 28 May 2019
Geraldine Scott
Thousands of men with prostate cancer will be able to avoid the damaging side effects of surgery thanks to a new research scanner that will be installed in Norwich.
Thanks to fundraising by the Norfolk Freemasons a state-of-the-art scanner which can differentiate between the majority of harmless prostate cancers, known as pussycat cancers, and the 10pc which are aggressive, known as tiger cancers.
The Freemasons raised not only the £144,000 needed for the scanner, which will be in a new screening laboratory at the University of East Anglia (UEA), but also another £146,000 for prostate cancer research.
Up until now there has been no way for doctors to tell the difference between the two types of the cancer, which led to tens of thousands of men having unnecessary operations with serious side-effects including incontinence and impotence.
Each operation costs the NHS £7,500 to perform, so there are also significant savings to be made from performing less unnecessary surgery.
The clinical research team behind the test, which is enabled by the scanner, is led by Professor Colin Cooper, who is developing the new test after a laboratory breakthrough made using artificial intelligence.
He is hoping to raise £2m to continue his vital research into this condition over the next three years, to create the new clinical test.
The £290,000 donation from Norfolk Freemasons includes a £100,000 grant from the Masonic Charitable Foundation, which is funded by Freemasons, their families and friends, from across England and Wales..
You may also want to watch:
Prof Cooper said: "I am extremely grateful to Norfolk Freemasons for their generous grant, which will fund not only the scanner itself, but also the continuing research into prostate cancer.
"Many lives will be saved as a result and many unnecessary operations will be avoided, saving patients from some very unpleasant side-effects.
"There is a critical problem at the moment of men who are diagnosed with prostate cancer."
Prof Cooper had been working on the issue for 15 years, but it was only when he came to UEA he was able to get to the bottom of the issue.
His research will be the only of its sort in the country, and could have ramifications worldwide.
He said when they first stumbled across the answer to how to distinguish between the aggressive and non-aggressive types of prostate cancer, none of his four-strong team believed it.
He said: "Once a week for two years we sat in a room and pulled it apart. Ever time we had a meeting one of us did not believe it for some reason.
"We ended up somewhere very different to where anyone has ended up before."
Stephen Allen, head of Norfolk Freemasons said: "I'm delighted that we've been able to not only achieve our goal of buying the scanner, but we've raised more than double the amount needed. This will allow us to make a very significant contribution to Professor Cooper's ongoing research."
- To support the research contact the UEA Development Office, email email@example.com or call 01603 592945 for more information.
If you value what this story gives you, please consider supporting the Eastern Daily Press. Click the link in the yellow box below for details.


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Bernard Gibbs (MC), 2nd Lieut., 6th attd. 1st Battalion, Rifle Brigade
Died 6th July 1915 in Belgium, aged 22
Son of George R. and Elizabeth Gibbs, of "Rycott", St. Helens Park Rd., Hastings. Educated at Pencarwick, Exmouth, Macclesfield Grammar School, Shrewsbury School, and Pembroke College, Cambridge.
More information will be added here when research is complete.
2nd Lt. Bernard Gibbs is buried in grave ref. I. D. 8. of Talana Farm Cemetery, near Ypres, Belgium. At the request of his father, a cross and the following inscription were added to his headstone:
"I will go down into the grave unto my son mourning"
The Commonwealth War Graves Commission holds casualty details for 2nd Lt. Bernard Gibbs, and he is listed on the Imperial War Museum's Lives of the First World War website.
In Macclesfield, 2nd Lt. Bernard Gibbs is commemorated on the King's School war memorial.
Elsewhere, he is commemorated on the Shrewsbury School, Pembroke College Cambridge, Ashford-in-the-Water and Ashbourne St Oswald's Church war memorials.


text: "What would you be glad you did–even if you failed?" –Brene Brown Note from Gail…I wrote this as a guest blogger on http://www.agingbutdangerous.com about a year ago. Since my hunky hubby and I are taking some time away from technology this week, I thought a repost was in order! Stories To Tell You just knew she had stories to… Read More


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The novel is an archaeological and witchcraft thriller. The novel protagonist, Nora Kelly, an assistant professor at Santa Fe Archaeological Institute receives a letter from her father whom dissapeared sixteen years ago from an archaeological trip. The letter prompts Nora to go on a journey to discover what had happened to her father and an ancient city called Quivira.
The story deals with the ancient Anasazi culture, a native American culture. It will be fascinating for people who likes to know some ancient cultures and archaeological work.
I find it hard to imagine the mentioning of archaeological features or cave features, to picture the scenes, maybe due to my lack of vocabulary (e.g. what is a Kiva?).
The characters are well developed, I can imagine the distinct characteristics of each character. The plot is good, the mysteries, such as why did the Anasazi abandon Quivira, why did the Anasazi left Quivira leaving behind everything, who are the feral humans or animals, who sent the letter, what is the function of Quivira, have well explanations. The plot deals with the struggle to be the first to discover an epic archaeological site, the seriousness of preserving the site, etc.
The witchcraft strikes me as kind of dark, especially the rituals. An interesting look into the practice of witchcraft and ancient beliefs.
Readers who like this book may refer to the author's references to learn more about witchcraft and ancient culture, and archaeology.
"The authors made use of information from a number of other publications, the most important of which include: Clyde Kluckhohn, Navaho Witchcraft; Blackburn and Williamson, Cowboys and Cave Dwellers; Basketmaker Archaeology in Utah's Grand Gulch; Crown and Judge, eds., Chaco and Hohokam: Prehistoric Regional Sytems in the American Southwest; Kathryn Gabriel, Roads to Center Place: A Cultural Atlas of Chaco Canyon and the Anasazi; James McNeley, Holy Wind in Navajo Philosophy; David Roberts, In Search of the Old Ones; George Pepper, Pueblo Bonito; Hester, Shafer, and Feder, Field Methods in Archaeology; Lynne Sebastian, The Chaco Anasazi; Levy, Neutra, and Parker, Hand Trembling, Frenzy Witchcraft, and Moth Madness; Mauch Messenger, ed., The Ethics of Collecting Cultural Property; Chris Kincaid, ed., Chaco Roads Project, Phase I: A Reappraisal of Prehistoric Roads in the San Juan Basin; Tim D. White, Prehistoric Cannibalism at Mancos; Christy Turner, Man Corn: Cannibalism and Violence in the Prehistoric American Southwest; and Farouk El-Baz, "Space Age Archaeology," Scientific American, August 1997." – Author's Note, Thunderhead (1999)
Amazon link: Thunderhead