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PPARs/RXRs in Cardiovascular Physiology and DiseaseView this Special Issue
Review Article | Open Access
Annie Demers, Amélie Rodrigue-Way, André Tremblay, "Hexarelin Signaling to PPAR in Metabolic Diseases", PPAR Research, vol. 2008, Article ID 364784, 9 pages, 2008. https://doi.org/10.1155/2008/364784
Hexarelin Signaling to PPAR in Metabolic Diseases
Investigating the metabolic functions of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) has been extremely rewarding over the past years. Uncovering the biologic roles of PPAR and its mechanism of action has greatly advanced our understanding of the transcriptional control of lipid and glucose metabolism, and compounds such as thiazolidinediones which directly regulate PPAR have proven to exhibit potent insulin-sensitizer effects in the treatment of diabetes. We review here recent advances on the emerging role of growth hormone releasing peptides in regulating PPAR through interaction with scavenger receptor CD36 and ghrelin GHS-R1a receptor. With the impact that these peptides exert on the metabolic pathways involved in lipid metabolism and energy homeostasis, it is hoped that the development of novel approaches in the regulation of PPAR functions will bring additional therapeutic possibilities to face problems related to metabolic diseases.
1. Introduction
Vascular diseases impose the greatest burden upon health care systems and are predicted to remain the leading cause of death and disability in industrialized countries. The identification of excess body weight as a major risk factor, the epidemic of obesity and diabetes in Western societies and their increasing prevalence in children indicate that pathologies associated to the metabolic syndrome will continue to impact the health of individuals. Insulin resistance is a recurrent trait associated with increased adiposity, and despite the amplitude of health problems related to metabolic disorders, the mechanisms underlying excessive fat storage by adipocytes remain largely undefined.
The adipocyte is the major site of fatty acid storage in the body and plays a critical role in maintaining normal glucose and lipid homeostasis. If the capacity of the adipocyte to store lipids is exceeded, it can no longer regulate normally the release of fatty acids into the circulation, which ultimately leads to the abnormal accumulation of lipids in fat tissues and nonadipose depots. Such buildup of lipids in fat, liver, pancreatic islets, and muscle cells is associated to metabolic dysregulation of these tissues, resulting in many pathologic states of the metabolic syndrome, such as central obesity, atherosclerosis, type 2 diabetes, and insulin resistance [1, 2]. Over the recent years, with the unveiling of their ability to behave as master regulators of an array of genes that coordinate numerous pathways in lipid, glucose, and energy metabolism, the peroxisome proliferator-activated receptors (PPAR) have been considered important targets in the therapeutic management of metabolic disorders.
2. The PPARs, Fatty Acid Sensors
The PPARs consist of three isoforms, PPAR (NR1C1), PPAR (NR1C2), and PPAR (NR1C3), all of which are bona fide members of the nuclear receptor family. Upon ligand activation, the PPARs act as transcription factors by directly binding DNA as obligate heterodimers with retinoid X receptor RXR (NR2B) to a peroxisome proliferator response element (PPRE) contained in the promoters of target genes. With identified ligands such as mono- and polyunsaturated fatty acids, and derivatives such as eicosanoids, the PPARs have been recognized as physiologic sensors for fatty acids that control the transcription of many genes governing lipid metabolism [3–5].
PPAR is predominantly expressed in the liver, where it activates a broad range of genes involved in fatty acid uptake, glycerol metabolism, - and -oxidation of unsaturated fatty acids, and their transport into peroxisomes [6]. PPAR deficiency results in hypoglycemia and hypoketonemia, fatty liver, and elevated plasma fatty acids, revealing its importance in the hypoglycemic response [7, 8]. When fed a high-fat diet, PPAR-null mice are unable to catabolize fatty acids and develop severe hypertriglyceridemias without aPPARent obesity [9]. It is therefore predicted that fibrates, which selectively activate PPAR, are effective in treating hyperlipidemias [10]. PPAR is expressed ubiquitously and while biochemical and genetic evidence has linked PPAR to aspects of the metabolic syndrome [11–13], its emerging role in lipid metabolism remains to be further ascertained. Although the benefit of targeting PPAR and/or PPAR in lipid disorders is not excluded, the current review specifically emphasizes on PPAR and its metabolic control by growth hormone releasing peptides.
3. PPAR, A Metabolic Regulator of Insulin Resistance
Insulin resistance is marked by hyperinsulinemia, enhanced hepatic gluconeogenesis, and impaired insulin-stimulated glucose uptake into skeletal muscle and fat. Elevated levels of circulating fatty acids, associated with obesity and insulin resistance, increase fat accumulation in insulin target tissues and contribute to defective insulin action. In addition, obese adipose tissue-derived inflammation and altered secretion of adipocyte proteins, also known as adipokines or adipocytokines, can also impair insulin signals and affect systemic metabolism [14, 15]. The resulting hyperglycemia, dyslipidemia, and hypertension of the metabolic syndrome cause endothelial dysfunction and hasten vascular diseases.
Over the recent years, a number of adipokines, some of which being adipocyte-specific while others are not, have been identified to be produced and secreted by mature adipocytes. Adipokines, such as adiponectin and leptin which exhibit insulin-sensitizing effects, or resistin, tumor necrosis factor (TNF), and interleukin-6 (IL-6) which act as insulin resistance factors, all share autocrine, paracrine, or endocrine activity that regulates insulin sensitivity, therefore, establishing a role for the adipose tissue to function as an endocrine organ [14, 16, 17].
Remarkably, the thiazolidinediones (TZDs), which have been described as high-affinity ligands for PPAR [18, 19], can modulate in a beneficial manner the expression of many if not all of these adipokines at the gene level, thereby correlating adipokine production with PPAR activation. Originally discovered because of their potent insulin-sensitizing and glucose-lowering effects, TZDs are being used in clinics to correct abnormalities of lipid and glucose homeostasis, such as in type 2 diabetes, by reducing tissue insulin resistance [20]. For example, TZDs enhance adiponectin gene expression and circulating protein levels [21, 22], and decrease resistin [23, 24], TNF [25], and IL-6 [26]. This suggests that the effect by which TZDs enhance insulin sensitivity likely resides in their ability to promote a beneficial profile of hormones secreted by adipocytes, which can then influence glucose disposal by the liver and muscle.
However, the mechanism by which TZD activation of adipocyte PPAR leads to insulin sensitivity is not completely understood. Adipocyte-derived leptin is a circulating regulator of appetite and energy expenditure, whose increased levels reduce food intake and minimize ectopic lipid deposition by promoting fatty acid oxidation in peripheral tissues [27]. These effects contribute to the insulin-sensitizing properties of leptin, but its expression was found downregulated by PPAR ligands [28, 29]. TZDs were also found to stimulate adipogenesis by upregulating many PPAR target genes involved in fatty acid metabolism and storage [30]. Studies in rodent models and in humans have shown that TZD treatment causes weight gain [31, 32], an unwanted side effect that limits TZD efficacy on insulin sensitivity by increasing adiposity. This paradox remains largely unexplained, and among the likely hypotheses raised are a selective unequal accumulation of subcutaneous fat compared to visceral depots, and a possible activation of distinct yet overlapping adipogenic/antidiabetic gene programs in the adipocyte induced by TZDs [20, 33].
The use of genetic mouse models including tissue-specific deletion of the PPARg gene has enabled the identification of fat tissue as the primary target for TZDs but also revealed that other insulin-sensitive organs, such as liver and muscle, albeit expressing lower levels of PPAR compared to fat, were also responsive to some extent to TZDs. Mice lacking white adipose fat, resulting in a phenotype similar to that of humans with lipoatrophic diabetes, fatty liver, hyperglycemia, and insulin resistance [31], or mice lacking adipose PPAR, which also exhibit an insulin resistance phenotype [34], were refractory to the antidiabetic, but not the hypolipidemic effect of TZDs. In addition, these mice were highly predisposed to hepatic steatosis, an effect mainly attributed to liver PPAR [35, 36]. TZDs also retained their glucose-lowering effects in liver- and muscle-specific PPAR knockout mice [37, 38], arguying for a predominant role of adipose PPAR in the insulin-sensitizing effects of TZDs, although another study reported that muscle PPAR contributes to some extent to insulin resistance which was not improved by TZDs [39]. The kidney also appears as a target for TZDs in which however, renal PPAR activation lead to fluid retention by inducing the Na+ transporter ENaC in the collecting duct [40, 41]. This adverse effect of TZDs is viewed as a serious complication for patients with preexisting congestive heart failure [42]. In addition, the prototype TZD troglitazone was withdrawn from clinics due to life-threatening hepatic toxicity, whereas the other two TZDs, rosiglitazone and pioglitazone, are still being used in large-scale clinical practice. Hence, the crucial benefit of TZDs to consistently lower fasting and postprandial glucose concentrations as well as free fatty acid concentrations in clinical studies is clearly established, but also tempered by other effects, mostly undesired, therefore adding complexity in our understanding of the systemic response to PPAR ligands [43]. It thus becomes essential and of fundamental interest that other ways need to be identified in order to avoid the adverse effects of TZDs while keeping the benefits of correcting whole body glucose and fatty acid dysfunctions.
4. The GHRP-PPAR Pathway in Macrophages
One critical step initiating fatty streak formation in atherosclerosis consists in the accumulation of oxidized lipoprotein particles, mainly oxLDL, into the intima and their subsequent uptake by monocyte-derived macrophages, leading to the formation of cholesterol-loaded foam cells. Many lines of evidence suggest that the endocytosis of oxLDL by macrophages is mainly dependent upon their interaction with CD36, a member of the class B scavenger receptor family [44–47]. Studies in macrophages have shown that oxLDL uptake through CD36 provides a source of oxidized fatty acids and oxysterols that activate, respectively, PPAR and LXR (liver X receptor; NR1H3), thereby inducing a metabolic cascade resulting in enhanced expression of downstream genes, such as apolipoprotein E and ABC sterol transporters, and ultimately in cholesterol efflux to high density lipoproteins (HDL) [48]. However, these aPPARent beneficial effects are opposed by a positive feedback loop in which PPAR activation by internalized fatty acids enhances the expression of CD36, a process shown to mediate foam cell formation [49–53].
CD36 is an 88 kDa glycoprotein originally identified as a platelet receptor and also known as fatty acid translocase, which is expressed in numerous cell types including monocytes/macrophages, platelets, endothelial cells, and adipocytes [53–55]. CD36 is a multiligand receptor that is recognized by fatty acids, anionic phospholipids, thrombospondin, and oxidized lipoproteins. It is this latter property of scavenging (e.g., clearing) oxLDL which implicates CD36 in the initial steps of atherogenesis, as evidenced with studies in mice [53, 56] and humans [57].
The findings that growth hormone releasing peptides (GHRPs) serve as ligands for CD36 [58, 59] led to the evaluation of their potential role in regulating cholesterol metabolism in macrophages. The GHRPs belong to a class of small synthetic peptides known to stimulate growth hormone release through binding to the GH secretagogue-receptor 1a (GHS-R1a), a G-protein-coupled receptor originally identified in hypothalamus and pituitary [60] and later recognized as the receptor for ghrelin [61]. The peripheral distribution of the ghrelin GHS-R1a receptor in tissues, such as heart, adrenals, fat, prostate, and bone, has supported physiological roles of ghrelin and GHRPs not exclusively linked to GH release. For example, GH-independent effects on orexigenic properties, fat metabolism, bone cell differentiation, and hemodynamic control have been reported for ghrelin and GHRPs [62, 63]. Also, in conditions in which GH release was not promoted or in GH-deficient animals, the GHRP hexarelin was shown to feature cardioprotective effects by preventing ventricular dysfunction [64, 65], and by protecting the heart from damages induced by postischemic reperfusion [66]. These studies suggest that part of the beneficial effects of hexarelin may not involve GH release.
To evaluate the potential of hexarelin to regulate cholesterol metabolism in vivo, apolipoprotein E (apoE)-null mice maintained on a long-term high-fat and high-cholesterol diet, a condition known to promote atherosclerosis, showed a significant regression in plaque formation when treated with hexarelin compared to saline-treated controls [67]. These beneficial effects were observed in conditions in which GH was not upregulated by hexarelin [67], and also using EP80317, an hexarelin derivative with no GH release activity [68], supporting a GH-independent role for GHRPs.
To address the mechanism by which hexarelin exerts these beneficial effects, treatment of differentiated THP-1 macrophages or mouse peritoneal macrophages with hexarelin resulted in an increase in cholesterol efflux, which correlates with an enhanced expression of LXR, apoE, and sterol transporters ABCA1 and ABCG1, all involved in promoting the high density lipoprotein (HDL) pathway (see Figure 1). In addition, these effects were severely impaired in treated peritoneal macrophages isolated from PPAR heterozygote mice, implying an essential role for PPAR in mediating the response to hexarelin [67]. We further showed using cell reporter assays that the interaction of hexarelin with CD36 or with ghrelin receptor resulted in an enhanced transcriptional activation of PPAR, suggesting that both receptors signal to PPAR [67]. These studies have helped to define that the beneficial effects of hexarelin involved the activation of the PPAR-LXR-ABC metabolic cascade, thereby causing macrophages to mobilize excess cholesterol into the HDL cholesterol reverse pathway [67]. These findings therefore support a novel regulatory pathway by which CD36 and possibly ghrelin receptor may impact PPAR-regulated functions. Consequently, a detailed knowledge of the concerted modulation of CD36 and ghrelin receptor signaling pathways may help to provide additional strategies in pathologic conditions such as atherosclerosis.
5. A GHRP-PPAR Pathway in Adipocytes
Based on our observations that hexarelin promotes PPAR activation through CD36 and ghrelin receptors in macrophages [67], we wanted to address whether hexarelin could exert activation of PPAR and subsequent downstream effects in adipocytes. PPAR is considered a master regulator of fatty acid metabolism in fat through its direct role in regulating the expression of a broad range of genes involved in fatty acid and glucose metabolism. Among the genes upregulated by PPAR are found genes related to fatty acid uptake (fatty acid transport protein FATP, CD36), glucose uptake (GLUT4), -oxidation (acyl-CoA dehydrogenase, carnitine palmitoyltransferase CPT-1, acyl CoA oxidase), gluconeogenesis (phosphoenolpyruvate carboxykinase PEPCK), and lipid storage (adipophilin) ([69, 70], and references therein). Increased expression of many of these genes might result in a net influx and trapping of fatty acids into adipocytes, which is considered a mechanism by which TZDs consistently reduce circulating free fatty acids.
Mature adipocytes are known to express CD36 but not the other hexarelin receptor GHS-R1a ([71, 72], and data not shown). Whereas the role of CD36 in mediating oxLDL-derived cholesterol and fatty acid uptake by macrophages is recognized, the mechanisms by which CD36 may impact the overall metabolic activity of fat storage and mobilization by adipocytes is not completely understood. With these considerations and the central role of PPAR in regulating many aspects of fatty acid metabolism, it was expected that hexarelin may impact PPAR-regulated events in adipocytes.
As such, we recently reported the ability of hexarelin to regulate PPAR-dependent downstream events in cultured adipocytes and in fat tissues from treated mice [73], thereby providing evidence that hexarelin may target different PPAR expressing tissues. In these studies, we observed that treatment of differentiated 3T3-L1 adipocytes with hexarelin resulted in a depletion in triglyceride cellular content, accompanied by profound changes in the gene expression profile of key markers of fatty acid metabolism [73]. Interestingly, many of these genes were shared with TZD troglitazone treatment, indicating that PPAR may be considered as a common regulator in both responses. Consistent with this, among the genes upregulated by hexarelin, we found many established PPAR targets, such as nuclear receptor LXR, FATP1 (fatty acid transport protein), and F1-ATP synthase (see Figure 2). Other genes involved in various aspects of entry, transport, synthesis, and mobilization of fatty acids, such as hormone-sensitive lipase (HSL), fatty acid synthase (FAS), and acetyl-CoA synthase (ACS) among others, were also upregulated, whereas glycerol-3-phosphate acyltransferase (GPAT), which catalyzes the initial and committing step in glycerolipid biosynthesis, was downregulated by hexarelin [73]. All together, this type of profile is strongly suggestive of an increase in the cellular mobilization of free fatty acids in response to hexarelin.
However, the response to hexarelin was not totally mimicked by troglitazone as other described PPAR targets, such as adipocyte fatty acid binding protein FABP4 (also referred to as aP2) and lipid droplet-associated protein adipophilin remained mostly unchanged upon treatment with hexarelin [73]. It is also important to note that gene expression and protein levels of CD36, a well-known target of PPAR [49, 50], were not changed by hexarelin, as opposed to troglitazone which significantly induced both in treated adipocytes. Similar results were also found in macrophages, indicating that this regulation is not cell-specific [67], and may prevent any undesired increase in macrophage CD36, a situation that correlates with proatherosclerotic events [55, 74]. Also, as opposed to troglitazone which decreased PPAR expression, hexarelin contributed to maintain expression and steady-state levels of PPAR in adipocytes and macrophages [67, 73]. The exact mechanism(s) by which hexarelin exerts such gene-specific regulation compared to TZDs are not clearly understood, but differences in PPAR occupancy of targeted promoters and/or posttranslational modifications of PPAR are certainly among the likely possibilities to consider in the response of PPAR to hexarelin ([67], see below).
6. Hexarelin Promotes Mitochondrial Activity and Biogenesis
Uptake of fatty acids and glucose by muscle and fat tissues is an important component regulating energy expenditure and defects in CD36 have been associated with impaired fatty acid and glucose homeostasis in humans [75, 76]. However, the role of CD36 in regulating energy metabolism in adipocytes remains an unresolved issue.
By transposing the ability of hexarelin to promote PPAR activation to adipocytes, it was interesting to observe that many genes upregulated by hexarelin were characteristic of an enhanced profile of fatty acid oxidation and mitochondria morphology [73]. More specifically, among the genes upregulated were found acetyl CoA acyl transferase, CPT-1, and several subunits of the ATP synthase and of the cytochrome c oxidase complexes, all suggesting an increased fatty acid mobilization towards the mitochondrial oxidative phosphorylation pathway [73].
Enhanced mitochondrial oxidative potential is required to supply adequate ATP production in high energy-demanding processes, such as adaptation to cold in brown fat, heart and skeletal muscle contraction, and liver gluconeogenesis in response to fasting. Such mitochondrial energy-producing capacity correlates with active -oxidation of fatty acids and increased expression of PPAR coactivator-1 (PGC-1) in these tissues [77–82]. PGC-1 is a coactivator of most nuclear receptors that was discovered as a molecular switch that turns on several key components of the adaptive thermogenic program in brown fat, including the stimulation of fuel intake, mitochondrial fatty-acid oxidation, and heat production [83, 84]. These metabolic changes are supported by the ability of PGC-1 to upregulate the expression of UCP-1, a biological uncoupler of mitochondrial oxidative phosphorylation, and of genes of gluconeogenesis, such as PEPCK and glucose-6-phosphatase (reviewed in [84, 85]). Thus, modulating the relative activity of PGC-1 within a particular tissue may lead to a fine tuning of mitochondrial function in fatty acid oxidation and energy balance. Interestingly, hexarelin induced an increase in PGC-1 and UCP-1 in 3T3-L1 adipocytes as well as in epididymal fat of treated mice, indicating a potential fat burning phenotype taking place in white fat in response to hexarelin [73]. Consistent with these changes, electron microscopy of hexarelin-treated 3T3-L1 adipocytes showed an intense and highly organized cristae formation that spans the entire width of mitochondria compared to untreated cells, accompanied with an increase in cytochrome c oxidase activity, two features characteristic of highly oxidative tissues [73]. A similar mitochondrial phenotype and gene expression profile was detected in epididymal white fat of mice treated with hexarelin, and shown to be dependent on CD36, indicating that the ability of hexarelin to promote a fat burning-like phenotype was maintained in vivo [73]. These studies therefore support a functional GHRP-PPAR signaling cascade in adipocytes, which provides a potential role for CD36 to impact the overall metabolic activity of fatty acid usage and mitochondrial biogenesis in fat. These aspects are particularly relevant to the emerging association of mitochondrial dysfunction with insulin resistance and type 2 diabetes [86].
7. Hexarelin Increases PPAR Phosphorylation
The exact mechanism(s) by which PPAR activity is modulated in response to hexarelin remains to be clearly defined. In an attempt to partly characterize such a response, we found that PPAR was highly phosphorylated in macrophages treated with hexarelin, therefore providing a basis on how PPAR can respond to hexarelin signaling [67]. Although macrophages do express both receptors recognized by hexarelin, our observation that GHS-R1a activation by hexarelin enhanced PPAR activity in transfected heterologous cells may therefore suggest that GHS-R1a signals to activate PPAR [67]. Consistent with this, the activation of GHS-R1a receptor by hexarelin or its natural ligand ghrelin leads to the phosphorylation of PPAR in macrophages, while a GHRP selective for CD36 did not ([67] and unpublished observations). These findings rather implicate GHS-R1a signaling in the phosphorylation of PPAR, at least in macrophages.
The effects of phosphorylation on PPAR activity have been reported to vary, often in opposite directions, depending on the cellular and promoter context [87]. In that respect, it is interesting to note that while PPAR ligands of the TZD family are recognized to upregulate CD36 gene expression [49, 50], no significant changes in CD36 expression were measured in response to GHRPs despite PPAR activation [67, 68, 73]. In order to further investigate the mechanism by which this unexpected regulation of CD36 by hexarelin may result, chromatin immunoprecipitation assay has revealed that the relative occupancy of the CD36 promoter region by PPAR remained mostly unchanged, whereas that of nuclear receptor LXR, also a known target of PPAR [88], was occupied by PPAR in a greater extent in macrophages treated with hexarelin, indicating that LXR upregulation by hexarelin may result from a preferred recruitment of PPAR to the LXR promoter, as opposed to CD36 [67]. Whether PPAR phosphorylation may discriminate for promoter usage is not yet known but interestingly, it was reported that PPAR phosphorylation could decrease CD36 transcription in macrophages [53]. Given the ability by which posttranslational modifications such as phosphorylation could regulate PPAR transcriptional activity and that ligand-independent recruitment of transcriptional coregulators is favored by nuclear receptor phosphorylation [87, 89–91], it is predicted that such mechanism may contribute in the cellular response to hexarelin by selectively regulating PPAR-targeted genes. These aspects need to be further investigated in order to ascertain such selectivity.
8. Concluding Remarks
Although the exact mechanisms by which GHRPs promote their metabolic response are not fully understood, it becomes clear that interacting with CD36 and/or GHS-R1a receptors induces profound changes in metabolic activities of target tissues, especially regarding PPAR-regulated events. However, it is important to note that the sole activation of PPAR may not be exclusive in translating the signal by hexarelin or other GHRPs. Indeed, in view that hexarelin can also promote PPAR and PPAR activation [67], and with the propensity of PGC-1 to coactivate other nuclear receptors besides PPAR, such as thyroid hormone receptor TR, retinoic acid receptor RAR, estrogen-related receptor ERRs, and PPAR [83], it is expected that these pathways may also be affected by hexarelin. So clearly, the mechanism(s) by which hexarelin exerts its metabolic effects represents a promising avenue which deserves further investigation to face problems related to multipathological states associated with metabolic syndrome.
The important contribution of Huy Ong, Sylvie Marleau, Roberta Avallone, and Walter Wahli is greatly acknowledged. We are also grateful to members of the laboratory for their valuable contribution and discussion. This work was supported in part by the Canadian Institutes of Health Research (CIHR), the Canadian Diabetes Association, and the Canadian Foundation for Innovation. A. Demers holds a doctoral award from the CIHR and A. Rodrigue-Way from the Natural Sciences and Engineering Research Council of Canada. A. Tremblay is a New Investigator of the CIHR.
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This courtyard, this building, this cafe, this oasis - Villa Kynthia is all of these. An old, restored building with exotically furnished rooms or suites, each with plenty of atmosphere. Right in the centre of the seaside village of Panormos.
Furnished with antiques, gilt-edged mirrors, Persian-style rugs, and decorated with murals describing stories or legends from ancient Greek mythology. Several bathrooms have faux windows which are illuminated and fitted out in Italian style of a bygone era.
Breakfast is served in the homey, country-style dining room or in the pool courtyard. The pool, under an ancient pine-tree, is large enough to take a swim if the beach, which is only a three minute stroll away, seems too far!
When you stay at Villa Kinthia , you are one of a few guests (only 5 rooms and suites). There is a remarkable atmosphere reminiscent of an old Italian pensione – the type of place where true travellers exchange stories or enjoy a hidden joy in their rooms.
A high-ceilinged, separate bar is excellent for both quiet or animated discussions and sometimes (small and select) live music events. A good, cosy taverna on the pedestrian street a couple of buildings away is very convenient for meals near the hotel. Alternatively, they will deliver happily to you in your suite or the pool courtyard.
Panormos village, apart from two delightful sandy beaches, has a most central location along the north coast of Crete that allows for exploring many parts and sights of Crete. For example, you can visit easily Bali, Anogia, the historic Arkadi Monastery, south coast towns & beaches of Plakias, Agia Galini and Matala, Preveli Monastery and Phaestos.
There is a little "train" in the summer with excursions through Panormos to the Melidoni cave, Margarites potteries, and Langa where you will see old farm implements. The proximity (20 minutes) from Rethimno and its historic old town puts it high on the list of "must do" activities. Heraklion, Knossos and the airport are about one hour away.
- Hotel Name: Villa Kynthia Hotel
- Area: Rethimno, Panormos
- Why Go: Art & Culture,Elegant,Friendly enviroment,Village Athmosphere
Why we like it
- Kynthia Hotel is a renovated villa, perfect for your relaxing holidays; a magical environment that makes you feel like home.
- Kynthia's rooms have a very unique character and each one is completely different.
- The owners are friendly and helpful. The staff are really happy with bright smiles for you.
- An exquisite little getaway with an atmosphere that is a cross between simple village hotel and an exclusive retreat.
- The small village of Panormos, just perfect, with plenty of delicious tavernas and 2 sand beaches.
What to know
- Not all rooms have their own private space to sit out. Two rooms have small balconies.
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In games where girls/females look really good (slender, powerful, etc), I play female characters along with guy characters.
darthjt wrote:I have 9 male characters and 3 female characters...I have a female life, ice, and myth...I love them all... Although, the only thing that is funny about playing the girls, is that guys try to pick me up all the time... go figure!
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Porter admits abusing children as priest, apologizes
Says he remained in clergy until 1974
By Stephen Kurkjian, Globe Staff, 7/15/1992
In a one-paragraph statement in which he apologized for his actions, Porter stated that he had not abused any children since he left the priesthood in 1974, which is four years later than had been previously reported.
"I was a very sick man while I was a Roman Catholic priest in the 1960s," Porter said. "As a result of my illness, I sexually abused a number of children. I sought help for my illness on several occasions and, when I finally realized I could not control my behavior while remaining a priest, I left the priesthood. I have not had sexual contact with any child since I left the priesthood in 1974. I am deeply sorry for all of the pain that I have caused, particularly to the children and their families."
Porter, who now lives in a suburb of St. Paul with his wife and four children, said in the statement released by a lawyer there that he would not be available for further comment. His lawyer refused to answer questions, including a request to identify the churches or dioceses where Porter had served between 1970 and 1974.
Porter served in Massachusetts parishes in the 1960s and in a Minnesota parish in 1969-70. A lawsuit filed yesterday by an Albuquerque lawyer alleged that Porter had served as a part-time pastor in 1972 and 1973 in a small New Mexico parish and abused two boys there.
Porter's written statement contained two apparent inconsistencies with statements he made last year in several hours of recorded telephone interviews with Frank Fitzpatrick, a Rhode Island private investigator, who says he was abused by Porter in the 1960s.
Porter told Fitzpatrick, who had tracked him down in Minnesota, that he had been forced to leave the priesthood. His statement yesterday implied he left voluntarily. He also told Fitzpatrick that he left the church in 1969, not 1974, as he said yesterday.
Porter's statement came within hours of the announcement at a St. Paul news conference that seven men will file lawsuits against Porter and the Catholic Church alleging that Porter had sexually abused them while he served as a priest in Minnesota in 1969 and 1970.
Attorney Jeffrey Anderson filed the lawsuits on behalf of the seven former altar boys at St. Philip's Church, in a parish in Bemidji, Minn., where Porter served as assistant priest in 1969 and 1970. According to Anderson, Porter was assigned to St. Philip's after a New Mexico treatment center run by the Catholic Church pronounced him cured of a compulsion to molest children.
The lawsuit also charges that church officials "systematically and clandestinely" transferred Porter from one parish to another despite a history of sexual abuse, and "held Porter out to the new parishes as a competent, fit and moral Roman Catholic priest."
"It is their problem and it is their practice, and it has caused these children to be sacrificial lambs," Anderson said.
Two of the seven whom Porter allegedly abused in the Bemidji parish appeared at the St. Paul news conference. Dan Dow, 34, and James Grimm, 34, said news reports of Porter's alleged behavior in Massachusetts were part of the reason they came forward. "All the memories came rushing back in my head," Grimm said. "It felt like my head was going to explode."
Both were in sixth grade at the time they were allegedly assaulted by Porter. They said Porter repeatedly abused them after Mass when they served as altar boys and when he coached the basketball team at St. Philip's school.
The lawsuits are the first formal claims of sexual abuse filed against Porter, a Boston-area native, who has been accused by scores of people of molesting them while he was a priest.
In addition to Porter, named as defendants in the lawsuits are the diocese of Crookston, Minn., where the Bemidji church is located, the Fall River Diocese, where Porter served between 1963 and 1967, and The Servants of the Paraclete Inc., the New Mexico center that treated Porter in the 1960s and possibly the 1970s.
Porter's lawyer, Bruce Jones, declined to say where Porter might have served as a priest between 1970, when he was expelled from the Bemidji parish, and 1974, when he said he left the priesthood. However, a lawsuit filed yesterday by Bruce Pasternack, an Albuquerque lawyer, alleged that Porter had served as a part-time pastor in 1972 and 1973 at St. Edwin's Church, in a small parish near the Paraclete treatment center in Jemez Springs, N.M. While at the church, he abused two young boys, Pasternack's suit alleged.
Nancy Ryland, communications director for the Santa Fe Archdiocese, where St. Edwin's is located, said church officials were checking their personnel files to determine if Porter had served there during the 1970s. The former priest in the parish told the Albuquerque Journal Monday that he often used priests being treated at the Paraclete center to fill in for him but could not recall if Porter had been one of them.
The Fall River Diocese, which under church rules had ultimate responsibility for what parishes Porter could be transferred to, released a statement expressing "profound sadness" at the accusations leveled in the lawsuits but declined further comment. Officials of the Crookston Diocese and the New Mexico treatment center declined to comment on the lawsuits.
The office of Bristol County District Attorney Paul Walsh, which is investigating the allegations of abuse by Porter to determine if he should be prosecuted, could not be reached for comment.
Roderick MacLeish Jr., a Boston lawyer who represents more than 60 persons allegedly molested by Porter at churches in North Attleborough, Fall River and New Bedford, said that Porter's statement amounted to a "public confession" and should assist Walsh in his investigation.
However, MacLeish said that the accusers to whom he had spoken yesterday rejected Porter's apology. "It is too little, too late. It does not mitigate, justify or excuse the predatory and horrendous behavior that he put these people through as children," he said.
MacLeish said that after learning of Porter's statement, he contacted Porter's lawyer and requested that Porter consent to an interview with MacLeish.
If Porter is truly apologetic for his actions, MacLeish said, he should help in the efforts by investigators to determine who within the Catholic Church authorized his transfers to other churches knowing that he was sexually abusing children.
This story ran in the Boston Globe on 7/15/1992.
© Copyright 2004 The New York Times Company
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Being aware of your credit score is an important part of maintaining financial wellness. Your credit score is used by a variety of service providers, from leasing offices to credit card companies, to determine what kind of credit or loan you could be approved for.
The health of your credit score also influences interest rates, which ultimately means that your credit score helps determine how much it will cost you to borrow money.
With so much riding on the state of your credit, how can you stay up-to-date? Luckily, you have a number of options for getting a free credit score.
How do I get a free credit report?
First off, it's important to understand the difference between a credit report and credit score. Think of your credit report as your entire consumer credit history on accounts both active and closed, including credit cards, auto loans, mortgages and so on. Your credit score is more like a snapshot of your credit at a given moment in time.
Knowing your credit score is essential for making informed decisions about your finances. Not only that, but it will also help you understand the criteria that creditors and lenders use to determine your qualifications. It's a good idea to check your credit report once a year, though monitoring your credit score regularly is ideal.
Checking your credit score for free is pretty easy. Sources of free credit scores include:
Credit scoring websites
A simple Google search will point you in the direction of many online resources. Stick to reputable websites that have addresses beginning with "https" (the "s" is for secure, to help protect your personal information from prying eyes). One example is Annual Credit Report.com.
Existing credit accounts
A growing number of credit card issuers, banks and other financial institutions have started providing customers with free credit scores. Check your monthly statements to see if you already have access to a free credit report.
What about free credit reports?
Under federal regulations, you're entitled to get one free copy of your credit report every 12 months from each of the three nationwide credit reporting bureaus: Equifax, Experian and TransUnion. You can order online from AnnualCreditReport.com or by phone at 1-877-322-8228.
Will a credit check affect my credit score?
Credit inquiries fall into two categories, hard and soft. A hard inquiry into your credit is usually done by a lender or service provider when you apply for credit or a loan. Hard inquiries do affect your credit score, but they make up only a small percentage of the total score.
The other kind of inquiry is a soft inquiry. A soft inquiry can occur when your employer checks your credit or an existing creditor checks your report. When you check your own credit report it is also considered a soft inquiry. This kind of inquiry does not affect your credit score.
Is my credit score the same as my FICO score?
Your credit score is a number meant to show your level of creditworthiness. This number is determined by looking at a variety of personal financial information. There are two main credit scoring companies, VantageScore Solutions and Fair Isaac Corp. (FICO).
A FICO score looks at five factors of your financial life to predict your creditworthiness. Those factors are your payment history, the amounts you owe, the length of your credit history, the types of credit you carry and how much new credit you carry. The FICO score is the most common kind of credit score used by lenders.
Why should I know my credit score?
Your credit score is an important piece of information that lenders and creditors use when they evaluate your viability. It will come into play when you apply for most loans, including car loans, student loans and home loans. Your credit score will also affect the kinds of credit cards you can get. Higher credit scores can give you access to lower interest rates and higher tier rewards programs.
If you've been thinking about applying for a rewards card or increasing your credit limit on your current card, your credit score will likely have an effect on the outcome. For this reason, among others mentioned in this article, it is good practice to check your credit score regularly.
How can I keep tabs on my credit score?
It's essential to monitor what's happening with your credit. There's always the possibility that your credit score could be compromised in some way through an error or, worse, an identity theft.
Regularly monitoring your credit allows you to keep tabs on your credit activity and catch any suspicious activity in a timely fashion.
Bottom line
Whether you're looking to buy a car, go back to school or rent a home, your credit score will affect what kind of loan or credit you can get. Finding out your credit score starts with requesting a credit report. This report will give you important information about your credit status and can help you to take steps to improve or maintain your score. It can also help you monitor your accounts and identify suspicious behavior in a timely fashion.


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Hotel Reservation in Naga, Camarines Sur
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Medieval Martial Arts in the Rocky Mountains
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Salvator Fabris: "On Defense, or the Science of Arms" Manual in English$119.00 A unique and beautiful translation of the original Italian treatise designed to resemble the look and feel of the original, but read in English!
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Silver Swordfight T-shirt$29.00 Look snappy in a Swordfight Canada silver tshirt. 50/50 poly-cotton blend for carefree maintenance.
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Fiore de' Liberi: "The Flower of Battle" Manuscript in English$99.00 – $395.00 A unique and beautiful translation of the original Italian manuscript designed to resemble the look and feel of the original, but read in English! Available in wire bind, and hand-stitched leather bind.
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Safety & Policies
- View the Safety WaiverRespectful behaviour is expected of all Swordfight students at all times. Together we learn and practice the art in equality, honour and decorum.
- Present oneself with all due consideration: clean clothes, clean bodies.
- All Swordfight Canada participants must agree to a release of liability waiver.
- Anyone under 19 years of age must also have their waiver signed by a parent or legal guardian.
- No drugs or alcohol are permitted on the field and should not be consumed prior to any Swordfight Canada event.
- We have a cancellation policy of 48 hours.
Our Learning Environment
- we are made up of a welcoming and inclusive group that creates a safe space and is open to everyone
- we foster a place where each student is empowered to be their own best teacher and learner
- we practice authentic swordfighting techniques sourced from period manuals and applied with a modern teaching style, using safe tools closely resembling their deadly counterparts
- we engage in physical activity that gets us in touch with our strengths and weaknesses, with respectful and controlled contact at all times
- we expect and deliver professional conduct; instructors start classes on time with equipment and lessons prepared; students show up on time and work diligently, taking care of themselves, their equipment and their classmates
Swordfighting is a martial art with certain inherent risks. Although our instructors make every effort to ensure a safe experience, neither the company, its owners, nor anyone else associated, shall be held responsible for any losses, damages or injuries to person or property, due to any cause whatsoever. Read the safety waiver here.
Youth under the age of 19 must print and deliver to the Instructor a signed waiver before the beginning of class. Read the safety waiver here.
Ongoing Classes
Swordfight Canada's ongoing classes allow you to learn medieval combat techniques in dagger, longsword and spear by building one skill upon the next, and putting it all together in a structured and coherent system of martial practice. Swordfight Canada uses the same world-class curriculum and teaching methods taught at Academie Duello in Vancouver, BC.
Start with the basics by taking an introductory course or workshop, then progress through stages of curriculum that explore new topics every month. Along the way you'll be able to learn new skills, practice them to proficiency, and enjoy sparring and freeplay within a supportive community of fellow students and mentors.
There are skill assessments and a list of techniques that each rank is able to learn and focus on. Finally, prepare for your examination to progress to the next level of study! It's challenging work, and requires focus, time and energy, but the rewards of pursuing swordfighting are enormous! Confidence, physical grace, and knowledge of a treasured art are just a few. Each student finds their own joy in the pursuit of swordfighting mastery. Start your journey today! Purchase tuition for ongoing classes here.
About Swordfight Canada
Based in the alpine village of Valemount, British Columbia, Swordfight Canada was founded is 2016 by Greg Reimer and holds classes and worships throughout BC and Western Canada. In 2015, Greg received his Provost certification at Academie Duello in Vancouver, BC, where he studied swordfighting for over ten years.
Greg has been studying Italian martial arts since 2006, and has taught over 5,500 hours to students in unarmed, dagger, rapier (and secondaries), sidesword & buckler, longsword, pole weapons and mounted combat.
Greg has also participated in various tournaments, winning the 2013 and 2014 Carosella Mounted Combat games, the 2014 Senior Students Invitational rapier tournament, and the 2015 Spring Clash Tournament (rapier & longsword videos below) in Vancouver, BC. He has travelled across Western Canada and into Washington State to meet, teach and enjoy learning and sparring with other sword fighters.
Greg enjoys sword fighting and sharing it with others, no matter what age, physical ability or martial experience.
Videos of Live Combat
Forms & Historical Interpretations
Upcoming Events
View All EventsWield a sword and fight like a knight! Grow in your knowledge, acquire real martial skills, and journey the path of swordfighting mastery within a welcoming community. Registration is limited, so purchase your tickets and reserve your seat now. Purchase tuition for ongoing classes here.


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The new Mythos Corfu is idyllically situated in the northwest of the green island of Corfu in the small village of Arillas, in a central but quiet location. Beach, tavernas, cafes, bars and small shops are within an easy five minute walk.
Surrounded by olive groves, Arillas offers brilliant chances for relaxing days on the beach and the turquoise Mediterranean sea. It is also an excellent starting point for walks or hikes to hidden coves, ancient mountain villages, breathtaking vantage points, and for boat trips to the nearby islands Erikoussa and Mathraki.
The Venetian Old Town of Corfu town , only 34 km away, makes for a delightful visit with its typical Mediterranean atmosphere.


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An obscure internet executives decision to shut down a neo-Nazi website has rightly sparked a debate about how to govern the global computer network. On a technical level, though, it also demonstrates how vulnerable this supposedly resilient mode of communication has become.
The Daily Stormer, which spreads neo-Nazi propaganda using cartoon frogs and anime avatars, was far from the most beloved page on the web. The site had already relocated to a Russian domain after multiple U.S. registrars canceled its name registration. Then Matthew Prince, CEO of content network provider Cloudflare, delivered the decisive blow, explaining in a company-wide email that the people behind the Daily Stormer are assholes and Id had enough.
Cloudflare was capable of shutting down The Daily Stormer thanks to the critical role the company plays in our internet infrastructure. When you visit Bloomberg.com, youre not connecting to a server in New York -- the site would be far too slow for readers on the other side of the globe. Youre actually connecting to a content delivery network that caches copies of this site in data centers all around the world. By distributing traffic across hundreds of servers, such networks respond quickly to visitors while protecting sites against denial of service attacks -- attempts to make a service unavailable by overwhelming it with junk traffic from networks of bots. These days, hackers can rent a botnet for as little as $20 an hour, which makes services like Cloudflare essential for sites that might provoke vigilante botnet attacks.
Although Cloudflares terms of service allow it to terminate users at its own discretion -- and it wouldnt be alone in doing so -- the company has long sought to take a neutral stance. It has faced criticism for serving ISIS propaganda sites and enabling the spread of malware and pirated content, and has argued that its job was to maintain the pipes, not monitor them. Recognizing that his approach toward the neo-Nazis represented a departure, Prince emphasized that the state of affairs was not optimal: Literally, I woke up in a bad mood and decided someone shouldnt be allowed on the Internet. No one should have that power.
Indeed, this is not how the internet was supposed to work. It was designed to be a decentralized communications system with enough distributed capacity to survive a nuclear strike. But over the years, economies of scale have led sites and services to pile into just a few infrastructure providers like Cloudflare, leaving large portions of the internet vulnerable at multiple levels. Last October, an attack on a domain-name service provider disabled many popular sites for most of a day. More recently, a cloud-storage malfunction reminded the world that Amazon Web Services controls 31 percent of the global cloud infrastructure market. And now we see that the internet is vulnerable to the mood swings of a content delivery network CEO.
Prince recommends that a legal framework be established for content restrictions, so that censorship decisions arent dominated by a handful of providers. This might make sense in an ideal world, but we should bear in mind that Donald Trump is president before suggesting that the government set rules for online discourse. Beyond that, if we create a content regulation framework, we may be resigning ourselves to an internet controlled by a few common carriers.
That would be unfortunate, because the whole point of the Internets distributed structure is to allow information to get around points of failure or blockage. Recent attempts at online censorship have motivated the organization of the Alt Tech Alliance, a movement to build alternative internet services for those shunned by mainstream providers. While we might disagree with their criteria for content acceptability, the availability of competing service providers makes the entire internet more resilient.
In other words, if we want a reliable system, well also have to abandon the idea of setting uniform rules for content -- no matter how reprehensible some users may be.


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Almo Pro Debuts Video Wall Guide
Almo Professional AV has announced the arrival of a new resource: the 2014 Video Wall Guide.
The guide, the company said, "explores ways to run video wall content without a PC, what really matters in video wall panels, new ways to program video walls together, how to create content for video walls in different applications, and examples of how video walls have made an impact across various markets."
It contains 19 new products, 21 videos, as well as articles and case studies. Included manufacturers include Barco, Sharp, Peerless, Samsung, ATEN, BrightSign, LG, Panasonic, Chief, NEC and Premier Mounts.
The guide can be viewed, in PDF form, here.
Related Content


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Did you vote in our "Who Jumped It Best? Red Hills CIC3* Water Complex" poll? If so, you've seen photos from the second water complex on course — a hugely influential fence. This video from RNS Video Media captures the action that unfolded at the first water complex earlier in the course, which presented a big question of its own.
A job well done to all the Red Hills competitors!
Red Hills Links: Website, Final Scores, EN's Instagram


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Calphalon in the Dishwasher
Calphalon is a brand of cookware available in stainless steel and anodized aluminum. You can select Calphalon with a nonstick or a regular surface, in commercial and home use grades. Choose from skillets, saucepans, Dutch ovens and stock pots.
Proper care will ensure your Calphalon remains looking good for a lifetime of use.
Dishwasher Use
In the Use and Care notes on the Calphalon website, Calphalon notes that stainless steel cookware is dishwasher safe, but recommends against washing Calphalon in the dishwasher. Harsh dishwasher detergents can discolor or dull the aluminum surface of the pan. Also, other objects hitting against the cookware while it's in the dishwasher could result in dings, pits or dents.
Nonstick Caphalon
If you have Calphalon with a nonstick interior and stainless exterior, you can safely wash these pots in the dishwasher. However, Calphalon recommends you wash by hand instead. And although the website says you can wash your nonstick Calphalon in the dishwasher, the warranty does not cover any damage due to dishwasher use.
Calphalon carries a lifetime warranty against defects in workmanship that show up in normal household use. Simply Calphalon carries a 10-year warranty. The warranty specifically excludes any damage due to the cookware being washed in the dishwasher. This includes nonstick Calphalon.
Manufacturer's Recommendation
Calphalon recommends you wash your cookware with a dishwashing liquid such as Dawn. Scrub stains with a non-abrasive cleanser such as Bar Keeper's Friend. Use a soft sponge or brush. Rinse and dry with a soft cloth. Avoid using harsh or abrasive cleaners. Allow the cookware to cool completely before you submerge it in water. Submerging a hot pan could cause it to crack or warp.


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Game information
- Game title: Rise of the Titans
- Category: Action Games
- Game ID on Flash Game: 6559
- Game author: Evilspacechicken
- Total hits of the game: 6564 times
- Best screen resolution: 700 x 450 pixels
- Game instructions for Rise of the Titans:
In the action game Rise of the Titans, your objective is to damage the villages. Move with WASD keys and target with the mouse. Use the space bar to attack with skill 1, which is for killing adjacent enemies. Left click to attack with skill 2, which has a long range. Smashing things and buildings earns you credit points. Try to clear the area in the limited time! More free games are on www.flash-game.net!


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Pet Theft Awareness Day 2021 is on Sunday, February 14, 2021: National Pet Theft Awareness
Sunday, February 14, 2021 is Pet Theft Awareness Day 2021. National Pet Theft Awareness Day National Pet Theft Awareness
Pet Thievery Awareness Day is supposed to call focus on the significance of pet identification techniques. It's a day for thinking about simply how much the existence of a pet can enrich a household as well as the responsibility which goes by using it. It's a day that encourages individuals with pets to do something to guarantee the animal's security as well as their own satisfaction.Released in 1988 through the Last Opportunity for Creatures organisation, Pet Theft Awareness Day is targeted at educating animal proprietors to keep their pets protected from thieves. With almost two million pets being stolen yearly in American alone, the threat is real. Two choices are to possess pets micro-chipped or inked, which could offer an chance for many group connecting. An indelible imprint denoting who goes to who are able to bind a few as well as their pets until dying do them part. Not for that more unpredictable though.


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Woodgrove saga
continues in Portlaoise
THE "long, ongoing saga" of the problems with the pumping stations in Woodgrove in Portlaoise looks set to continue, as County Hall have still not been able to call in the bond on the estate.
At the recent town council meeting, Cllr Caroline Dwane called on the county council to ensure the pumping stations are up to a proper standard and are kept working properly. Cllr Dwane said that the residents have written to the council and asked for the estate to be taken in charge.
She was informed by the town clerk, Susan Rooney that the estate is not in the charge of the county council and the water service is looking after it.
"It's a long, ongoing saga and the council are in the process of calling in the bond," said Cllr Dwane. "When the pumps stop working in the estate the alarms in the pumping stations go off for days. The residents find a strong odour coming into their houses and spillage on the roads."
Cllr Alan Hand added that there is also a problem with subsiding walls in the estate, although he said that the council had made every effort to resolve the issue of the pumping stations.
Cllr Jerry Lodge asked was the bond still current. "There's a time limit on the bond and the problem has been there for some time," he said.


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Welcome to Marvel, Josh Brolin. It's good to have you around — for a second time, that is. In the past month, the big-named actor has appeared in two blockbuster action films (both from Marvel, albeit under different umbrellas): Avengers: Infinity War in April, and now Deadpool 2 in May.
A decade ago, it would've been hard to imagine Brolin in this spot, as a major role player in the superhero genre. Then again, it would've been hard to imagine studios churning out movies of this type at such a high rate. The star of No Country for Old Men, the man we once knew — and cherished — as Llewelyn Moss, has evolved from rural everyman hero to the main source of conflict in some of the biggest films of 2018.
Deadpool 2, which hit theaters last Friday, finds Brolin jumping back in time as an executioner. His mission has nothing to do with Wade Wilson, even if the movie finds its protagonist in the hands of death many times. Last month, he was also an executioner — and more than that, an executioner with tons of power, ready to play god. It's hard to imagine the man behind the god-fearing Texan character of No Country taking up the task of murdering half of the universe, but I guess someone had to one-up Anton Chigurh. Infinity War brings back the familiarity of, "They say, 'You don't have to do this,'" but Thanos will, and Brolin does justice to the villain by flexing plenty of muscle.
As far as his journey as an actor is concerned, it's easy to make the assumption that he's undergone quite the evolutionary career arc to reach this point. But you only have to go back to last year to realize he's still the same cinematic all-American we know and love.
With Only the Brave, he reminded us how well he could play the plaid-shirted, family-oriented, and most of all, determined hero — and he did it mere months before his cold, heartless Marvel debut. It's Brave where Brolin perhaps plays his most heroic character to date: A real-life firefighter who led a team of "hotshots" into the heart of deadly blazes. If you missed it, be sure to rent it, but have a box of tissues on standby.
For those who identify the actor with Llewelyn Moss (or even his True Grit rendition of Tom Chaney), you can't get much more prototypical Josh Brolin than that. But he's quickly turned the tides with his two newest roles, and it's making him out to be one of the most versatile and dynamic stars in Hollywood today. Sure, his low voice is always a dead giveaway, and sure, he looks much more like himself with a thick mustache. Yet, it's his giant, hairless, purple Eternal-Deviant hybrid that has in a short time gone down as the most memorable Marvel villain to date (make fun of his overly CGI appearance all you want, but you sure as hell remember him).
Fast forward to Deadpool 2, and Brolin is once again on a mission. His Cable has a robotic arm and a glowing eye, like some sort of Terminator-Winter Soldier hybrid. The Winter Soldier comparison even makes up one of Deadpool's handful of jabs at superheroes (he even goes as far as referencing Thanos, which was perfect timing since it came out not only a month after the new Avengers flick). The movie sure knows how to make you laugh, whether you're a casual moviegoer or a cinema nerd.
For a film that rarely takes itself seriously, who knew where Brolin would fit in as a serious dude yet again? But his intensity makes for a fun contrast when put up against the incessantly goofy Wade Wilson. More so than the first Deadpool, the sequel uses humor to offset tragedy, violence, and the dark surroundings; as a co-worker recently told me, the entire thing is "comic relief," or, as I snarked back, "comic book relief." The biggest relief is that it's still funny (Ryan Reynolds' writing credit may have played a part, and his ridiculously over-the-top jab at Green Lantern is a thing of a beauty), and Cable fits in snugly as another awkward fighter in a land of misfits. It's his seriousness that compels. Plus, it's why we had a plot at all — and yes, Deadpool also points this out (Is there anything he doesn't make fun of in this film?).
Looking across the majority of Brolin's roles, it's a sense of earnestness that glues everything together: his serious care, his intensity, his willingness to do what he's set out to do. Pun intended, the True Grit star has always had some serious grit, and it's gotten him far in Hollywood.
He may have had his outlier moments — anyone remember him playing George W. Bush in Oliver Stone's W. (pronounced "dubbya" or else you're not doing it right)? There's also Inherent Vice, the Paul Thomas Anderson '70s stoner caper than we didn't deserve (or even need) but got anyway. It was disjointed cinema at its finest, a pure haze-dream of Brolin's weed-filled adventures as a private investigator. However you feel about it and wherever it fits in his catalogue, it's an ambitious endeavor from the actor that flaunts his diversity in role choices.
About the only big Brolin role I haven't talked about is Sicario, and his reprisal of Matt Graver comes this summer — the actor's third big role already this year (remember, Thanos returns next year, as does Cable later on in the recently announced Marvel film X-Force). No one could've imagined the guy who first made his mark as a teenager in The Goonies would end up where he is now. Still, Sean Astin had Lord of the Rings and Corey Feldman had…well, we're not going to talk about that.
If there was anyone more destined for continual greatness, though, it was Brolin. He's not Tom Cruise, nor is he Liam Neeson, but, like the two action stars, he's carved his own niche — and with that, an adaptable edge. It's going to be interesting to watch where he takes his stone-faced ruggedness next, and luckily for us, we don't have to wait long.


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Vintage Florida Souvenir Handkerchief with Flamingos and Palm Trees
The Pink Rose Cottage
A fun vintage souvenir of Florida handkerchief! The colors are bright and beautiful; teal, yellow, and red. The design features a map of Florida, palm trees, flamingos, swordfish, and more! So fantastic!
This vintage hanky is unused. Hand rolled edges. Measures about 13 1/4 inches square. Excellent condition.


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A completely unique position overlooking the pistes, lifts and nursery slopes and just 100m from the shops, bars and restaurants. Ski hire is provided by Loup Sport, just a three minute walk from the chalet.
This chalet is built around an atmospheric cobbled courtyard at a giddying altitude of 2000m, and surrounded on two sides by piste. Imagine stone walls, slate roofs, vaulted ceilings, solid timber floors, hi-tec entertainment, snappy chic en-suite bathrooms, hot tubs, saunas... and you've got Chalet Le Manoir. Chalet Manoir sleeps 12 and offers the ultimate in ski-in ski-out convenience.
This is the perfect choice for family ski holidays - as one of our dedicated family chalets, infants and children are welcome in this chalet all season long. With a nursery slope under your nose, our famed nanny service to look after the kids and spa treatments for a little spoilt indulgence, for the first time the discerning skier seeking supreme comfort can enjoy everything that Alpe d'Huez has to offer.
As one of our dedicated family chalets we accept room by room bookings in Chalet Manoir all season, and families with children or infants are welcome on all dates.
Chalet Le Manoir sleeps 12 guests with rooms spread across three floors. Each of the 6 suite bedrooms has a balcony, some of which actually spill straight onto the piste.
* Pets may be allowed on request.
Le Village, Chalet Le Manoir (Sleeps 12) - 6 Bedrooms
(Ground floor) - Twin with balcony, en suite bath, hand basin and WC.
(First floor) - Twin with balcony, en suite shower, hand basin and WC. Space for a cot or a temporary extra bed.
(Second floor) - Double with balcony, en suite shower, hand basin and WC. Limited space for a cot.
(Second floor) - Twin with balcony, en suite shower, hand basin and WC.
(Second floor) - Twin with balcony, en suite bath, hand basin and WC.
(Second floor) - Twin with balcony, en suite bath, hand basin and WC. Limited space for a cot.
Our Executive Chef is passionate about food and hugely sensitive to the appetite of a hungry skier whilst considering a balanced diet. The new and refined menus are heavy enough to reward mountain exertion yet light and simple enough to leave you grinning not groaning.
All our catered ski holidays include;
|Sun 13 Dec 202013/12/20
|Sun 20 Dec 202020/12/20
|Sun 27 Dec 202027/12/20
|Sun 03 Jan 202103/01/21
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|Sun 17 Jan 202117/01/21
|Sun 24 Jan 202124/01/21
|Sun 31 Jan 202131/01/21
|Sun 07 Feb 202107/02/21
|Sun 14 Feb 202114/02/21
|Sun 21 Feb 202121/02/21
|Sun 28 Feb 202128/02/21
|Sun 07 Mar 202107/03/21
|Sun 14 Mar 202114/03/21
|Sun 21 Mar 202121/03/21
|Sun 28 Mar 202128/03/21
|Sun 04 Apr 202104/04/21
|Sun 11 Apr 202111/04/21
|Sun 18 Apr 202118/04/21
•Glacier Skiing •Awesome Après Ski •300 days of sunshine
Buckets of off piste and an incredible terrain park make this a freeriding and freestyling paradise - combine this with 250km of pisted runs and you've got something for everyone. The town offers a colourful variety of après ski from ice caves to nightclubs and activities for all ages that will put the cherry on top of any ski holiday.
Great for •Nightlife •Off Piste •Terrain Parks •Groups •Families
Snow Report: Top 0cm, Bottom 0cm
Snow Forecast: 0cm expected this week
Snow History: December average depth 82cm
Approx. airport transfer times depend on conditions:
|Grenoble (GNB)
|158km 1h50m
|France, Alps.
|First opened:
Alpe d'Huez lift pass price last reported as €225 (adult 6 day). Ask for a quote when booking Le Village, Chalet Le Manoir.
Night skiing: Yes
Alpe d'Huez has NSEW facing slopes.
Usually open for skiing December – April.
|Town altitude:
|Top of slopes:
|Bottom of piste:
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|Total length of trails:
|Longest piste:
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Paxil Injuries – Fetal Heart DefectsFDA Warns Pregnant Women of Paxil Injuries Like Fetal Heart Defects
Fetal heart defects are congenital conditions that vary from simple defects such as pulmonary stenosis to life-threatening defects like hypoplastic left heart syndrome. Treatment for fetal heart defects typically involves one or more surgeries that can leave the parents of the infant with numerous and costly medical bills and can lead to future heart and medical problems for the child upon reaching adulthood. Many of the more severe fetal heart defects enable blood from one side of the heart to improperly flow to the other side of the heart, creating an imbalanced pressure on the other side of the heart that could ultimately lead to poor blood oxygenation or even heart failure.
Paxil Injuries
Paxil Injuries are the result of Paxil consumption during pregnancy. Recent findings have linked fetal heart defects to the things a pregnant woman consumes during gestation. Several fetal heart defects have been linked to use of the antidepressant drug Paxil during pregnancy. Currently, law suits are being filed against the pharmaceutical company GlaxoSmithKline for Paxil related fetal heart defects. Fetal heart defects like atrial septal defect, Tetralogy of Fallot, VSD heart defect, and even Persistent Pulmonary Hypertension of the Newborn (PPHN). Mothers who took Paxil during pregnancy whose children developed fetal heart defects should seek an attorney to discuss a potential law suit for Paxil-related fetal heart defects.
Pulmonary Stenosis
Pulmonary Stenosis is a congenital heart defect characterized by a heart valve that is too thick or has fused shut, slowing or preventing the flow of blood from the heart through the pulmonary artery into the lungs. This constriction on blood flow causes the affected ventricle to pump even harder in order to supply the lungs with enough blood for oxygenation. Mild Pulmonary Stenosis may go unnoticed a child's entire life. However, more severe cases of Pulmonary Stenosis require the insertion of a balloon catheter which is used to temporarily open the obstruction and relieve unbalanced pressure.
Other treatment for Pulmonary Stenosis includes pulmonary valve replacement, a surgery with a high success rate in recent years. These surgeries introduce other risks such as endocarditis (infection in the blood stream) and precautions in the form of antibiotic treatments must be taken when the child undergoes dental procedures and other minor operations. Prevention methods of Pulmonary Stenosis are unknown. However, a link between mothers who take the drug Paxil during pregnancy and Pulmonary Stenosis has arisen recently. Mothers who used Paxil while carrying a child who was later born with Pulmonary Stenosis should contact a lawyer about a possible Paxil lawsuit.
Atrial Septal Defect
Atrial Septal Defect (ASD) has been linked to Paxil use during pregnancy. Atrial Septal Defect is an opening in the wall that normally separates the chambers of the upper heart (known as the atria). This congenital defect causes blood to flow from the left to right atria (chamber), resulting in excess pressure on the lungs and right atria. This opening is sometimes called a "shunt," and large shunts tend to cause the greatest threat to the patient. Atrial Septal Defect increases the risk of other complications such as stroke, pulmonary hypertension, adult atrial fibrillation, and heart failure.
Smaller Atrial Septal Defects are not always detected at birth, and their symptoms can manifest later in the child's life in the form of strong palpitations (uncomfortable sensation of feeling one's heart beating), breathing difficulty, and chronic respiratory infections. While the smallest Atrial Septal Defects may never require treatment, larger shunts with more severe symptoms require a procedure in which an "ASD closure device" is inserted through an incision in the groin and up a blood vessel into the heart, where it is placed as a plug in the defective atrial wall. However, this procedure is not possible for all patients.
Large Atrial Septal Defects have long term dangers and complications. Arrhythmia, stroke, and other disabling symptoms can become onset early. Contact an attorney if you took Paxil during pregnancy and have concerns about your child's Atrial Septal Defects.
Paxil Injuries Lawsuit
The Stenger Law Firm, LLC is currently filing Paxil Injuries Lawsuits on behalf of families whose children currently suffer or have suffered from any of the above mentioned injuries or death due to Paxil. Our firm can provide a free case evaluation to potentially file a Paxil Injuries Lawsuit. Call The Stenger Law Firm, LLC at our toll free number today: (888) 665-0077.
Please provide as much information as possible about your case. If you do not provide adequate case information, including injuries or damages sustained it may take us longer to process your inquiry.
There is no charge for this Paxil evaluation.


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This could be your 90 seconds of fame! NAI is forming a partnership with the American Society of Microbiology's MicrobeWorld radio program, http://www.microbeworld.org, and we're looking for NAI scientists to be subjects of these short segments. They are broadcast on numerous radio stations across the country in the style of NPR's "Earth and Sky" series, and are also are available as podcasts (downloads are in the hundreds of thousands per year). If you're interested, please contact NAI's E/PO Coordinator, Daniella Scalice, email@example.com.
Please follow Astrobiology on Twitter.
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