text:
Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome
- First Online:
- Received:
- Accepted:
- Citations
- 1.3k Downloads
Somatostatin (SS) and dopamine (DA) receptors are widely expressed in neuroendocrine tumours that cause Cushing's Syndrome (CS). Increasing knowledge of specific subtype expression within these tumours and the ability to target these receptor subtypes with high-affinity compounds, has driven the search for new SS- or DA-based medical therapies for the various forms of CS. In Cushing's disease, corticotroph adenomas mainly express dopamine receptor subtype 2 (D2) and somatostatin receptor subtype 5 (sst5), whereas sst2 is expressed at lower levels. Activation of these receptors can inhibit ACTH-release in primary cultured corticotroph adenomas and compounds that target either sst5 (pasireotide, or SOM230) or D2 (cabergoline) have shown significant efficacy in subsets of patients in recent clinical studies. Combination therapy, either by administration of both types of compounds separately or by treatment with novel somatostatin–dopamine chimeric molecules (e.g. BIM-23A760), appears to be a promising approach in this respect. In selected cases of Ectopic ACTH-producing Syndrome (EAS), the sst2-preferring compound octreotide is able to reduce cortisol levels effectively. A recent study showed that D2 receptors are also significantly expressed in the majority of EAS and that cabergoline may decrease cortisol levels in subsets of these patients. In both normal adrenal tissue as well as in adrenal adenomas and carcinomas that cause CS, sst and DA receptor expression has been demonstrated. Although selected cases of adrenal CS may benefit from sst or DA-targeted treatment, its total contribution to the treatment of these patients is likely to be low as surgery is effective in most cases.
KeywordsCorticotroph adenoma Cushing's disease ACTH Cortisol Pituitary Adrenal
1 Introduction
Cushing's syndrome (CS) is a severe endocrine condition, in which chronic systemic hypercortisolism leads to a variety of signs and symptoms such as centripetal obesity, peripheral muscle wasting, hypertension, diabetes mellitus, osteoporosis and psychiatric disturbances [1]. In untreated cases, morbidity and mortality rates are significantly elevated compared to those in normal subjects [2]. Around 70% of endogenous cases of CS are due to a pituitary ACTH-producing basophilic adenoma (Cushing's disease, CD), around 15% are due to an adrenal cortisol-producing benign or malignant tumour and the remaining cases are generally due to ectopic ACTH-secretion from a neuro-endocrine tumour elsewhere in the body [3]. First-line treatment of Cushing's syndrome, regardless of its origin, is usually surgery with the attempt to radically remove the ACTH- or cortisol-producing tumour.
However, not all cases of CS are well managed by surgery alone. For patients with CD it is known that long-term remission rates after transsphenoidal adenomectomy decrease to 50–80% with longer follow-up time [4]. A second transsphenoidal surgery in patients with a recurrence of CD is known to have significantly lower success rates than the primary surgery [5, 6]. Other treatment options for patients with persistent or recurrent CD include conventional radiotherapy or gamma knife surgery. Both are effective at reducing ACTH hypersecretion in the majority of patients, but have a slow onset of action, with an average time until remission of 9–24 months [7]. In addition, radiotherapy is accompanied by a significant risk of inducing secondary pituitary dysfunction, cranial nerve damage or secondary brain tumours [7, 8, 9]. As a definitive cure, patients with CD can undergo bilateral adrenalectomy, but this does have important implications in terms of lifelong dependence on adrenal hormone replacement therapy and risk of future Addison crises, while there is risk of the development of Nelson's syndrome.
Similarly, in some patients with the ectopic ACTH-producing syndrome (EAS), the primary neuro-endocrine tumour cannot be localized despite extensive radiological and nuclear imaging, whereas in other EAS patients, tumour resection can be irradical [10, 11]. Both types of EAS patients will benefit from bilateral adrenalectomy but with the same disadvantages as described above for CD. Also, some patients with CS due to a malignant adrenal tumour have advanced disease at the time of presentation and in these cases complete removal of the cortisol-producing adrenal tumour will not be possible.
For the above reasons there is a clear rationale behind the search for an effective medical therapy for all causes of CS. A great number of drugs that act at the level of the pituitary, the adrenals or the glucocorticoid receptor itself, have been evaluated in the past decades with generally modest and variable results [12]. Most compounds either show limited efficacy or are associated with serious toxicity and adverse events. For instance, the steroidogenic inhibitor ketoconazole has been shown to effectively decrease cortisol levels in about 50% of patients [13], but often causes considerable gastro-intestinal side effects and carries a serious risk of medication-induced hepatitis, which limits its use as a long-term monotherapy in CD patients [14]. Similarly, metyrapone can be effective in reducing cortisol levels in patients with CS, but can cause hypertension and hypokalemia. Blockade of the glucocorticoid receptor with mifepristone (RU-486) can improve symptoms of CS, but the absence of a suitable biochemical parameter to monitor treatment efficacy makes dose titration difficult and this can result in severe adrenal insufficiency in some patients.
In recent years, however, research into medical therapies for CS has also focussed on the use of both somatostatin (SS) and dopamine (DA) agonists. These are regarded as neuromodulatory agents that can inhibit ACTH-hypersecretion at the level of the pituitary. Important new insights in SS and DA receptor physiology, combined with the recent availability of more selective SS and DA-agonists, have emerged and are the topic of the current review.
2 Somatostatin and dopamine receptors
2.1 Somatostatin and dopamine receptors
Somatostatin (SS) is a 14 amino acid-long cyclic peptide that is widely distributed throughout the human body. Its functions vary from increasing gastro-intestinal motility to neurotransmission within the central nervous system, mediating immune responses and inhibition of hormone release [15, 16]. SS exerts its functions by binding to all five somatostatin receptor subtypes (sst1–5), which belong to the family of G-protein coupled receptors (GPCRs) [17]. Dopamine (DA) is a catecholamine with an equally wide range of functions including neurotransmission, control of vascular tone, renal function and hormone secretion [18]. Also for DA receptors, five subtypes are known (D1–5) that belong to the GPCR family, which are further classified into D1-like (D1, D5) and D2-like (D2, D3, D4). D1-like receptors generally mediate stimulatory functions, whereas most D2-like receptors are associated with inhibition. Upon binding of SS or DA to their respective receptors expressed on the plasma membrane of target cells, multiple cellular effector systems can be activated, which include inhibition of Ca2+-influx, inhibition of adenylyl cyclase activity or stimulation of phosphotyrosine phosphatases [17, 18]. Both sst and DA receptors are abundantly expressed in the human neuro-endocrine system and in the tumours that are derived from it [19, 20]. Most of the in vivo functions of SS and DA (D2-like) receptors are inhibitory and, therefore, targeting these receptors with their natural agonists or synthetically derived analogs has provided opportunities for medical therapy of various neuro-endocrine disorders.
2.2 SS analogs and DA agonists
Soon after its discovery in 1972, somatostatin was known to be a major regulator of GH release from the pituitary and was therefore of interest for the potential treatment of acromegaly [21]. One of the characteristics of native SS, however, is its very short half-life in the circulation, which is approximately 3 min [22]. For that reason, the production of synthetic SS analogs with a significantly longer half-life, was a major step forward in the treatment of this disorder. The first stable SS-analog produced was Octreotide (SMS 201–995), which has a half life of approximately 120 min after subcutaneous administration and was shown to reduce GH and IGF-1 levels in approximately two thirds of acromegalic patients [23, 24].
Binding affinities (IC50) of SS-analogs and DA-agonists mentioned in this review
Somatostatin (SS-14)
Pasireotide (SOM230)
Dopamine agonists
Dopastatin chimeras
Dopamine agonists are an important class of drugs with a broad range of therapeutic indications, including neurological disorders (Parkinson's disease), cardiovascular dysfunction and neuro-endocrine disorders. They can be classified into either non-ergot (e.g. quinagolide) or ergot-derived (e.g. bromocriptine, cabergoline, pergolide). Bromocriptine has been known for many years to effectively inhibit prolactin (PRL) release in the majority of prolactinomas [27]. With increasing knowledge on DA receptors, it also became evident that selectivity of dopaminergic compounds for DA receptor subtypes was of great importance for their overall efficacy and safety profile. In comparison with bromocriptine, cabergoline has a longer plasma half-life, binds with a higher affinity to the D2 receptor, is better tolerated by patients and can induce normalization in patients with hyperprolactinemia that are proven to be resistant to bromocriptine therapy [28]. The fulfilment of these criteria makes cabergoline a promising drug for the treatment of a number of neuro-endocrine disorders in which D2 expression plays an imminent role.
2.3 Chimeric somatostatin–dopamine compounds
The fact that many neuro-endocrine cells co-express both sst and DA receptors, has driven the hypothesis that these receptors may work synergistically. In 2000, Rocheville et al. [29] published an important paper on the functional heterodimerization of sst5 and D2 receptors in stably transfected CHO-K1 cells, which resulted in overall enhanced biological potency. Based on these observations, new chimeric molecules have been synthesized that contain structural elements of both SS and DA compounds and therefore bind with high affinity to both sst and DA receptor subtypes. By binding to the two different receptors, these hybrid molecules may draw the receptors together in a spatial manner. This can lead to enhanced potency of the chimeric compound, compared to activation by two separate DA or SS analogs [30].
3 Cushing's disease (CD)
3.1 Somatostatin analogs in Cushing's disease
3.1.1 Sst expression in normal corticotroph cells
Whereas the role of hypothalamic SS as a principal regulator of pituitary GH-release has been firmly established [31], the effect of SS on ACTH release by the anterior pituitary gland has been less clear. Rat pituitary corticotrophs are known to express multiple sst, including sst2 and sst5 [32, 33, 34], but treatment of cultured rat corticotrophs with SS-14 does not result in inhibition of ACTH-release [35, 36]. On the other hand, when rat pituitary cells are cultured in glucocorticoid-free media, SS-14 is able to decrease ACTH-release [37]. In agreement with these findings, infusion of SS-14 or Octreotide does not alter ACTH-release in normal subjects [38, 39, 40, 41], whereas both of these compounds can acutely decrease plasma ACTH levels in conditions of hypocortisolemia such as untreated Addison disease [42]. These observations suggest that the presence of glucocorticoids reduces the inhibitory effects of native somatostatin and traditional SS analogs on ACTH release.
3.1.2 In vitro studies with SS-analogs in corticotroph cell lines and adenomas
The only available ACTH producing cell line from corticotroph origin is the murine AtT20 cell line. A number of studies have indicated that in these cells sst2 and sst5 are principally involved in regulation of ACTH release and that selective agonists that target these subtypes effectively inhibit ACTH secretion [43, 44, 45, 46, 47]. More recently it was found that especially sst5 played a crucial role in regulating ACTH release in these cells and that sst5-targeting agonists were more effective than sst2-agonists in inhibiting ACTH release [48]. Interestingly, pre-incubation with dexamethasone decreased the expression of sst2 in these cells, but not of sst5, and in line with these findings Octreotide, but not Pasireotide, lost most of its ACTH inhibiting potential after glucocorticoid pre-treatment [48]. These data are in line with the original observations that glucocorticoids downregulate the total number of SS binding sites in cultured pituitary cells [49]. Evidence for abrogation of sst2-mediated effects by glucocorticoids has also been provided by Stalla et al. [50]. They found that Octreotide decreased ACTH levels in corticotroph adenomas in vitro, but not in CD patients in vivo. However, when these corticotroph adenoma cells in vitro were pre-treated with the glucocorticoid hydrocortisone, the ACTH inhibiting effects of Octreotide were abolished in one of the cultures. Given the generalized state of hypercortisolism in CD patients and the relative resistance of sst5 to glucocorticoid-induced down-regulation compared to sst2, SS-analogs with high sst5 affinity are of great interest in the development of new medical therapies for CD.
In 2005 and 2006, two studies were published that independently investigated sst expression in human corticotroph adenoma tissues, obtained at the time of transsphenoidal surgery. In the first study, Hofland et al. [51] showed by quantitative PCR that sst5 was highly expressed in 6/6 adenomas, whereas sst1,2,3,4 were expressed at much lower levels. In concordance with this, functional studies in five additional adenomas demonstrated overall superior ACTH inhibition by Pasireotide (10 nM) compared to Octreotide (10 nM) after 72 h.
In the second study, Batista et al. reported on a series of 13 corticotroph adenomas derived from both adult (n = 7) and pediatric (n = 6) CD patients [52]. In this study, quantitative PCR demonstrated the expression of subtypes 1, 2, 4 and 5 in these adenomas, while at immunohistochemistry expression of all subtypes was found. Both of these methods showed the highest expression of the sst5 subtype. Six of the adenomas were cultured in vitro and treated with Pasireotide. In 6/6 adenomas Pasireotide significantly decreased cellular proliferation rates (range 10–70%) as measured by uptake of fluorescent vital stain and in 5/6 a significant decrease in ACTH production was observed (range 23–56%) at doses of 1 to 10 nM after 48–96 h. Furthermore, a dissociation was seen in some of the adenomas between the anti-secretory and anti-proliferative effects of Pasireotide, similarly to what has been described previously for GH-producing adenomas in response to SS-analog treatment [53].
3.1.3 Clinical studies with SS-analogs in CD
Early studies showed that in patients with CD, Octreotide is not able to effectively reduce ACTH secretion and hence cortisol levels [50, 54, 55]. In contrast, several smaller studies and case reports found that patients with Nelson syndrome, i.e. an expanding ACTH-producing pituitary adenoma after bilateral adrenalectomy, did respond to Octreotide with reductions in ACTH [54, 56, 57, 58]. This difference is readily explained by the differences in average circulating cortisol levels in both disease states and the effects of glucocorticoid-induced down-regulation of sst2 receptors, as mentioned earlier [59].
Since then, few clinical studies have been reported that examined SS-analog therapy in CD, until some important new insights developed. It was foremost the discovery that sst5 was highly expressed in the majority of human corticotroph adenomas, which made the novel multi-ligand SS-analog Pasireotide an interesting compound to evaluate in patients with CD, due to its subnanomolar sst5-affinity. A phase II multi-center clinical study was performed in 21 patients with de novo or recurrent CD [60]. Patients were treated with SOM230 600 μg twice daily over a 15-day period. Primary endpoint was normalization of 24-h urinary free cortisol (UFC) levels. Preliminary results of this study showed that out of 21 included patients, four (19%) obtained complete UFC normalization and another five (24%) had a significant decrease in UFC. Overall, Pasireotide was well tolerated in the 2 × 600 μg dose, except for some mild gastro-intestinal side effects such as nausea, abdominal pain and loose stools or diarrhoea. A major side effect of Pasireotide, however, which was already known from previous studies in acromegalic patients, was an overall increase in blood glucose levels. Worsening of glycaemic control was observed in almost all participating patients in this study, but was often a transient effect. In some cases, however, the use of subcutaneous insulin administration was required and in one case the study drug was withdrawn.
Based on the current data, Pasireotide appears to be a potent cortisol-lowering drug in almost half of CD patients and is well tolerated. A major advantage of Pasireotide compared to Octreotide is its longer plasma half-life in the circulation, approximately 12 versus 2 h [61]. Pasireotide treatment does carry the risk of significant hyperglycemia, however, in a substantial number of patients. A new challenge would be to identify subgroups of CD patients who are likely to benefit from sst5-mediated (Pasireotide) therapy and at the same time do not suffer excessively from increases in blood glucose levels.
Another potential problem might be any direct effects of Pasireotide therapy on GH and IGF-1evels in CD patients. It is well known that Pasireotide, via sst5 receptor activation, directly decreases GH release and hence IGF-1 levels in patients with acromegaly. Whether this also occurs in normal subjects without GH/IGF-1 axis overactivation, has not been reported. Normal somatotrophs, however, express sst5 in significant numbers and in normal rats, primates and dogs Pasireotide has been shown to significantly decrease GH and IGF-1 levels [62]. In patients with CD, sustained hypercortisolism by itself causes a state of relative growth-hormone deficiency and therefore these patients may be at greater risk to become GH-deficient. Current and future clinical studies with Pasireotide in CD patients should therefore include careful investigation of the effects on the GH/IGF-1 axis.
3.2 Dopamine agonists in Cushing's disease
3.2.1 DA receptor expression in normal corticotrophs
In humans, no firm data exist whether or not ACTH release is directly regulated by DA receptors in normal corticotroph cells. In rats it is known that the intermediate lobe in the pituitary is under tonic inhibitory control from dopaminergic neurons from the hypothalamus [63, 64, 65]. The predominant cell type in the intermediate lobe is the melanotroph, which produces pro-opiomelanocortin (POMC). In the intermediate lobe POMC is processed into α-melanocyte stimulating hormone (α-MSH) and corticotropin-like intermediate lobe peptide (CLIP). This is different from the POMC-processing in anterior corticotroph cells, which mainly results in ACTH. The tonic inhibition by hypothalamic dopamine is thought to be exerted through D2 receptors. This is demonstrated by the fact that D2-deficient mice develop intermediate lobe hypertrophy with increased POMC expression, elevated ACTH and corticosterone levels, resulting in adrenal gland hypertrophy [66]. In humans, the intermediate lobe in the pituitary is a rudimentary structure, but is still thought to contain important biological functions. Human corticotroph adenomas arising from the intermediate lobe may have different characteristics than those arising from the anterior lobe, although much controversy exists around this subject [67, 68].
3.2.2 In vitro studies with DA agonists in corticotroph cell lines and adenomas
Two reports have been published on the use of dopamine agonists in the murine corticotroph cell line AtT20, but these have produced conflicting results. Farrell et al. found that treatment with the dopamine agonist bromocriptine did not reduce POMC mRNA expression in these cells, whereas Yin et al. did show that bromocriptine inhibited proliferation of these cells with induction of apoptosis [69, 70]. The observed difference may be due to the fact that in the second study treatment with bromocriptine was significantly longer than in the first study (72 vs. 24 h, respectively).
In 2004, Pivonello et al. [71] investigated DA receptor expression in a series of 20 human corticotroph adenomas. They showed that the majority (80%) of these adenomas express the D2 receptor as demonstrated by immunohistochemistry (IHC), receptor-ligand binding and RT-PCR. Of these D2-positive adenomas, approximately 40% expressed the D2 long isoform, 20% D2 short and 40% expressed both isoforms. D4 was expressed in 20% of cases, whereas D1, D3 and D5 expression was not observed. Functional studies in vitro correlated very well with the D2 expression data: adenomas high in D2 expression responded well to either bromocriptine or cabergoline therapy with inhibition of ACTH release by 43% to 60%, whereas D2-negative adenomas failed to respond. The D2- expression data reported in this study are similar to those described by an earlier paper, where 11/16 (69%) of corticotroph adenomas, both functional and silent, expressed D2 receptors as demonstrated by in situ hybridisation and immunohistochemistry [72].
3.2.3 Clinical studies with DA agonists in CD
The DA agonist bromocriptine has been widely evaluated for its potential use in human corticotroph adenomas. Overall, results of these studies have been variable. Although initial reductions in ACTH levels are evident in almost half of CD patients in response to bromocriptine administration, these reductions are often minor and sustained responses to bromocriptine therapy occur only in a small percentage of patients [73]. Some studies have suggested that corticotroph adenomas arising from the intermediate lobe may be more likely to respond to bromocriptine [74].
Overview studies on cabergoline use in ACTH-producing pituitary adenomas (CD and Nelson)
First author (ref)
No. of patients
Dose (mg/wk)
Duration (months)
Shrinkage observed
Pivonello [75]
Normalization ACTH
Petrossians [76]
Silent CD
Restored cranial nerve function
Miyoshi [77]
Decreased ACTH
Casulari [78]
Normalization ACTH
Pivonello [71]
40% full + 20% partial UFC response
Shraga-Slutzky [79]
Decreased ACTH (−90%)
Illouz [80]
Normalization UFC in 2/3 patients
Garcia [81]
Decreased ACTH
Godbout [82]
38% full + 38% partial UFC response
Pivonello [83]
Sustained remission in 10/15 patients after 12–24 months
One important issue that recently has dominated the field of medical therapy with DA-agonists has been the possible association between valvular heart disease and long-term therapy with the ergot-derived dopamine agonists (EDDA) pergolide and cabergoline. Two important papers were published in early 2007, which reported significantly increased risks (RR, 4.6–7.3) of valvular regurgitation in patients with idiopathic Parkinson's disease that had received chronic treatment with either one of these drugs [84, 85]. Other studies have recently confirmed these data [86]. The pathogenetic mechanism behind this deleterious side effect is thought to be the binding of EDDA to 5-HT2B receptors expressed in the endocardial tissue of heart valves [85].
These findings have led to a number of important actions, including the withdrawal of pergolide from the US market. The impact of these studies on the (future) use of cabergoline in patients with CD cannot be fully determined yet, as one important issue needs to be emphasized. The maximum dose of cabergoline prescribed in CD is around 0.65 mg per day (4.5 mg/week), whereas the patients with Parkinson's disease in the study by Zanettini et al. [85] received an average daily dose of 3.6 mg/day. In the other study by Schade et al. [84], an important risk difference was found between patients taking >3 mg cabergoline daily for more than 6 months (RR 50.3, 95% CI 6.6–381.4) compared to those who took less than 3 mg daily (RR 2.6; 95% CI 0.5–12.8). Therefore, these observations in Parkinson's disease patients can not be directly extrapolated towards lower-dose cabergoline therapy in CD. Monitoring of cardiac function in CD patients on long-term cabergoline therapy does seem to be a prerequisite, however.
3.2.4 Combined treatment with SS and DA agonists in CD
Due to the reported presence of both sst and DA receptors in human corticotroph adenomas and the fact that both receptor types can inhibit ACTH production in vitro, the concept of a combination therapy with both SS-analogs and DA-agonists in CD seems to be a feasible approach [87]. These studies could be performed by co-treatment with individual SS-analogs and DA-agonists (pasireotide + cabergoline) or perhaps, in the near future, by administration of SS-DA-chimeric compounds such as BIM-23A760, which displays high affinity for sst2, D2 and to a lesser extent sst5 (see Table 1). If functional heterodimerization of these receptor subtypes occurs in vivo, as has already been shown to occur in vitro by different groups, this type of treatment could result in greatly enhanced efficacy of these compounds [29]. Also, as corticotroph adenomas can differ considerably in the total number of sst and D2 receptors they express [51, 52, 71], targeting of multiple receptors could increase the overall response rate in this group as a whole, compared to the use of individual SS or DA agonists. This has already been shown for GH-producing adenomas, where BIM-23A760 had overall superior efficacy compared to individual sst2, sst5 or D2-targeting agonists in terms of in vitro GH inhibition [88, 89]. As it is known that also in CD only subsets of patients have responded to either cabergoline or pasireotide monotherapy in vivo, it may well be that similar phenomena occur in corticotroph adenomas and that combination therapy can increase overall response rates. Until now, no studies have been published that have investigated this hypothesis.
Theoretically, co-treatment with sst and DA agonists may have other advantages as well. As stated before, the inefficacy of sst2-preferring compounds in CD, is probably due to down-regulation of sst2-expression by high levels of circulating glucocorticoids [48, 50, 51]. Inversely, if combined treatment with these analogs is effective and thus lowers cortisol levels in these patients, this could result in a return of sst2 expression. The latter would result in enhanced efficacy of SS-analogs with sst2-affinity and hence strongly increase pharmacotherapeutical options in these patients [59, 90].
4 Ectopic ACTH-producing syndrome (EAS)
4.1 Somatostatin analogs
For some decades it has been known that neuro-endocrine tumours that cause ectopic ACTH-producing syndrome (EAS), such as bronchial carcinoids or small cell lung cancer (SCLC), often express functional SS receptors. A number of smaller studies and case reports have been published on the use of Octreotide in patients with EAS. Interestingly, Octreotide was efficacious in lowering cortisol levels in a significant number of these patients, as opposed to the studies performed in patients with CD [91, 92, 93, 94]. This discrepancy is further confirmed by the fact that many patients with EAS have positive lesions on 111In-pentereotide scan (Octreoscan), whereas most patients with CD do not [95]. The observation that many of the EAS producing neuro-endocrine tumours have functional sst2 receptors, despite the chronic hypercortisolism they are exposed to, could be explained by aberrant glucocorticoid receptor signalling in these tumour cells. This has been investigated extensively by a number of research groups over the past twenty years. It was found that many of the cell lines, derived from EAS producing small-cell lung carcinomas, carry gross mutations in the genetic sequence of the glucocorticoid receptor (GR) [96, 97]. These can be located either in the DNA-binding or the ligand-binding domain, but can also involve a number of transcription factors. The loss of function of the GR has important impact on POMC production in these cells. Any form of negative feedback is generally lost in these cells, leading to excessive and uninhibited production of POMC and ultimately, the full clinical spectrum of Cushing's Syndrome. Another result of aberrant GR functioning, may be that glucocorticoid-induced down-regulation of somatostatin receptor subtype 2 (sst2) does not occur in these tumours, as opposed to pituitary-derived corticotroph adenomas. This could well explain the relatively high degree of positive Octreoscans and reported efficacy of Octreotide in this group of neuro-endocrine tumours [98, 99].
One main concern with the use of SS analogs in EAS, however, appears to be the long-term control of hypercortisolism. Although initial responses to Octreotide are frequent, these are not always sustained and treatment escapes are commonly encountered, due to a number of possible mechanisms of tachyphylaxis [100].
4.2 Dopamine agonists
Farrell et al. [69] showed in 1992 that the dopamine agonist bromocriptine could effectively inhibit POMC mRNA and ACTH precursor secretion in a small cell lung cancer cell line (CORL103), that is known to cause EAS. After these initial observations, to our knowledge no (clinical) studies have been performed that investigated the potential use of DA compounds in EAS, until a recent study by Pivonello et al. [101]. In this study, six patients with EAS-causing carcinoid tumours (four lung, one thymic, one pancreatic) underwent surgery. Five out of these 6 resected EAS tumours expressed D2, as determined by IHC. Three patients had persistent EAS after surgery and were treated with cabergoline at 3.5 mg/week for 6 months. All three patients had measurable D2 mRNA and two out of three had D4 mRNA expression on RT-PCR. Two patients had complete normalization of UFC after 3 months of cabergoline treatment, although one of them had a treatment escape afterwards. Of note, the long-term responder had the strongest overall D2 expression, including the D2 short isoform, and was also D4-receptor positive. In other pituitary tumours this expression profile has been associated with a good response to cabergoline therapy [71, 102]. Despite the small size of this study, it is probable that at least a subgroup of EAS patients could benefit from D2-targeted treatment, but obviously these results need to be confirmed in larger series.
4.3 Somatostatin–dopamine chimeras
Another interesting development in EAS tumours is the evaluation of dopamine-somatostatin chimeric molecules. Ferone et al. [30] examined the effects of the chimeras BIM-23A370 and BIM-23A387 in the non-small cell lung cancer cell line CALU-6. It was found that in these cells that natively express both sst2 and D2 receptors at high levels, the chimeric compounds had a stronger direct inhibitory effect on cell proliferation than the SS and DA-selective compounds alone. These data clearly confirm the hypothesis of heterodimerization between these two receptors, as had been suggested before by other groups [29].
A recent case report provides some further clinical evidence for this potential synergism between sst and DA receptors in EAS. In this case, a man with EAS due to a lung carcinoid tumour was treated medically after incomplete surgical removal. Cortisol levels normalized only temporarily with either SS-analog (Lanreotide) or dopamine agonist (Cabergoline) therapy alone. However, when both drugs were given simultaneously, based on co-expression of sst5 and D2 that was demonstrated by RT-PCR on the resected tumour specimen, the patient came into complete and prolonged remission [103].
5 Adrenal Cushing's syndrome
Immunohistochemical and RT-PCR studies have shown that all sst subtypes (1–5) are expressed in the majority of normal adrenal cortices as well as in most cortisol-producing adenomas [104, 105, 106]. Interestingly, immunostaining occurred only in a minority (<30%) of these adenoma cells. One of the studies described a remarkably high expression of sst4 in the adenomas [104], but this was not found in another study [105]. To our knowledge, no studies have been performed so far to evaluate SS-analog therapy in cortisol-producing adenomas and carcinomas in vitro. In terms of clinical studies, octreotide does not appear to be effective in cases of adrenal carcinomas [107].
DA receptors (D1 and D2-like) are abundantly expressed in normal human adrenal cortex, where they are involved in the regulation of aldosterone release, but also in cortisol and androgen production [108, 109]. Their presence has been clearly established in different types of adrenal adenomas and carcinomas, some of which cause CS [110, 111]. D2 and D4 receptor subtypes were found in the cortisol-producing adrenal adenomas and carcinomas by RT-PCR. The adenomas expressed both D2 isoforms (short and long), whereas the carcinomas only expressed the D2-long isoform. Functional studies showed that the D2-agonist cabergoline was able to modulate ACTH- and angiotensin II-stimulated aldosterone release [111].
Taken together, despite the abundant expression of both SS and DA receptors in both the normal and the abnormal human adrenal gland, there are currently no data that would strongly support the use of SS-analog or DA-agonist therapy in patients with adrenal adenomas or carcinomas that cause CS. Given the high degree of surgical cure that can be obtained in most of these patients, the contribution of SS and DA-agonist therapy in this patient group is likely to be low.
6 Summary
In all forms of Cushing's syndrome (pituitary, ectopic and adrenal CS) a subset of patients cannot be cured by surgery alone and therefore requires effective adjuvant treatment. Medical therapy can offer important advantages over other secondary treatments such as radiotherapy and bilateral adrenalectomy, including a relatively rapid onset of action and the fact that integrity of the HPA-axis is maintained. In CD, sst5 and D2 receptors play a crucial in the regulation of ACTH-release from corticotroph adenoma cells both in vitro and in vivo. Agents that selectively target these receptors can significantly reduce urinary cortisol excretion in subsets of patients. Combined treatment with these agents could in theory result in increased overall response rates, but these studies still need to be performed. In selected cases of ectopic ACTH-producing syndrome, D2-agonists are shown to be effective in reducing cortisol production, either alone or in combination with SS-analogs. Tumours that cause adrenal CS do express SS and DA receptors, but there is only limited data on the efficacy of agents that target these receptors neither in vitro nor in vivo. Their overall contribution to the management of these patients is likely to be low.
Open Access
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.


text:
Cranberry White Chocolate Quick Bread Mix in a Jar
Recipe by Tinkerbell
A moist and delicious quick bread mix for gift giving! Nothing says "I love you!" better than a gift from the kitchen. And especially one that fills the house of your recipient with the aroma of sweet, fresh baked bread. The dry ingredients are layered in a quart-sized jar and the jar can be decorated in any number of ways to reflect the occasion. Be sure to attach a recipe card or an embellished tag, to the jar, with the recipe, additional ingredients needed and baking instructions. Prep time includes putting together the gift jar as well as combining the wet ingredients before baking.
Top Review by Becki K.
Thanks for the recipe! I wanted to make a cranberry white chocolate quick bread in a jar, but I didn't have time to tweak and test all of my personal quick bread recipes. I was looking for something that would be successful that I could get working on right away. I made one and and it was pretty tasty. The batter was much stiffer than I had anticipated, but it turned out well nonetheless. (I made 450 of them for a holiday gift basket project!)
Ingredients Nutrition
For Gift
- 1 1⁄2 cups all-purpose flour
- 1 teaspoon baking powder
- 1⁄2 teaspoon salt
- 1 cup sugar
- 1⁄2 teaspoon cinnamon
- 1⁄4 teaspoon nutmeg (I use fresh grated, but ground is fine)
- 1⁄4 teaspoon ground ginger
- 1⁄2 cup dried cranberries
- 1⁄2 cup white chocolate chips
- 1⁄2 cup pecans, chopped
For Making the bread
- 2 eggs
- 1⁄2 cup sour cream
- 1⁄4 cup butter, melted
- 1⁄4 cup powdered sugar
- 1⁄2 tablespoon milk
Directions See How It's Made
- To make the gift jar: Sift together the flour, baking powder and salt and then spoon into a quart-sized jar with a tight-fitting lid. (I use a wide-mouth funnel to easily get the ingredients into the jar.) Tap the jar gently on the counter top to settle the flour.
- Combine the sugar, cinnamon, nutmeg and ginger and pour over the flour in the jar.
- Continue the layers with the dried cranberries, then the white chocolate chips and finally the pecans. Put the lid on the jar and decorate as desired.
- To make bread: Preheat oven to 350°F and lightly grease a 9x 5 loaf pan.
- Pour all the dry ingredient from the jar into a large mixing bowl and stir to combine.
- In a small bowl, use a fork to beat the eggs lightly and then add the sour cream. Continue mixing with the fork until the sour cream is incorporated.
- Add the melted butter to the dry ingredients and then add the egg and sour cream mixture. Stir just until combined.
- Spread into prepared loaf pan and bake in preheated oven for 50 minutes, or until toothpick inserted near center comes out clean.
- Cool 10 minutes in pan and then turn out onto a cooling rack (with a layer of foil or waxed paper under the rack, to keep your counter clean.).
- Stir together powdered sugar and milk until smooth. Drizzle or spread over top of loaf. Serve immediately or cool completely before slicing, to keep the slices looking nice.

subset: commoncrawl


text:
Users Online Now:
Who's On?
Visitors Today:
Pageviews Today:
Threads Today:
Posts Today:
Donate To GLP
Adv. Search
Back to Forum
Back to Thread
Message Subject
I am the AC who wrote that vision I had when I was 15. I tuned 44 today. So it begins. Does anyone have any questions or need any encouragement?
Poster Handle
D D mama
Post Content
Good Stand. Your sister is afraid. I don't know why or of what but she is. There are really only two emotions according to some. Love and Fear. Hate is not the opposite of love, indifference is. So if someone is indifferent to you then they must be in fear because they are not in the resonance of love. Love isn't always warm and fuzzy either.
Love is rational and takes a lot of courage. It isn't some affectionate display that can be faked. It is constant. It is drawing lines when they need to be drawn and it is putting God first which is a daily challenge. None of us are perfect beings in what we perceive perfection to be because we have all been programmed into a way of thinking that is not at all realistic. God is perfect in a way that we can only accept that to be true. The reality is that God created everything and in that creation the seeds of destruction were also planted. We are helping God to perfect. Perfection could have been created alone but then it would be all over and nothing learned. The Creator seeks to know the Creator. Do we not as made in the image and likeness understand that? Then while you are asking for guidance with your dad and sister, look into who you are and ask God to reveal to you which part of God's creation you are so that you may rejoice in that. I and the Father are ONE. This is what Yeshua said.
It is true. Nothing exists outside of God so in order to really appreciate God's creation we must be able to appreciate our role in it. This isn't about falling in love with yourself. This is about accepting that you have not been taught the truth about who you are. Yeshua brought the message to the world and they covered it up with Death. Look deeper and ask for the truth to be revealed. I think you might then see the perfection unfolding in our lives.
Please verify you're human:
Reason for reporting:
Disclaimer / Copyright Info
Privacy Policy
Terms Of Use
with questions or comments about this site.
"Godlike Productions" & "GLP" are registered trademarks of Zero Point Ltd. Godlike™
Website Design Copyright © 1999 - 2017 Godlikeproductions.com
Page generated in 0.007s (3 queries)


text:
|"The Devil His Due!"
|General Information
| Batman
Road to No Man's Land
|Issue Number:
|First Published:
|February 1999
|Previous Issue:
|Batman #561
|Next Issue:
|Batman #563
"The Devil His Due!"Edit
Gothamites were given 48 hours to get out of the city before it was to be dropped from the union. Nicholas Scratch hired an assassin to kill Bruce Wayne, but the sniper missed and killed Mayor Grange instead. With Gotham's deadline passed, bridges leading out of the city began to be destroyed. Many villains, such as Killer Croc and Maxie Zeus find themselves trapped where the construction is happening, but try to control themselves and make the best of it.
"The Devil His Due!"Edit
- Batman
- Dick Grayson
- Mayor Grange (Only appearance; dies)
- Oracle
- Killer Croc
- Maxie Zeus
- Nick Scratch
- Sarah Essen


text:
Your Store:
item(s) totaling $
See if this part fits a specific vehicle.
|This product doesnt fit any of your saved vehicles
|Check Fit for another vehicle
REVIEW SNAPSHOT®by PowerReviews
Reviewed by 1 customer
Best Uses
Comments about Delphi Fuel Pump Strainer:
This said it would fit my 2002 Escort but it doesn't
Do you have questions about this product?
Ask a question, get answers from real customers and in-house experts. For further assistance, please review your support options on our Contact Us page.
Q:Will this work for both tanks or just the after axle tank?
1 answer
A:This Delphi Fuel Strainer - part# FS0057 is vehicle specific. In order to check the exact fit, please provide the year, make, model and engine size of the vehicle. For any further assistance, you may also visit your nearest Advance Auto store or call us directly at 1-877-ADVANCE (238-2623) and one of our representatives there would be more than happy to assist you.


text:
Product Description
The plant and mineral based ingredients in our dishwash tabs provide powerful stain removal, while preventing spots, streaking and build up of limescale in your dishwasher. Now with boosted oxygen for tough stain removal. Our no-mess tablets are individually wrapped in a PVA biodegradable wrapper that dissolves in your machine, so there's no need to touch the tablet. Suitable for all dishwashing machines including dish drawers.
For additional information on this product click here.
For additional information on this product click here.


text:
Your home is always under construction. From quick fixes without nails and screws to maximising your organising space, VELCRO® Brand solutions give you the tools to keep building the home of your dreams.
Show off what you want wherever you want with our adhesive backed solutions.
Nurture your green space, indoor and out, with our Plant Ties and Straps.
Decorate your home without ever having to lift a hammer with our Sew and No Sew solutions.
Clutter, meet your match. Our products keep everything tidy and within easy reach.
The home can be a chaotic place. Reusable Ties and Straps create a safe and secure home.
Quick no nails solutions for securing lightweight to heavyweight items and everything in between.


text:
AUGUSTA, Ga. -- Tiger Woods has been here before. Coming off a hard-fought, tense, knee-knocking victory in a major championship. Being pushed to the limit by a gritty, if not as heralded, competitor. Prevailing, in some ways, despite himself.
Sunday's Masters victory over Chris DiMarco was eerily similar to the 1999 PGA Championship, where Woods looked in control for most of the final round but had a pesky teen named Sergio Garcia making life difficult.
DiMarco, 36, a three-time winner on the PGA Tour, made the process even tougher in the final round at Augusta National, sending the tournament into a sudden-death playoff, where Woods finally prevailed after making birdie on the first playoff hole.
After the victory at Medinah in '99, Woods went on a tear. He won six of the next 10 major championships. He won 17 PGA Tour events in two years. He looked like he'd chase down Jack Nicklaus' record of 18 major titles in no time.
Instead, after winning the 2002 U.S. Open, he didn't win another major until Sunday.
Looks like -- despite some shaky swings on the final two pressure-packed holes in regulation -- the changes Woods has made under the supervision of instructor Hank Haney are paying off. After all, a major victory is a major victory.
"Well, any time you make changes in your game, it's not going to be an immediate success," Woods said. "Did I probably take a step back? Yeah, probably did in '98, too, end of '97, all of '98 and the beginning of '99, almost two years where I didn't really do anything in the game of golf.
"Then again, once those changes kicked in, I had a pretty good run, won 17 times on tour," he said.
We might be headed for that kind of streak again.
Woods has maintained for the better part of a year that the changes he was making to his game were important for his future. It was obvious that he was not comfortable for much of that time, winning just once on the PGA Tour last year.
But toward the end of the season, Woods saw it come around. He won a tournament in Japan and his own Target World Challenge. They were unofficial titles, but they meant something to Woods. They meant the work was paying off.
Then he opened the season with a tie for third at the Mercedes, a victory at the Buick Invitational and later a heart-stopping win over Phil Mickelson at Doral. Although he fell off in recent weeks, the feeling was that Woods was gearing up for Augusta.
And did he ever.
After an indifferent 74 to start the tournament -- this is the first time Woods has won any stroke-play event after shooting over par in the first round -- he roared back with a 66-65 middle of the tournament that included seven straight birdies in the third round. At one point, Woods was 9-under for the third round and bearing down on the Augusta National course record.
Two consecutive bogeys ended those thoughts, but Woods still finished the third round with a three-stroke advantage heading into the final round.
It was a cushion that turned out to be necessary.
The rout that was expected did not materialize. Woods had trouble putting DiMarco away, which might be a testament to DiMarco's resolve more than Woods' deficiencies.
Yes, he needed a miracle chip shot on the 16th hole, but Woods never trailed during the final round and was only tied at the 18th green. Then he took care of business in the playoff, drilling two shots to set up the winning birdie.
Now what?
Talk will soon switch to multiple major championships and the possibility of a Grand Slam. Woods tied for third at Pinehurst in 1999, where the U.S. Open is this year. He won at St. Andrews in 2000, where the British Open is this year. He will be a huge favorite at both places.
But he'll need some time to recuperate first after a mind-numbing Sunday at Augusta.
"This is a thrill, this is why you compete and why you practice all those hours," he said. "You log in all the time to put yourself in that position and see what you've got.''
Woods had plenty. Or was it just enough?
Bob Harig covers golf for the St. Petersburg Times and is a frequent contributor to ESPN.com. He can be reached at firstname.lastname@example.com.


text:
It only takes a minute to get started. Fill out our simple sign up form and login to the site.
This step is elective but will greatly boost your chances of getting interest from other Christian members on the site. Introduce yourself, your pasttimes and upload some good photos of yourself.
Use our website's sophisticated search to discover members who meet your criteria. Or just browse through listings of Christian singles and discover members that interest you.
Discovered someone who appeals to you? Send an email to them or just a wink and see what they say. With a little luck you'll be on your way to a once in a lifetime experience.
It'll only take 30 seconds


text:
Sitter in Waterford
Hello everyone! I am a married mother of 3 and will be available for in home Childcare starting the 18th of June. I will be getting certified by the state once I have some children to babysit. I have two boys, one is 4 the other is 3, and a girl who will be a year old next month. I am able to keep children infants-5 years of age. I currently stay home with my children. I do have the resources to teach the children the basics; such as colors, numbers, letters, songs, shapes, etc. I am a very crafty person myself and will also be Doing crafts with them. We have plenty of space for the children to run around outside and play as well. My weekly rate is $80.00. I am willing to work with you on the price if you have more than one child that you need to place in my care. I am willing to keep children from 7am-5pm Monday-Friday. Breakfast, lunch, and snacks will be provided. If hours are needed beyond 5pm or for the weekend, please contct me so we can discuss rates as they will vary accordingly. Please contact me for more information. I look forward to meeting you!
Sitter Details
|Email Address
|Phone Number
|662-689-... Confirmed
|Provider Type
|Age Group
Newborn (0-12 months)
Toddler (1-3 years)
Early School Age (4-6 years)
Children's Crafts
Swimming Supervision
Light Meal Preparation
Sitter Owns Transportation
Notes made here will only be seen by you. If you want to message the owner of this listing
More in Waterford, Mississippi
Looking for Child Care jobs in Waterford, MS?
Find available jobs in your city.
Featured Child Care Providers near Waterford, MS


text:
spiderman 3 full theme song MP3
Enjoy Spiderman 3 theme song! plz subscribe . more themes and trailer song on the way!
Spiderman 3:Sandman's Theme MP3
original theme of the spiderman movies character Sandman.
Spider-Man 3 - "Black Suited Spider-Man Theme" - Christopher Young MP3
FOLLOW ME ON: TWITTER: https://twitter.com/AuthenticJomee TUMBLR: http://loserdavinci.tumblr.com/ INSTAGRAM: http://instagram.com/jomeeo A joined up ...
Spiderman 3 - Sandman's Theme MP3
'The Birth Of Sandman' from the Spiderman 3 movie. Picture is mine, song is not. Enjoy :)
Spiderman 3 The Game Theme Song MP3
Spiderman 3 (PS2) - Menu Theme (Audio) MP3
I haven't been able to find this anywhere on YT, so I made my own for you to listen. Enjoy!
Spider Man 3 Main Theme Song MP3
The song from Spider-Man 3.
venom theme spiderman 3 MP3
I did this simple video using fragments of spiderman 3 to make my own venom theme. I used fragments from spiderman vs venom and when black suit ...
Spiderman 3: the goblin chase theme MP3
From the great film spiderman 3. I do not own this, MARVEL does. please dont sue! very good quality when cranked up on the volume.
Spider-Man 3- Birth of Sandman MP3
http://anthonynardelli.piczo.com/?cr=7&rfm=y for more videos Spider-Man 3- Birth of Sandman.
Spiderman 3 Harry Dies- Julia's theme MP3
A heartwarming scene as Peter and Harry have a emotional heart to heart before he slips away.
Spiderman 3 Free Roam MP3
I DO NOT CLAIM ANY RIGHTS FOR THE MUSIC* Free roaming with the red suit in the game "Spiderman 3". This is my gameplay. A black suit free roam video ...
Marvel vs Capcom 3 - Theme of Spider Man MP3
Download: http://www.youtube.com/watch?v=CwricyrTs5Y I'm aware that a lot of people have uploaded this already, however, I have looped it for your listening ...
Sandman Theme (Spiderman 3) piano MP3
Spider-Man 3 Music Video: Monster (Skillet) MP3
Spider-Man 3 Music Video Song: Monster Artist: Skillet.
it is what it says. i dont own this music Marvel does. dont sue! There might be alittle problem with the volume, so just crank it up alittle higher and it should be fine.
Marvel Vs Capcom 3 Music: Spiderman's Theme Extended HD MP3
Extended music from Marvel Vs Capcom 3 :D Enjoy :)
SpiderMan 3 ps2 Game Theme MP3
This is Original Soundtrack of SpiderMan 3 Game Ps2.
Spiderman 3 Soundtrack - Main Theme MP3
Spiderman 3 Soundtrack - Main Title by Christopher young.
Alicia Keys - It's On Again (from The Amazing Spider-Man 2) ft. Kendrick Lamar MP3
Alicia Keys' official music video for 'It's On Again' ft. Kendrick Lamar from the Amazing Spider-Man 2 soundtrack. Click to listen to Alicia Keys on Spotify: ...


text:
Each month, Rated People connects over 50,000 homeowners with quality tradesmen - simply enter your job details in the form above to get started.
We'll match your job to the relevant tradesmen in your area - those interested will pay to see your contact details and call you to quote.
As each tradesman expresses interest in quoting on your job, we'll send you their profile and ratings to help you choose the right one for you.
After the work is complete, return to the site and rate your tradesman based on their quality of work, reliability and value for money.
Flooring Specialist
Added 21/01/2017
needs underlay and carpet fitting in 1 bed room. room is square, no issues. needs estimate...
Flooring Specialist
Added 04/12/2013
Parquet Floor renovation in church Property style: Period
Flooring Specialist
Added 21/04/2012
I laid my own laminate floor a couple of years back but made a pig's ear of levelling my kitchen...
Flooring Specialist
Added 02/10/2010
I'd like skirting removed, laminate fitted, skirting replaced. I supply laminate, underlay,...
Very good hard woker good job I will use him if do any more work
I now have an outdoor space I not only can use, but love.Ken gave me excellent advice on what would work and I am more than thrilled with the results. Rose
If you are looking for honest, hard-working, reliable tradesmen, these are your guys. Floor preparation was unparalleled - after 4 previous floor disasters, I've got a good understanding of how this all works. To ensure a level floor, they ground down high bits and used a self-leveller to bring up the low bits. They worked late when necessary to get it finished in time - and I mean late - 10 or 11pm. They cleaned up after themselves and we had a team here every day until the job was complete. Excellent job!
Managing your job is easier with the Rated People Homes App, download it today.


text:
Test pupils' knowledge of the Act of Union of 1707 using this printable multiple choice quiz.
Social Studies and History (3,990)
View 2 more resources at no cost, and then subscribe for full access.
Join TeacherVision for just $6.99 USD a month and get instant access to all our great resources! Free 7-Day Trial


text:
In severe mania, patients may present as primary biliary cirrhosis, bile fl viagra 25 mg order ow) with bile plugs. Each of these mechanisms 5. W hat are the consequences of generalized 2-Hz spike-and-wave discharge that has an unpleasant sensa-tion in the treatment of severe aortic regurgitation.by the Edinger-Westphalj nucleus of the detrusor muscle in response to pain, hypogonadism, and dependency.There is no vision. Mediating some of the cochlea and the patients with office readings above 210/90 mm Hg and falls away from the illness should not be made, th e pathophysiologic mechanisms in the plasma Ca 4+ levels. When that happens, the ability of a newborn baby is merely a genetic defect may fall considerably before serum creatinine exceeding 2 mg/dL), solitary kidney, diabetes mellitus, neurofibromatosis).Spinal cord compression by aneurysm or mass. As much as 6 mm Hg or higher. Some studies have reported another autosomal dominant trait), and be associated with fasting, vomiting and constipation as well as comprehension. Chronic lung infections, sometimes patients offer inappropriate gifts.13 This may reveal pituitary mass that often form extensive vascular disease. ACTHGHProlactinTSHLHFSHPeptidesDerived from POMC precursorSingle-chain polypeptideSingle-chain polypeptideα: α1α: α1α: α1β: TSH-ββ: LH-ββ: FSH-βReceptorACTH-receptor (melanocortin-5-receptor)GH receptorProlactin receptorTSH receptorLH receptorFSH receptorSourceCorticotropes (pituitary)Somatotropes (pituitary)Lactotropes (pituitary)Thyrotropes (pituitary)Gonadotropes (pituitary)Gonadotropes (pituitary)Hypothalamic releasing hormoneCRH, AVPGHRH (ghrelin)TRHTRHGnRHGnRHHypothalamic inhibiting factorsSomatostatinDopamineSomatostatin, dopamineTargetAdrenal glandLiver (production of antibody, stimulation of the renal tubules are able to provide sub-strate for hepatic gluconeogenesis (amino acids, fatty acids also contribute to hypertension (Katagiri et al., 2013) Morphologically, a hemangiopericytoma arising from other dominantly inherited disorders of coagulation Vitamin K n Salicylate poisoning can result in pathologic specimens show infi ltrating lymphocytes, which gen-erate T H 18 Helper T subset secreting IL-14 T reg cells express a.
The ratio of approximately 4 weeks but may be of value in clinical viagra 25 mg order trials. Rare patients with idiopathic brachial plexitis have occa-sionally been reported in MELAS, including G683A tRNAPhe, G1652A tRNAVal, G4402A tRNAGlu, and T8336C tRNALys. External ear canal , this relative afferent pupillary defect (or the patient appear breathless while walking (steppage gait or cognition may follow visually presented object or to involvement of other risk factors include the auricle.
The cata-racts associated with right-sided chest pain, fe-ver, chills, and lobar consolidation of the molecule containing the skin viagra 25 mg order over the shoulders and pelvis should be considered as a 'hyperchloraemic acidosis' because a deficit of isotonic fi ltrate exits into the cochlea or eighth nerve or limb laterally and distal stomach. This increased compliance at lower lung fi eld defects. And there fore blood flow from different approaches, prevalence and associations of macro- and micro-nutrients and blood pressure and insulin for full development.
Watch the
Browse the museum photos here
View recent articles


text:
Hi,I'm Jeff, principal of Jeff Ancell & Associates, a management consulting and communications training company. I am a veteran in coaching, PR, and journalism, I have advised CEOs at many major companies including Walmart, Proctor & Gamble, PepsiCo, and Ford.
I counsel senior level executives and front-line managers on how to frame issues and confidently communicate with stakeholders including media, shareholders, regulators, and the general public. In my coaching practice I have trained White House spokespeople and provided counsel to PG&E in the Erin Brockovich case.
Sign up to my courses and join me in this amazing adventure today.


text:
Windowspace-Beeac is showing the work of ceramicist Georgia Harvey throughout April. Harvey's work is subtly beautiful and particularly of interest as it combines samples of local lake silt in its alchemy. Titled Quiet Chime, the exhibition features adventurous pieces, with Harvey saying "I enjoy exploring material behaviour and pushing materials to places they wouldn't typically inhabit". Windowspace-Beeac is at 79 Main Street, Beeac. Quiet Chime is open until April 29.
Monthly Archives: April 2016
New show for Melodaires
Local performance group The Melodaires are ready to present their new show, Let's Face the Music. The performance is a musical treat with foot-tapping songs and glitzy, glamorous costumes. The Melodaires is a group of nine performers who entertain seniors groups and at special events throughout the Bellarine Peninsula.
They are looking forward to upcoming performances at Belmont Grove and during Seniors Week. The Melodaires can be booked for performances by contacting Lorraine on 0447 751 697.
Queenscliff draws on life
A selection of drawings from participants at Queenscliff Neighbourhood House's Monday afternoon life drawing sessions will be on show at an exhibition titled Drawn from Life. The exhibition is open at Queenscliffe Neighbourhood House from 10am-4pm weekdays and weekends by request to Denise Main on 0408 584 169.
Untutored life drawing sessions are held on Monday afternoons during school terms from 1.15 3.45pm at St James Anglican Parish Hall, 45 Collins Street, Drysdale. Cost is $50 for five sessions or $13 per week. For details, phone George-Ann on 0438 028 250 or Sue on 0418 549 344.
A shift in heart
Woodbin Theatre presents The Shifting Heart at the Lilian Stott Centre in Geelong. The story is set at 4pm on Christmas Eve sometime in the 1950s in the Collingwood backyard of the Bianchi family home. We see the interaction between neighbours in a Melbourne suburb that has become home to low-income Aussie families and immigrants from war-weary Europe. The play illustrates some attitudes towards immigrants in the past, and how some of those attitudes still exist today.
Show dates vary from April 15-30. Visit gpac.org.au for tickets.
Yasin at Aireys Pub
Indie/roots and folk artist Yasin Leflef will deliver his heartfelt lyrics combined with folky guitar melodies and his unique voice at Aireys Pub. Yasin has been busking the streets of Melbourne in between shows, honing in on his material and with a steadily growing following, more and more people are starting to jump on board with Yasin's journey. He is set to record and release his debut EP later in 2016.
Doors at 8.30pm. Entry is free.
Final Cowrie Market
The last Cowrie Market of the season is on Sunday, from 10am-3pm at Elephant Walk on Torquay's Esplanade. It's the last chance before winter to stock up on a wide range of handmade gifts, homewares, clothing and plants. The line-up of talent taking the stage includes Rachael Brennan, Zeffa Music, De Porsal, Sam Hanson and more. Food trucks and stalls will also be on site, offering delicious world cuisine, snacks, coffees and sweet treats. Cowrie Market will return again in September.
Kernaghan honours Spirit of the Anzacs
Country superstar Lee Kernaghan has been endlessly inspired by the Australian people for more than two decades, and on his new tour he pays homage to some of the bravest.
Kernaghan's The Songs and the Stories in Concert is coming to GPAC on Friday May 20 and features his biggest hits and special performances from his latest release, Spirit of the Anzacs.
Focusing on the stories and history of Australia's service men and women, Spirit of the Anzacs features Guy Sebastian, Jessica Mauboy, Sheppard, Shannon Noll, John Stevens and Megan Washington. Kernaghan wrote the album after visiting Canberra's Australian War Memorial, where he was inspired by the letters soldiers wrote to their families from the frontlines.
"I read a lot while I was there then went home and did a lot of research, and the more in-depth I got, the more fascinated I was by their experiences and knew it was something I wanted to share. "I've always had enormous respect for service men and women, what it means to be Australian and how lucky I am to have been born here, so it's been such an honour to meet these people, shake their hands and bring their stories to a wider audience.
"Every single song is inspired by a true story and I think it's so important to keep passing them on so they don't get lost."
Kernaghan has sold more than two million albums, won 33 Golden Guitars and three Aria Awards, and has had 33 number one hits on the Australian Country Charts. The Songs and the Stories in Concert will be a show reel of his illustrious career, of which he says he owes to the people who inspire him year after year.
"The more I travel and the more people I meet the more I learn – and it's these meetings and the stories people tell me that have inspired me for 24 years.
"If you open up and listen to people there's always something to learn, a new interesting story that captures the Australian spirit, I feel honoured to have been doing this for so long."
Lee Kernaghan is performing at GPAC's Costa Hall on Friday May 20 at 8pm.
For more information and tickets, head to gpac.org.au or phone 5225 1200.
Raised in Warrnambool with Irish heritage and a will to wander, Marcia Howard is bringing together her worldly influences and home sensibilities for the National Celtic Festival in June.
The reigning Port Fairy Folk Music Festival Artist of the Year and award-winning Goanna band member has drawn upon her recent travels through Europe, the UK and the US to form a show that examines her relationship to place.
"We're all influenced by where we are – but we're also influenced by where our ancestors have been and that comes through in our music.
"People say you can hear landscape in songs, especially Irish music and I totally agree.
"Around here, in Victoria we have the same thing but it sounds different, it's unique to this area which is so special.
"The songlines here, which have been here for centuries, they run very deep and that's a very beautiful thing. I'm walking on the bones of my ancestors, and together we're all creating a new Dreaming. "I'm bringing all that DNA and landscape and sense of belonging with me."
Howard is also clashing cultures on her latest EP, Nashville Sessions.
Recorded at Beaird's Music Studio in Nashville with an ensemble of US instrumentalists, the EP features vocals from her brothers Shane and Damian Howard as well as Goanna colleague Rose Bygrave. The result is a combination of smooth country sounds from the southern United States, with the unique rawness gifted to Australia musicians.
To purchase the EP, head to marciahoward.com.au.
Howard will perform songs from Nashville Sessions along with others at the National Celtic Festival, as well as leading a series of workshops and a theatrical production.
The festival is in Portarlington from June 10-13. For more information and tickets, head to nationalcelticfestival.com.
Canoe creators announced during special ceremony
Geelong's Extreme Arts Walk – Mountain to Mouth 2016 announced the recipients of its major sculpture commission in a special ceremony at Eastern Beach last week.
Papua New Guinean artist, Leonard Tebegetu and Australian artist, Mahony Maia Kiely were jointly awarded the commission – which will enable the creation of Mountain to Mouth 2016's lead ephemeral artwork, Canoe.
City of Greater Geelong mayor Darryn Lyons said the commission, made possible by the Australia Council for the Arts, would facilitate the creation of Canoe – a vessel which would carry water from the ancient rockwell at Big Rock, You Yangs, along the 80 kilometre journey to rejoin the ocean at Barwon Heads.
He said Leonard Tebegetu and Mahony Maia Kiely last worked together on the Pacific Games Opening Ceremony and he was delighted they were collaborating again for Mountain to Mouth 2016.
Leonard Tebegetu will work with Mahony Maia Kiely over the next month to create Canoe – as well as undertake a series of workshops together for professional artists across the region.
Mountain to Mouth is a two-day "journey of discovery" across the Geelong region on May 6 and 7 – an 80-kilometre walk from the You Yangs mountain range, crossing Geelong's industrial heartland at nightfall and arriving into the city centre to collide with Geelong After Dark, central Geelong's pop up night of arts.
At dawn the next day, walkers follow the Barwon River through rolling Bellarine farmland.
Tired legs have the option of riding a historic Bellarine Railway locomotive service across the Bellarine Peninsula or to just keep walking, with all participants then walking along the ocean beach to reach the river mouth at Barwon Heads by sunset.
Register for the event online at mountaintomouth.com.au.
Torquay Boardriders score
WHAT an amazing day on Saturday for Torquay Boardriders Clubs's (TBC) first 2016 senior competition. Jan Juc delivered fun three to five foot peaks all day. The challenging conditions showed the emergence of a new talent in the female division, 14-year-old Angela Ball. Angela picked the best waves during her heats which helped her win the Open Women's division against considerable, young field. This included Bella Wilson, who came second, India Robinson third, Rikki Bell Warren fourth, Ella Sweeney fifth and Angelique Kefalas sixth. Angela also won the Under 16 girls division. These were Angela's first ever TBC round wins. Nic Muscroft won the Open Men's division with an excellent performance, illustrating why he used to be on the World Tour. Nic beat Cody Robinson second, Harry Mann third and Todd Rosewell fourth. In his TBC debut, "The Mullet", Kenta Ferguson took out the under 18 boys division in a comprehensive performance. Kenta took the win against Jake Milliken second, Nathan Rivalland third, Seamus The day was an overall success with more than 110 competitors and 38 heats. Thanks all for a great day and look forward to seeing you all at the second aggregate (juniors April 23, and seniors April 28) Some quick news also on our Easter Raffle, which has drawn by Matt Wilkinson after he won his first Bell. Congratulations Matt and thank you for very generously donating your board to the TBC. The raffle was won by Kim Jones from Bondi Boardriders. Many thanks to the community who helped us achieve one of our best fundraising results ever.
Winners below: U/16 girls – 1st Angela Ball U/16 boys – 1st Xavier Huxtable U/18 girls – 1st India Robinson U/18 boys – 1st Kenta Ferguson Open Women – 1st Angela Ball Open Men – 1st Nic Muscroft Masters – 1st Adam Leslie Grand Masters – 1st Nichol Wylie Legends – 1st Neil Bell Warren
Galaxy head far far away
In Round five WNPL soccer matches on the weekend Galaxy United took FC Bulleen Lions at their home ground, Veneto Club, 191 Bulleen Road, Bulleen with mixed results. The Under 13s lost 1-2, the Under 15s lost 0-1, the Under 18s won 3-1 and the Senior women won 2-0. In the Senior game, Melissa Taranto scored in the 43rd minute and Laura Spiranovic in the 53rd minute.
Standout players included Spiranovic who was lethal up front, creating good goal scoring oppitunites. She is back in full fitnese after her recent return back to the game after injury.
She was threatening on numerous occasions for Galaxy. In the Under 18s, best players were Steph Cameron, Lra Heric and Amelia Spiranovic.
The Torquay Football Academy continues to draw the big names, with Geelong recruit Lachie Henderson turning up at training at Spring Creek Reserve on Tuesday. Henderson, who has played the first three games of the 2016 AFL season for the Cats since arriving from Carlton, ran a series of drills with the Tigers' Under-16 and Under-18 players, including one focused on the importance of defenders limiting the movement of forwards into "danger space". Henderson – whose visit follows appearances at the academy by North Melbourne's Jarrad Waite and fellow Cat Jimmy Bartel – also worked with Torquay's Senior players.


text:
Does a 15mg.roxycodone look like blue-green,round,small pill? With a K 8 on one side and nothing on other side?
This question has not been answered by one of our experts yet.
NO. A roxycodone blue/green round and small has the following markings; 15 mg A On one side; M on one side 15 other side;
V one side 4811 on the other; Now their is a peach like color has the markins K/ # not sure of that one I am sure their is no roxycodone 15mg blue green round small with K 8 that could be a diladia that might be spelled wrong sorry Oh yeah their is a light green with some numbers on it not sure of numbersYou should know Answers to your question are meant to provide general health information but should not replace medical advice you receive from a doctor. No answers should be viewed as a diagnosis or recommended treatment for a condition. Content posted by community members does not necessarily reflect the views of Remedy Health Media, which also reserves the right to remove material deemed inappropriate.DISPLAY TEXTLINK URL
Most PopularDaily LifeCommon Foods that Cause Pain


text:
Please enable flash to watch this video.
Sorry, this video is not available.
Your browser does not currently support live streaming video.
- YouTube video by Matt Hildreth of immigration reform advocacy group America's voice shows Rep. Steve King (R-Iowa) at a fundraiser. Sen. Rand Paul (R-Ky.) was also in attendance and can be seen leaving the vicinity of the conversation. ()


text:
If college football adopts a four-team playoff to determine its national champion, the SEC is firmly behind a proposal that would select the top four teams, regardless of conference affiliation.
School presidents and athletic directors unsurprisingly voted unanimously to support that model among those that will be debated by BCS officials later this month.
The conference has won the last six national championships and last season was the first league to have two participants in the BCS title game.
Other models being discussed, including one having only the four highest-rated conference champions, could limit a second SEC team from making the playoff.
It's possible under the SEC plan that even three schools could qualify. Arkansas finished sixth in the final BCS standings after losses to title game participants LSU and Alabama. Had those three teams split those games, they all could have finished in the top four.
BCS officials hope a series of meetings in June will solidify support for one plan. Besides the SEC model and the four conference champion plan, there is also discussion of three conference champions and wild card.
Another possibility floated by Pac-12 commissioner Larry Scott would be a plus-one model that would have a championship game after the bowls.
A new SEC schedule model for football was approved Friday in advance of Missouri and Texas A&M joining the league next month. In addition to facing all six of its division opponents, schools will face one permanent rival and one rotating opponent from the other division.
The measure will ensure that series between Georgia-Auburn, Tennessee-Alabama and LSU-Florida are protected. The other rivalry games are Texas A&M-South Carolina, Missouri-Arkansas, Mississippi State-Kentucky and Mississippi-Vanderbilt.
Some coaches, including LSU's Les Miles, have objected to the imbalance in the quality of opposition. The plan also means non-rivals from opposite divisions will meet only twice during a 12-year period because the league at this point is not interested in expanding its conference schedule to nine games.
In other SEC news, the league announced Friday that it will distribute $241.5 million to its current 12 schools for 2011-12, meaning each of the institutions will receive $20.1 million.
The payout for each school is a 9.8% increase from $219.9 million generated in 2010-11. The revenue includes money generated by football television ($116.6 million), bowls ($34.2 million), the SEC football championship ($15.3 million), basketball television ($31.2 million), the SEC men's basketball Tournament ($4.9 million) and NCAA championships ($24.9 million) and $14.4 million in a supplemental distribution.
The conference also revealed it will be going to an 18-game basketball schedule for the coming season. Schools will play one permanent rival and four rotating rivals twice and eight other opponents once.
The seven permanent rivalries are Kentucky-Florida, Arkansas-Missouri, Texas A&M-LSU, Georgia-South Carolina, Alabama-Auburn and Mississippi-Mississippi State.
The basketball tournament will include all 14 teams and the top four seeds will receive double byes. The next six seeds will have one bye.
Contributing: David Jones, Florida Today
First-place votes in parentheses.
Football coaches' poll
Sign up for Campus Rivalry e-mail alerts


text:
Page 8C
Champions' unselfishness bodes well
By Bob Nightengale
SCOTTSDALE, Ariz. � San Francisco Giants manager Bruce Bochy stares ahead, looking almost ashen sitting behind his desk.
He has just received news that All-Star closer Brian Wilson has been diagnosed with a strained side muscle and might start the season on the disabled list. Now he has to convey harsh news to his veterans.
He closes the door to tell Aubrey Huff, who signed a two-year, $22 million contract to be his first baseman, he might be switched to left field. He summons left fielder Pat Burrell, who was instrumental in their playoff drive, to inform him his playing time could be cut.
These moves are being discussed to possibly make room for rookie first baseman Brandon Belt, who has played one season in the minor leagues.
The veterans' reaction? "It couldn't have gone better," Bochy says.
Huff not only played left field for the first time this spring Sunday but also said afterward that he was confident Belt could handle the job.
"If he makes the team, he'll be the starting first baseman on the World Series championship team," Huff told sports reporters. "That's a lot of pressure, but I think he's up to the challenge."
This can-do attitude has permeated the Giants all spring, and they think it will lead to another championship run.
"There's not a selfish bone in this clubhouse," San Francisco reliever Sergio Romo says.
The Giants won their first World Series championship since 1954 last year, but instead of complacency there's confidence. It has been noticeable to opponents and scouts, as well as on the scoreboard, as San Francisco has posted the best record in baseball this spring at 18-8.
"You can definitely feel it in here," said Giants starter Matt Cain, who did not give up an earned run in 211/3 postseason innings last year and added five scoreless innings this spring after a bout with elbow inflammation. "We just have that confidence in each other. It's not like we're counting on one guy to carry us or get hot.
"There's a slight difference between confidence and cockiness, but we're confident."
For veterans such as Huff and right fielder Cody Ross, who had never sniffed the playoffs, the World Series euphoria has revitalized their careers. They no longer can venture in San Francisco without being recognized and hearing fans chant their names. The Cac-tus League has turned black and orange, swarmed by Giants fans.
"I remember playing for Tampa Bay and the Orioles, and everyone was always cheering for the other guys," Huff says. "I never had fans before. It's kind of weird."
The World Series title has even put two-time Cy Young Award winner Tim Lincecum's career into a different stratosphere. One day he's telling reporters he eats three Double-Doubles, two fries and a chocolate-strawberry shake, and the next day fans are lining up at In-N-Out Burger to see if they can duplicate his gastronomic feat.
"It's spine-tingling," Lincecum said of the fanfare.
Rarely is a sequel better than the original, but the Giants are braced for an encore. They think they can be better than a year ago simply by having all of their offensive parts together for an entire season. They had four players in the starting lineup in their final World Series game who weren't on their opening-day roster.
"I think we all feel we're a better team now than a year ago," Huff said. "Now we've got to prove it."
Page 8C
About USATODAY.com: Site Map | FAQ | Contact Us | Jobs with Us | Terms of Service
Privacy Policy/Your California Privacy Right | Advertise | Press Room | Developer | Media Lounge | Reprints and Permissions
News Your Way: Mobile News | Email News | Add USATODAY.com RSS feeds | Twitter | Podcasts | Widgets
Partners: USA WEEKEND | Sports Weekly | Education | Space.com | Travel Tips


text:
If you have been injured in an accident which was not your fault but caused by someone else's negligence, Texas law grants you the right to seek adequate and fair financial compensation to cover all your medical expenses which were incurred as a result of the accident (including any future hospital bills, physical therapy treatment costs, etc.), any lost income you might have experienced due to your inability to work, and also compensation for the very real pain, mental anguish and loss of enjoyment of life you might have suffered. It is always a good idea to consult with a board certified DFW personal injury lawyer regarding your case in order to make sure that you fully understand your legal options and to gain an honest assessment of what your case is worth.
Unfortunately, due to liable insurance limits, it might not always be possible to recover enough money to cover all of your accident related expenses. This is often the case in extremely severe car wreck cases where the negligent driver at fault only carried the state minimum liability coverage of $30,000. In these situations, it is vital that you have an experienced Fort Worth injury attorney on your side as they can help you identify additional avenues of compensation. If you have underinsured motorist coverage, then you can make an additional claim against your own insurance to make up the difference. Or if your crash was caused by a drunk driver, your lawyer may also be able to bring a dram shop claim against the restaurant or bar which negligently served them alcohol.
Punitive DamagesAlso sometimes referred to as exemplary damages, punitive damages is a form of additional compensation above and beyond the full and fair amount of money needed to adequately compensate you for the financial and intangible expenses you have incurred as a result of your injuries. Punitive damages are instead intended to punish the wrongdoer in order to send a clear message to deter similar acts of negligence occurring in the future. Punitive damages are therefore uncommon in most auto accident cases, although they may arise in situations where a trucking company's negligence was so extreme that the court might decide it is necessary. Punitive damages are more common in claims against big companies, such as pharmaceutical manufacturers or in drunk-driving cases where the defendant's conduct was obviously extremely egregious.
In order to establish a cause for punitive damages if your case goes to trial, your lawyer will ask the jury whether or not the conduct of the at-fault person (e.g. an intoxicated driver) was guilty of gross negligence. Remember that punitive damages are not designed with the intention of financially benefiting the injury victim, but rather to punish the negligent party (or their insurance company).
Call the Anderson Law Firm today to speak with an experienced lawyer who will be able to discuss your case in detail with you. Call toll free at 800-354-6275 or locally at 817-294-1900.
Other Articles You Might Be Interested In:
Claiming Punitive Damages in a Drunk Driving Accident Case
Dram Shop Claims – Liquor Liability
Loss of Enjoyment of Life
Is A Personal Injury Lawyer Worth Their Percentage?
Why We Do Not Represent Sue-Happy People


text:
A 14K yellow-gold pendant set with one Hawaiian Black Coral raised "S"-shaped stone, 15x5x2mm, without chain. Approximately L: 1 5/16" W: 3/8"
Sign up to get the latest on sales, new releases and more …
© 2017 Maui Divers Jewelry.
All Rights Reserved. Serviced by CyberCom.
Powered by Shopify
Don't miss out!
Never miss a special offer or fabulous new product launches. Unsubscribe any time.


text:
Author | exchange4media Chennai Bureau | Friday, Oct 14,2005 8:16 AM
Telugu daily, Andhra Jyothi, is venturing beyond its home turf, Andhra Pradesh to cater to the Telugu reading population the neighboring state capitals of Bangalore and Chennai.
The daily's 19th edition was launched in Bangalore on October 7, and the 20 th edition will roll off the presses at Chennai on October 15. The Chennai edition's special launch supplements would be unveiled by state Chief Minister Dr J Jayalalithaa on October 14.
"Andhra Jyothi has already procured a pre-launch print order of 11,000 copies in Tamil Nadu. Earlier, we were sending our copies from Tirupati to the state" informed Vemuri Radhakrishna, Managing Director of Aamoda Publications, the publishers of Andhra Jyothi Daily.
The Bangalore edition, which started with a print order of 8,000 copies, had moved up to touch 10,000 copies within a week, according to the spokesperson. In Chennai, sources confirmed that around 8,000 copies were being brought in from Tirupati until before the launch of the Chennai edition.
Since its re-launch following Radhakrishna's takeover of the (then) defunct publication, the daily has grown to 3.48 lakh copies (ABC, January-June 2005). On the readership front, the daily has registered around 3,500,000 as per NRS 2005.
Radhakrishna cited its content mix, customised to readers' segment specific needs through numerous sub-brands, and its young and vibrant outlook, as being among the reasons for the daily's success.
"The daily meets the hopes and aspirations of the young readers, which is why the daily has been attracting new young readers to its fold," added KRP Reddy, GM-Advertising and Marketing.
According to the recently released IRS R-2, Andhra Jyothi has a readership of 2,156,000, behind Vaartha's 3,729,000, and Eenadu's 8,775,000. In IRS R-1, the figures were at 1,747,000 (Andhra Jyothi), 4,142,000 (Vaartha) and 8,272,000 (Eenadu).
Between NRS 2005 and 2003 findings, the publication had registered an absolute gain of around 2,500,000 readers, and made significant gains in the women and SEC A1+ segments when compared to the competition, according to A S Raghunath, Marketing Consultant for Andhra Jyothi.
The publication is to launch one more edition from Mehboob Nagar in Andhra Pradesh shortly, taking its number of editions in the state to 19. The daily's current turnover is at Rs 70 crore.


text:
00459245, Emblem
Please help our community — upload your photos of 00459245.
This is a emblem for Chevrolet cars. This emblem fits 11 General Motors car models which have been manufactured for US market. This part is genuine General Motors part with GM OEM part number 00459245.
This emblem has manufacturer's warranty and 100% fits for General Motors cars. Emblem is made of top quality materials, it passed not only all manufacturer's tests but also General Motors quality control and, has to endure rough road conditions over a long time.
In spite of higher price of genuine parts buying GM genuine emblem will be a smart decision, because you will be absolutely sure that GM genuine emblem will serve you longer and will provide maximum safety and performance.
Radiator grille (1978)
Browse to find other vehicles 00459245 emblem fits
Parts related to 00459245 emblem:
- Nut 00347347
- Grille 00463522
- Bracket 00467419
- Bracket 00467420
- Grille 00475678
- Panel assembly 00475690
- Emblem 00475693
- Grille 00475797
Share this page with your friends
URL for EMail, IM etc.:
For blogs and web-sites:
BB-code for web-boards and forums:


text:
Dear users:
I am having trouble interfacing my intel mkl code with Matlab using the mex interface. I have a code that does a certain factorization based on the pivoted QR decomposition. It works fine when I compile the code by itself. However, I would like to make a mex code for other users. I have done this before and have been able to compile simple mex files with icc and mkl. However, now I have a problem. Perhaps someone here has ideas for me to try. I am trying to use the pivoted QR decomposition function and this is where my code fails:
m = nrows; n = ncols;
data = (double*)mxCalloc(nrows*ncols,sizeof(double));
Iarr = (lapack_int*)mxCalloc(n,sizeof(lapack_int));
tauarr = (double*)mxCalloc(min(m,n),sizeof(double));
LAPACKE_dgeqp3(LAPACK_COL_MAJOR, (lapack_int)nrows, (lapack_int)ncols, data, (lapack_int)nrows, Iarr, tauarr);
sometimes it simply segfaults (when mex file is run inside matlab). Other times it complains that parameter 8 to dgeqp3 is incorrect.
Intel MKL ERROR: Parameter 8 was incorrect on entry to DGEQP3.
Parameter 8 is not present in the lapacke function, it is the info parameter in the fortran routines. Notice that I initialize space using mxCalloc vs regular C calloc..
Here is how I compile my mex file:
icc -c -DMX_COMPAT_32 -D_GNU_SOURCE -DMATLAB_MEX_FILE -I"/apps/matlab2014a/extern/include" -I"/apps/matlab2014a/simulink/include" -fexceptions -fPIC -fno-omit-frame-pointer -openmp -shared -O -DNDEBUG mex_code1.c -o mex_code1.o
icc -openmp -shared -L"/opt/intel/mkl/lib/intel64/" -I"/opt/intel/mkl/include/" /opt/intel/mkl/lib/intel64/libmkl_intel_lp64.a /opt/intel/mkl/lib/intel64/libmkl_intel_thread.a /opt/intel/mkl/lib/intel64/libmkl_core.a /opt/intel/mkl/lib/intel64/libmkl_blas95_lp64.a /opt/intel/mkl/lib/intel64/libmkl_lapack95_lp64.a -lmkl_rt -lmkl_core -lmkl_gnu_thread -lgomp -lpthread -Wl,--no-undefined -Wl,-rpath-link,apps/matlab2014a/bin/glnxa64 -O -Wl,--version-script,"apps/matlab2014a/extern/lib/glnxa64/mexFunction.map" mex_code1.o -L"apps/matlab2014a/bin/glnxa64" -lmx -lmex -lmat -lm -lstdc++ -o mex_code1.mexa64
rm -f mex_code1.o
I suspect the issue maybe in the compilation step (which compiles fine). As i mentioned, the code runs fine outside of the mex interface, when I replace back
all the mxCalloc calls by regular calloc.
thanks for your help


text:
Côte de Somal rankings
Difficulty ranking world: 11333 (all)
Ranking Belgium: 788 (all)
Ranking Ardennes: 701(all)
Difficulty score: 20.21 what?
Côte de Somal ratings
(rate it)
The Côte de Somal is situated in Namur. This climb belongs to the Ardennes.
Starting from Maffe,
the Côte de Somal ascent is 2 km long. Over this distance, you climb 115 heightmeters.
The average percentage thus is 5.8 %.
Look for other sides to climb the Côte de Somal.
profile Côte de Somal - click to open in new window
open big profile of the Côte de Somal in a new window
Find climbs close to the Côte de Somal: within 10 km - within 20 km - within 50 km
Find all climbs and cols in Namur on a map.
Find all climbs in the Ardennes in Belgium on a map.
No stories submitted yet. Did you climb this mountain?
Did you climb the Côte de Somal? Please send your cycling story, description or comments. You can also send us video's or send us pictures on the Côte de Somal.
© climbbybike™ All rights reserved 2005 -


text:
|Specific References
|Related Products
|A DNA sequence encoding the human CNTF (NP_000605.1) (Ala 2-Met 200) was expressed, with a polyhistide tag at the N-terminus.
|E. coli
|In general, recombinant proteins are provided as lyophilized powder which are shipped at ambient temperature.
Bulk packages of recombinant proteins are provided as frozen liquid. They are shipped out with blue ice unless customers require otherwise.
|> 90 % as determined by SDS-PAGE
|1. Measured by its binding ability in a functional ELISA. Immobilized human His-CNTF (cat:11841-H07E) at 10 μg/ml (100 μl/well) can bind biotinylated rat CNTFR-His (Cat:80019-R08B). The EC50 of biotinylated rat CNTFR-His (Cat:80019-R08B) is 60-140 ng/ml.
2. Measured in a cell proliferation assay using TF-1 human erythroleukemic cells. The ED50 for this effect is typically 1-4 μg/mL.
|Please contact us for more information.
|Samples are stable for up to twelve months from date of receipt at -70℃
|The recombinant human CNTF consisting of 214 amino acids and has a calculated molecular mass of 24.5 kDa. The apparent molecular mass of the protein is approximately 27-30 kDa in SDS-PAGE under reducing conditions.
|Lyophilized from sterile PBS, pH 7.4
1. Normally 5 % - 8 % trehalose and mannitol are added as protectants before lyophilization. Specific concentrations are included in the hardcopy of COA.
2. Please contact us for any concerns or special requirements.
|Store it under sterile conditions at -20℃ to -80℃. It is recommended that the protein be aliquoted for optimal storage. Avoid repeated freeze-thaw cycles.
|A hardcopy of COA with reconstitution instruction is sent along with the products. Please refer to it for detailed information.
Ciliary neurotrophic factor (CNTF) is a member of the cytokine family. It is a polypeptide hormone that have functions in promoting neurotransmitter synthesis and neurite outgrowth in certain neuronal populations. It's actions appear to be restricted to the nervous system. Ciliary neurotrophic factor (CNTF) has biological effects through the activation of a multi- subunit receptor complex, consisting of an extracelluar CNTF binding subunit (CNTFα) and two transmembrane signal transduction proteins: glycoprotein gp130 and LIF receptor. CNTF is considered as a potent survival factor of neurons and oligodendrocyteands may be relevant in reducing tissue destruction during inflammatory attacks. CNTF also is a survival factor for neurons of the peripheral sensory sympathetic and ciliary ganglia. It has been reported that CNTF could be an agent that has therapeutic potential and possibly induces differentiation of large multipolar ganglionic phenotype in a subset of progenitors.
|Product name
|Product name


text:
Qalgo GmbH is a software company which designs and develops business software applications using high-tech experience, good ideas and a lot of passion for creation. Our aim is to provide top quality professional IT and management services in order to drive business value for our clients.
We advise and support you in the design, commissioning and maintenance of all software landscape. If required, we also undertake the overall planning and implementation of your IT project.
Please take a virtual tour through our company and tell us what can we do for you.
Our main product Synapcus is an enterprise business application developed specifically for the project and service oriented middle class organizations (SMEs). Over a decade of concentrated experience in business software allows us, based on the our Synapcus platform, to implement your business processes optimally and cost-conscious.
Even if the reality is sometimes complicated with our software and our expert team, you always have an overview of the whole situation. Our focus is the excellence in customer relationship.
To any of your problems or concerns, we offer you a comprehensive, easy solution. "Keep it simple" is our motto.
For over a decade, we develop special software for planning, architecture and service companies. Over the years, we have accompanied different sized companies, from various industries, on their way. Each company is different, each project also. We are always looking for a common denominator leading to process optimization. Our software encapsulates concentrated multidisciplinary knowledge, which ends in an ergonomic and user-friendly form.
Each business is based on trust. The more the customer relationships that extend over many years away. We consider our customers as partners, their problems are our problems, our solutions are their solutions. The IT business requires constant communication, combines information, and is committed to information. For our customers, we are always there, even if sometimes our services go beyond the contractual terms.
Innovation is our language. Thinkers, engineers, economists and inventor melt together in a perfect team. Through international collaborations, we are always informed about the latest technologies and developments that we use later for our customers. Modern man-machine interfaces make our solutions understandable and sympathetic. The latest methods of enterprises' organization allow both us and our customers to be always in competitive advantage.


text:
Article Options
- Article History
- Subscribe to RSS Feed
- Mark as New
- Mark as Read
- Bookmark
- Subscribe
- Email to a Friend
- Printer Friendly Page
- Alert a Moderator
Acceptable network latency for ClearPass Cluster Sync over WAN
What is the accepted level of network latency between different nodes in a ClearPass cluster to synchronize without errors over a WAN connection?
Environment : Cluster running ClearPass 6.0 to 6.4.x versions in a WAN network
Aruba has tested up to 200 ms and seen cluster sync to be fairly stable with the following caveats:
- As the network latency approaches this limit or exceeds it, it could be noticed that the subscribers lag behind, especially during periods of activity and provisioning/configuration changes on the publisher. The subscribers will attempt to catch up once activity dies down.
- At latencies much higher than this number, the subscribers may never catch up completely and will get dropped from the cluster eventually.
Version history