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Active Substance: atazanavir sulphate
Common Name: atazanavir sulphate
ATC Code: J05AE08
Marketing Authorisation Holder: Bristol-Myers Squibb Pharma EEIG
Active Substance: atazanavir sulphate
Status: Authorised
Authorisation Date: 2004-03-02
Therapeutic Area: HIV Infections
Pharmacotherapeutic Group: Antivirals for systemic use
Therapeutic Indication
Reyataz capsules, co-administered with low-dose ritonavir, are indicated for the treatment of HIV‑1-infected adults and paediatric patients 6 years of age and older in combination with other antiretroviral medicinal products.
Based on available virological and clinical data from adult patients, no benefit is expected in patients with strains resistant to multiple protease inhibitors (≥4 protease inhibitor mutations). There are very limited data available from children aged 6 to less than 18 years.
The choice of Reyataz in treatment-experienced adult and paediatric patients should be based on individual viral resistance testing and the patient's treatment history.
What is Reyataz?
Reyataz is an antiviral medicine that contains the active substance atazanavir. It is available as capsules (100 mg, 150 mg, 200 mg and 300 mg).
What is Reyataz used for?
Reyataz is used together with low-dose ritonavir and other antiviral medicines to treat patients aged six years and over who are infected with human immunodeficiency virus type 1 (HIV‑1), a virus that causes acquired immune deficiency syndrome (AIDS).
Doctors should only prescribe Reyataz to patients who have received anti‑HIV medicines before after they have looked at which medicines the patient has taken and carried out tests to establish that the virus is likely to respond to Reyataz. Based on the information available in adults, the medicine is not expected to work in patients in whom many medicines in the same class as Reyataz (protease inhibitors) do not work.
The medicine can only be obtained with a prescription.
How is Reyataz used?
Treatment with Reyataz should be started by a doctor who has experience in the treatment of HIV infection.
For adults (aged 18 years or over), the recommended dose is 300 mg once a day. In younger patients, the dose of Reyataz depends on body weight. There is no suitable dose for patients weighing less than 15 kg. Each dose must be taken with food. Reyataz is normally given with ritonavir to boost its action although in specific cases doctors can consider stopping ritonavir.
How does Reyataz work?
The active substance in Reyataz, atazanavir, is a protease inhibitor. It blocks an enzyme called protease, which is involved in the reproduction of HIV. When the enzyme is blocked, the virus does not reproduce normally, slowing down the spread of infection. Ritonavir, another protease inhibitor, is normally recommended to be given at the same time as a 'booster'. It slows down the rate at which atazanavir is broken down, increasing the levels of atazanavir in the blood. This allows a lower dose of atazanavir to be used for the same antiviral effect. Reyataz, taken in combination with other antiviral medicines, reduces the amount of HIV in the blood and keeps it at a low level. Reyataz does not cure HIV infection or AIDS, but it may delay the damage to the immune system and the development of infections and diseases associated with AIDS.
How has Reyataz been studied?
Reyataz has been assessed in four main studies involving patients aged 16 years and over. One study compared ritonavir-boosted Reyataz with ritonavir-boosted lopinavir (another antiviral medicine) in 883 patients who had not taken treatment for HIV infection before. The other three studies involved a total of 743 patients who had taken treatment for HIV infection before: the first two compared Reyataz, taken with saquinavir (another antiviral medicine) but without ritonavir, with ritonavir-boosted saquinavir or ritonavir-boosted lopinavir. The final study compared Reyataz plus either ritonavir or saquinavir with ritonavir-boosted lopinavir in 358 patients. The main measure of effectiveness was the change in the levels of HIV in the patients' blood (viral load).
Reyataz capsules boosted with ritonavir have also been studied in 41 patients aged between six and 18 years. Around half of these patients had taken anti‑HIV treatment in the past. The study looked at the effect of the medicine on viral load and on the immune system, among other measures.
A further main study involved 172 patients who had achieved undetectable viral loads (below 50 copies/ml) after treatment with Reyataz and ritonavir. It compared continued treatment with either Reyataz without ritonavir or the boosted combination.
In all of the studies, the patients also took two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs, a type of antiviral medicine).
What benefit has Reyataz shown during the studies?
In patients who had not been treated before, ritonavir-boosted Reyataz was as effective as ritonavir-boosted lopinavir. At the start of the study, the patients' viral loads were around 88,100 copies/ml, but after 48 weeks, 78% of the patients taking Reyataz (343 out of 440) had viral loads below 50 copies/ml, compared with 76% of those taking lopinavir (338 out of 443).
In patients who had been treated before, the results of the first study could not be interpreted, as a large number of patients left the study before its planned end. In the second study, ritonavir-boosted lopinavir caused a greater reduction in viral load than Reyataz taken without ritonavir after 24 weeks. In the third study, patients taking ritonavir-boosted Reyataz had similar falls in viral load after 24 and 48 weeks as those taking ritonavir-boosted lopinavir: they had fallen by around 99% after 48 weeks. This finding was maintained after 96 weeks.
In the patients aged between six and 18 years, 81% of those who had not taken anti‑HIV treatment in the past (13 out of 16) and 24% of those who had taken it in the past (6 out of 25) had viral loads below 50 copies/ml after 48 weeks. The patients also had improvements in their immune systems.
In the study in patients who had already achieved undetectable viral loads with ritonavir-boosted Reyataz, these were maintained in 68 of 87 patients (78%) who continued treatment with Reyataz without ritonavir, and in 64 of 85 (75%) who continued with the boosted combination.
What is the risk associated with Reyataz?
In adults, the most common side effects with Reyataz (seen in between 1 and 10 patients in 100) are headache, ocular icterus (yellowing of the eyes), vomiting, diarrhoea, abdominal pain (stomach ache), nausea (feeling sick), dyspepsia (heartburn), rash, lipodystrophy syndrome (changes in the distribution of body fat), fatigue (tiredness) and jaundice (yellowing of the skin and eyes associated with liver problems). In studies, side effects were similar in younger patients. For the full list of all side effects reported with Reyataz, see the package leaflet.
Reyataz must not be used in patients who have severe reductions in their liver function, who may be at increased risk of liver damage from the medicine; if given with ritonavir it must also not be used in patients with moderate reduction in liver function. In addition, Reyataz must not be given to patients taking rifampicin (used to treat tuberculosis), sildenafil (when this medicine is used to treat pulmonary arterial hypertension), St John's wort (a herbal preparation used to treat depression) or medicines that are broken down in the body in the same way as Reyataz and are harmful at high levels in the blood. For the full list of restrictions with Reyataz see the package leaflet.
Why has Reyataz been approved?
The CHMP noted that Reyataz's effectiveness had been shown in patients aged six years or over, although there is very limited information available from patients aged between six and 18 years. The Committee decided that Reyataz's benefits are greater than its risks and recommended that it be given marketing authorisation.
What measures are being taken to ensure the safe and effective use of Reyataz?
A risk management plan has been developed to ensure that Reyataz is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for Reyataz, including the appropriate precautions to be followed by healthcare professionals and patients.
Other information about Reyataz
The European Commission granted a marketing authorisation valid throughout the European Union for Reyataz on 2 March 2004.
For more information about treatment with Reyataz, read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.
Source: European Medicines Agency
Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.


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The Senate Armed Services Committee has approved its version of the National Defense Authorization Act, giving the green light for the bill to head to the upper chamber's floor sometime in June or July. At $631 billion, the budget includes $3 billion more than President Obama's original request.
It does not account for the potentially forthcoming sequestration process that would slash spending across the government and hit the Defense Department particularly hard – a scenario Defense Secretary Leon Panetta has deemed "catastrophic." However, the bill does include a provision that DOD leadership must produce a contingency plan for the potentially dramatic budget cuts.
The bill includes a number of mandates intended to cut down on duplicative programs and efforts and to increase oversight, and continues to fund anti-terror projects, a range of support programs to Afghanistan, and some plans for technology innovation, including $200 million for high-tech research and development.
Here's a brief rundown of some of the Senate bill's highlights:
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Amber Corrin is a former staff writer for FCW and Defense Systems.
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In the latest issue: grid security, agile development, BYOD and more!
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The latest version of the Defense Department-wide Enterprise Service Management Framework places more emphasis on managing IT risk.
Despite GSA's efforts to accelerate the FedRAMP approval process, the lack of agency reciprocity puts the program's central goals at risk.
Got some early-career colleagues who are doing great things in federal IT? Nominate them for FCW's 2016 Rising Star awards.
The agency software inventories required under the draft category management policy will be treasure maps that lead to efficient, effective, streamlined buying and unprecedented savings.
As experts warned of the "dire" threats posed by outdated federal technology, lawmakers grilled top feds, debated workforce issues and inched closer to backing a $3.1 billion fix-it fund.
The agency is making strides in developing and deploying border technologies but still has some weaknesses.
Agencies have spent almost $23 billion on legacy IT over the past three years, according to reports to Congress. Is a revolving fund the answer?
The United Kingdom will go live with its governmentwide digital identity platform, GOV.UK Verify, in the coming days. The U.S. government will need a little more time.
What contracting officer representatives really think is needed to fix contract management.
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Tarmac Floor Leveller, 10 kg
Tarmac Floor Leveller, 10 kg
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This Tarmac floor leveller is ideal for smoothing and levelling uneven floors and can be used in a variety of different rooms.
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CEMPAK wet mix patch repair concrete, repair of holes, breaks, cracks and other imperfections in all mortar beds. 100% fully prepared for use straight from the tub. Requires no mixing, just pop open the tub and load up your trowel Sets in approximately 240 minute
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Ideal for fixing wobbly paving slabs, repairing crumbling patio joints, laying new paving slabs and setting block paving Easy to use, conveniently packaged jointing repair, add water and mix in the tub
Designed specifically for cold weather working providing frost protection below -4oC Chemical care - Wear protective clothing, gloves and eye protection


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Reviewed1 Review
About Me
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- Michael's Airbnb Symbol
Hey, I'm Michael!
San Francisco, California, United States · Member since January 2013
We are from the united states, from the San Francisc, CA area.
All of us are dancers/musicians with a Philippine folk dance group made up of professionals.
We are interested if you also have information of places to visit during our short stay in Cuzco.


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Every once in a while an artist comes along with the the talent, grace and grind to move the hearts of millions and this one is definitely included alongside the majors.
Born and raised in East New York, Brooklyn at the tender age of 13 Brooklyn would write her first song at 14 her first rap and at 15 she would sign her first recording contract with Aftermath Records.
Known to many as the "favorite" Brooklyn would go on to write and influence such songs as "In The Hood" with 50cent & the drama worthy "Many MenRemix", "Rich Girl", "Money Shake" and the heart felt ballad "Messing With My Head". Brooklyn has been featured in XXL, Trace, Real Hip Hop,17Linx, Hear It First and the list goes on. We truly consider her to be #1 on the list of Hip Hop performers. After trading her recording contract with Aftermath Records for a publishing contract Brooklyn has played a big role in assisting some of your most beloved and favorite artist and performers making her one of the best ghost writers/vocal stylist of our time! Stay tuned.


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home | what we believe | worship | calendar | education | disciple making | ihn
Hello, my name is Jon Vollrath. I am a Christian. I am also a member and pastor of Our Savior's Lutheran Church, Eyota.
At one time, I could not believe that I would be best off in God's will and care. Now I cannot imagine being outside of it. This is what I know to be the transforming power of Christ Jesus and I want everyone to experience this also. I no longer have the fears, doubts, and anxieties that I use to. And I know a powerful remedy for the ones that re-emerge from time to time.
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This is a Commentary on Zhu et al. (J Bone Mineral Res. 2013:28:1870–1884. DOI: 10.1002/jbmr.1958).
ATF4 and HIF-1α in bone: An intriguing relationship
Version of Record online: 19 AUG 2013
DOI: 10.1002/jbmr.2045
Copyright © 2013 American Society for Bone and Mineral Research
Journal of Bone and Mineral Research
Volume 28, Issue 9, pages 1866–1869, September 2013
Additional Information
How to Cite
Schipani, E., Mangiavini, L. and Merceron, C. (2013), ATF4 and HIF-1α in bone: An intriguing relationship. J Bone Miner Res, 28: 1866–1869. doi: 10.1002/jbmr.2045
Publication History
- Issue online: 19 AUG 2013
- Version of Record online: 19 AUG 2013
- Accepted manuscript online: 22 JUL 2013 12:24AM EST
Funded by
- NIH (RO1 AR04819 to ES)
- People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013)
- Research Executive Agency grant agreement (300388 to CM)
- Abstract
- Article
- References
- Cited By
As in any other vascularized organ, one of the essential functions of blood vessels in bone is to be a source of O2, nutrients, hormones, and growth factors.[1] However, additional roles for bone blood vessels are emerging. For example, osteoblast precursors have been recently identified within the blood vessel wall,[2, 3] which suggests that blood vessels are a source of osteoprogenitors. Moreover, it has been shown that endothelial cells are specialized niches for hematopoietic stem cells.[4, 5] In light of these findings, identification of the molecular and cellular mechanisms controlling angiogenesis in bone is essential to reach a full understanding of how bone and bone marrow development and homeostasis are regulated.
In this issue of the Journal of Bone and Mineral Research, Zhu and colleagues[6] report that activating transcription factor-4 (ATF4) promotes angiogenesis in bone. This effect is associated with an increased production of vascular endothelial growth factor A (VEGF-A) by osteoblasts, and with stabilization of the hypoxia-inducible factor 1α (HIF-1α) in the same cells.[6] It has been known for quite some time that ATF4 controls bone homeostasis by stimulating both osteoblastogenesis and osteoclastogenesis[7-10]; now, Zhu and colleagues[6] add a new element to the picture by showing that mice lacking ATF4 have a reduced number of blood vessels in bone. The importance of their study is twofold: first, it provides convincing evidence that ATF4 regulates bone angiogenesis in vivo and ex vivo; and second, it shows that ATF4 contributes to stabilize HIF-1α protein in hypoxic-like conditions.
The vast majority of adult normal tissues functions at oxygen (O2) levels between 2% and 9%, with ambient air at 21% O2.[11] Cartilage, bone marrow, kidney medulla, and thymus, on the other hand, can exist at 1% O2 or lower.[11] When O2 tension goes below 2%, this condition is considered moderate hypoxia. When O2 tension goes below 0.5%, hypoxia is considered severe. HIF-1, a ubiquitously expressed transcription factor, is a major regulator of cellular adaptation to hypoxia.[12-18] It is a heterodimeric DNA-binding complex that consists of two proteins, HIF-1α and HIF-1β.[19] HIF-1α is activated when O2 levels drop below 5%[20-25]; on the other hand, HIF-1β is non–oxygen responsive. HIF-1α does not directly sense variations of O2 tension[26]; a class of 2-oxoglutarate-dependent and Fe2+-dependent prolyl-4-hydroxylases (PHDs) are the O2 sensors.[20] PHDs hydroxylate two prolyl residues (P402 and P564) in the HIF-1α region referred to as the O2-dependent degradation domain.[27] This modification occurs in normoxic conditions and mediates the binding of the von Hippel–Lindau tumor suppressor protein (pVHL), which is an E3 ubiquitin ligase, to HIF-1α. HIF-1α is then marked with polyubiquitin chains and targeted for degradation by the proteasome. Under hypoxic conditions, the activity of the PHDs is impaired and proline hydroxylation cannot occur. As a result, HIF-1α protein accumulates and this initiates a multistep pathway that includes nuclear translocation of HIF-1α, dimerization with its partner HIF-1β, recruitment of transcriptional coactivators, and binding to hypoxia-responsive elements within the promoters of hypoxia-responsive genes.[28]
HIF-2α, another member of the family, has been recently identified and characterized.[17] Similarly to HIF-1α, HIF-2α is degraded by the proteasome in normoxia, whereas it is stabilized in hypoxia.[17, 18] VEGF is one of the direct downstream targets of both HIF-1α and HIF-2α.[17, 29]
Despite its high degree of vascularization, a gradient of oxygenation is present in the bone marrow, and the endosteal surface of cortical bone is among the most hypoxic areas, as revealed by staining with the hypoxia marker pimonidazole.[30-32] This gradient of oxygenation within the bone marrow is most likely created by the high degree of bone marrow cellularity, the high levels of O2 consumption by hematopoietic cells, and the slow flow in the bone marrow sinusoids.[32, 33]
Several laboratories are currently investigating how bone cells and bone blood vessels relate to each other. In particular, it has been recently shown that either osteoblastic stabilization HIFs or osteoblastic overexpression of VEGF, one of the most powerful proangiogenic growth factors, leads to a dramatic increase of trabecular bone and to a significant augmentation of the number and/or volume of bone marrow blood vessels.[1, 18, 29, 34-36] These findings have prompted researchers to conclude that an osteogenesis-angiogenesis coupling is likely to exist and to play a role in bone development and homeostasis.[18] ATF4 has now been added to the list of transcription factors that control bone angiogenesis and, possibly, this osteogenesis-angiogenesis coupling.[6] Notably, Zhu and colleagues[6] show in their article that ATF4 not only is sufficient to drive angiogenesis, but is also necessary to ensure a normal number of blood vessels in bone. Moreover, they propose, although they do not experimentally prove, that osteoblastic VEGF downstream of osteoblastic HIF-1α is the key mediator of this novel function of ATF4.[6] Increased release of VEGF from the matrix upon activation of bone resorption by osteoclasts could be an additional contributing factor.[6]
Taken together, these are interesting and intriguing findings. However, because Zhu and colleagues[6] have used the global knockout of ATF4 for their study rather than its conditional knockout in cells of the osteoblast lineage, at this stage we cannot conclude with absolute certainty that osteoblastic ATF4 is indeed the main factor responsible for the angiogenic phenotype observed in mutant mice lacking ATF4. Along these lines, the activation of osteoclasts and the release of VEGF from the bone matrix occurring upon universal loss of ATF4 are probably both osteoblast-dependent and osteoblast-independent effects.[6]
The notion of an osteogenesis-angiogenesis coupling, which would be essential not only in bone development and bone repair but also in bone homeostasis, is potentially very important. However, numerous issues still need to be addressed and resolved. Undoubtedly, all the studies presented and discussed to this end strongly suggest the existence of a correlation between osteogenesis and angiogenesis.[1, 3, 18, 29, 34, 35] Nonetheless, although it has been convincingly established that stabilization of HIFs in cells of the osteoblast lineage or overexpression of VEGF in the same cells causes a dramatic increase of bone mass in the trabecular compartment as well as an augmentation of bone vascularity,[1, 18, 29, 34-36] it has never been experimentally determined whether the increased number of blood vessels is an essential prerequisite for the high bone mass phenotype observed in these models. The same consideration applies to the global knockout of ATF4: loss of ATF4 impairs both bone mass and bone angiogenesis,[6] but we cannot unequivocally conclude that the decreased number of blood vessels is the main factor contributing to the low bone mass phenotype observed in ATF4-null bones. Supporting our concern, it has recently been shown that osteoblastic VEGF controls osteoblastogenesis mainly through an intracrine mechanism, rather than by regulating the number of blood vessels in the bone marrow.[37]
Moreover, it is well established that osteoblasts regulate bone marrow angiogenesis[18] and that VEGF is a very powerful proangiogenic factor,[38] but the involvement of additional cytokines and/or growth factors produced by osteoblasts cannot be excluded.
In addition, a notion has recently emerged that osteoclasts could also be angiogenic cells by either producing angiogenic factors or by releasing them from the bone matrix.[39]
Last, both ATF4 and HIFs are likely to control bone homeostasis with a variety of mechanisms that go beyond angiogenesis.
In this regard, HIF-1α is a crucial regulator of glucose metabolism. In aerobic conditions, glucose is converted to pyruvate in the cytoplasm. Pyruvate then enters the tricarboxylic acid (TCA) cycle and oxidative phosphorylation takes place in the mitochondria.[40] Louis Pasteur was the first to record that O2-deprived cells convert more glucose to lactate than cells in normoxic cultures. This is the so-called "Pasteur effect." Induction of the Pasteur effect depends on HIF-1α, which upregulates glucose transporters, glycolytic enzymes, and the enzyme lactic dehydrogenase.[41-43] Moreover, HIF-1α inhibits mitochondrial oxidative phosphorylation, at least in part, by augmenting levels of pyruvate dehydrogenase kinase, an enzyme that phosphorylates and inhibits pyruvate dehydrogenase and thus conversion of pyruvate into acetyl coenzyme A (CoA).[44, 45] By inhibiting the entry of pyruvate into the mitochondria, HIF-1α attenuates not only mitochondrial respiration, but also diminishes reactive oxygen species (ROS) production in hypoxic cells.[46] Notably, it has been recently reported that both activation of non-oxidative glycolysis and accumulation of ROS significantly affect bone homeostasis,[47-49] which implies that HIFs could indeed control bone mass at least in part by modulating glycolysis and oxidative phosphorylation in osteoblasts.
With respect to ATF4, it has already been unequivocally shown that ATF4 in osteoblasts activates both gene transcription and amino acid import, and both functions are crucially important for ATF4-dependent regulation of osteoblastogenesis.[7-9]
Notably, ATF4 is a critical mediator of the endoplasmic reticulum stress response, particularly in hypoxic conditions.[50] Hypoxia increases ATF4 levels in a HIF-independent manner[50] and, at least in part, through inhibition of PHD3 activity.[51] These findings indicate that the PHD-oxygen sensing recruits both HIFs and ATF4. Zhu and colleagues' article[6] closes the loop between hypoxia, ATF4, and HIF-1α by showing that in cells of the osteoblast lineage, ATF4 is essential for proper stabilization of HIF-1α in hypoxia.[6] The details of this interaction are not yet clear, though they may again involve the oxygen-sensing machinery. In any event, the finding that HIF-1α and ATF4 appear to converge on common O2/nutrient sensing pathways in higher animals is consistent with the emergence of these two transcriptional pathways at a similar time in metazoan evolution.[52, 53] Interestingly, RUNX2, another regulator of VEGF expression,[54] has also been reported to interact with HIF-1α and control its stability.[55]
All in all, an interesting feedback mechanism has been established in which hypoxia increases ATF4 stability in a HIF-independent fashion, and this leads to further stabilization of HIF-1α with modalities that need to be further elucidated. At this stage, it is unknown whether this novel loop occurs only in osteoblastic cells, or whether it is indeed a more general mechanism of HIF-1α regulation also present in other cell types. Moreover, it is unknown whether stabilization of HIF-2α in hypoxia requires interaction with ATF4.
All authors state that they have no conflicts of interest.
This work was supported by the NIH (RO1 AR04819 to ES) and by the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under the Research Executive Agency grant agreement (300388 to CM).
Authors' roles: All of the authors contributed to the writing of this manuscript.
- 1Regulation of osteogenesis-angiogenesis coupling by HIFs and VEGF. J Bone Miner Res. 2009; 24(8):1347–53., , ,
- 2Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell. 2007; 131(2):324–36., , , , , , , , , ,
- 3Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev Cell. 2010; 19(2):329–44., , , , , , ,
- 4Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature. 2013; 495(7440):231–5.,
- 5SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005; 121(7):1109–21., , , ,
- 6ATF4 promotes bone angiogenesis by increasing VEGF expression and release in the bone environment. J Bone Miner Res. 2013; 28: XXXX–XXXX., , , , , , , , , , ,
- 7Transcriptional control of skeletogenesis. Annu Rev Genomics Hum Genet. 2008; 9:183–96.
- 8ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell. 2004; 117(3):387–98., , , , , , , , , , ,
- 9ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab. 2006; 4(6):441–51., , , , , , ,
- 10Activating transcription factor 4 regulates osteoclast differentiation in mice. J Clin Invest. 2010; 120(8):2755–66., , , , , , , , , , , , , , ,
- 11The role of oxygen availability in embryonic development and stem cell function. Nat Rev Mol Cell Biol. 2008; 9(4):285–96.,
- 12Oxygen sensing and molecular adaptation to hypoxia. Physiol Rev. 1996; 76(3):839–85.,
- 13HIF-1 as a target for drug development. Nat Rev Drug Discov. 2003; 2:803–11., ,
- 14How oxygen makes its presence felt. Genes Dev. 2002; 16(12):1441–5.
- 15Regulation of transcription and translation by hypoxia. Cancer Biol Ther. 2004; 3(6):492–7.,
- 16Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003; 3(10):721–32.
- 17HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nature reviews. Cancer. 2011; 12(1):9–22., ,
- 18Hypoxia-driven pathways in bone development, regeneration and disease. Nat Rev Rheumatol. 2012; 8(6):358–66., ,
- 19Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995; 92(12):5510–4., , ,
- 20Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 2006; 441(7092):437–43., ,
- 21Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1alpha. J Biol Chem. 2002; 277:40112–7., , ,
- 22HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001; 292:464–8., , , , , , , , ,
- 23Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001; 292:468–72., , , , , , , , , , ,
- 24Structure of an HIF-1alpha-pVHL complex: hydroxyproline recognition in signaling. Science. 2002; 296:1886–9., , , , ,
- 25General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci U S A. 1993; 90(9):4304–8.,
- 26Coordinate regulation of the oxygen-dependent degradation domains of hypoxia-inducible factor 1 alpha. Mol Cell Biol. 2005; 25:6415–26., , ,
- 27HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J. 2003; 22(16):4082–90., , , , ,
- 28Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway. J Biol Chem. 1999; 274(10):6519–25., , , ,
- 29VEGF-independent cell-autonomous functions of HIF-1alpha regulating oxygen consumption in fetal cartilage are critical for chondrocyte survival. J Bone Miner Res. 2012; 27(3):596–609., , , , , , , ,
- 30Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci U S A. 2007; 104(13):5431–6., , , ,
- 31Positioning of bone marrow hematopoietic and stromal cells relative to blood flow in vivo: serially reconstituting hematopoietic stem cells reside in distinct nonperfused niches. Blood. 2010; 116(3):375–85., , , , ,
- 32A central role for hypoxic signaling in cartilage, bone, and hematopoiesis. Curr Osteoporos Rep. 2011; 9(2):46–52., ,
- 33Modeling pO(2) distributions in the bone marrow hematopoietic compartment. I. Krogh's model. Biophys J. 2001; 81(2):675–84., , ,
- 34The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest. 2007; 117(6):1616–26., , , , , , , , , , , , ,
- 35The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell. 2012; 149(1):63–74., , , , , , , , , ,
- 36Increased skeletal VEGF enhances beta-catenin activity and results in excessively ossified bones. EMBO J. 2010; 29(2):424–41., , , , , , , , , , , , , , , , , , ,
- 37Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation. J Clin Invest. 2012; 122(9):3101–13., , , , , ,
- 38Multiple roles of vascular endothelial growth factor (VEGF) in skeletal development, growth, and repair. Curr Topics Dev Biol. 2005; 65:169–87.,
- 39Osteoclasts are important for bone angiogenesis. Blood. 2010; 115(1):140–9., , , , , , ,
- 40Biology of HIF-1alpha. Cell Death Differ. 2008; 15(4):621–7.,
- 41Two HIFs may be better than one. Cancer Cell. 2002; 1:211–3.,
- 42Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1alpha. Genes Dev. 1998; 12:149–62., , , , , , , , , ,
- 43Transcription factor HIF-1 is necessary mediator of the Pasteur effect in mammalian cells. Mol Cell Biol. 2001; 21:3436–44., , , , , , ,
- 44HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006; 3(3):187–97., , , ,
- 45HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006; 3(3):177–85., , ,
- 46HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell. 2007; 129(1):111–22., , , , ,
- 47WNT-LRP5 Signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation. Cell Metab. 2013; 17(5):745–55., , , , ,
- 48FoxO1 is a positive regulator of bone formation by favoring protein synthesis and resistance to oxidative stress in osteoblasts. Cell Metab. 2010; 11(2):147–60., , , , , ,
- 49FoxO-mediated defense against oxidative stress in osteoblasts is indispensable for skeletal homeostasis in mice. Cell Metab. 2010; 11(2):136–46., , , , , , , , , ,
- 50ATF4, an ER stress and hypoxia-inducible transcription factor and its potential role in hypoxia tolerance and tumorigenesis. Curr Mol Med. 2009; 9(4):411–6.,
- 51Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor. Blood. 2007; 110(10):3610–7., , , , , , , ,
- 52The yeast genome may harbor hypoxia response elements (HRE). Comp Biochem Physiol C Toxicol Pharmacol. 2007; 146(1–2):255–63., , ,
- 53Tribbles in disease: signaling pathways important for cellular function and neoplastic transformation. Cancer Sci. 2011; 102(6):1115–22.,
- 54Tissue specific regulation of VEGF expression during bone development requires Cbfa1/Runx2. Mech Dev. 2001; 106(1–2):97–106., , , , , ,
- 55Physical and functional interactions between Runx2 and HIF-1alpha induce vascular endothelial growth factor gene expression. J Cell Biochem. 2011; 112(12):3582–93., , , , , ,


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Certificate III in Aged Care (12)
OCTEC Limited
Certificate III
|Mid Year Intake?
|Study Mode
|Entry Requirements
|Flexible Delivery, Full-time internal, Part-time internal
No minimum education
Course Description
This qualification is part of the Community Services Training Package. It addresses work primarily in residential facilities under direct or regular supervision within clearly defined organisation guidelines and service plans. It is the standard entry qualification for workers in this sector and will introduce individuals to all aspects of a carer's role including personal care, well-being and assistance with daily activities. Individuals involved in this type of work need the physical capacity to deal with personal care and must demonstrate genuine compassion and empathy towards others.
Subjects you can Study
Core: Support older people to maintain their independence; Work effectively with older people; Provide support to people living with dementia; Work effectively in the community sector; Provide support to meet personal care needs; Participate in the implementation of individualised plans; Support individual health and emotional well being; Recognise healthy body systems in a health care context; plus more. Electives: Work effectively with culturally diverse clients and co-workers; Collect technical data to support client health care plan; Advocate for clients; Provide support and care relating to loss and grief; plus more.
About OCTEC LimitedEstablished in 1976, OCTEC Ltd is a not-for-profit Registered Training Organisation providing employment, education, training and advocacy services to western and central west New South Wales. With the main training venue in Orange, OCTEC has branch offices in Bathurst, Cowra, Forbes, Lithgow, Mudgee, Parkes, Young, Armidale, Glen Innes, Taree, Forster, Campbelltown, Narellan, Camden, St Marys, Penrith, Port Macquarie, Queanbeyan, Albury, and Dareton NSW . The provider aims to maintain flexible delivery of services to meet the needs of clients, including those who are disadvantaged or isolated. RTO code: 90142
Certificate IIICourse code: CHC30212
- Flexible Delivery
- Full-time internal = 2 months
- Part-time internal = 8 months
14 units: 10 core; 4 elective
Entry Requirements
No minimum education
Life after Study
Related Careers
Aged Care Worker
Aged care workers provide care, supervision and support for aged people in residential establishments, clinics, hospitals and private residence. Aged care workers assist with the maintenance of personal care, domestic duties and management of illness. They also provide companionship and emotional support, and promote independence and community participation.
Community Worker
Community workers encourage and assist community groups to identify their needs, participate in decision-making and develop appropriate services and facilities to meet those needs.


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Writing for Comics & Graphic Novels with Peter David Paperback – 16 Sep 2009
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In the past two decades, comic writers have become superstars in the industry, and Peter David is one of them, well known for his work selling millions of publications, including recent work on the comic-book versions of Stephen King's The Dark Tower. He's been Comics Buyer's Guide's most popular columnist for 13 years. He's constantly working on new things with many major entertainment companies and publishers.
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Exploring more on this Element Collage (thx @Dan) and really feeling this process.
There seems to be a lot less self-induced pressure to produce something that makes logical sense from all aspects - functionality, architecture, etc.
Just design something, design another part, move it around, change it, kind of the same way my Illustrator art board ends up when designing logos or wireframes.
I'll definitely keep stretching this process further.
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Unless you're listening to "Dark Side of the Moon" on your smartphone, it's hard to see them as devices for relaxation. More often, they're for aggressive thumb-tapping, Angry-Birding exercises.
But for every yin there is a yang. And mobile phones are no exception.
A path to a quiet mind can travel through apps dedicated to guided meditation and sleep enhancement. And fortunately, for those who need more, or better, rest, or who are inclined to still their minds for a few minutes a day, some good ones exist on all the major mobile platforms.
Simply Being ($1 on Apple, Android and BlackBerry) and Mindfulness Meditation ($2 on Apple, with an Android version in the works) are among the better ones, while Universal Breathing - Pranayama Free (free on Apple) and Pranayama Free (on Android) are useful for those who want to test the waters.
Those with pressing insomnia issues should consider Pzizz Sleep ($6 on Apple, with a Lite version for $2). On Android, the app costs $5.69 and goes by the name Pzizz, the Insomnia Solution. Another good, but pricey, option, is Mayo Clinic Insomnia Wellness Solutions ($25 on Apple).
The meditation apps, though, may well be enough to get you to sleep — or at least help calm you down.
Pranayama Free is the simplest. It leads you through exercises meant to limit you to seven breaths per minute, five breaths per minute, or about four breaths per minute. When I tried it, the graphics were helpful, but the music was a tad obtrusive.
A bigger problem was that it was slow to load and not very responsive to the touch (at least on my Droid2), so it was barely more relaxing than frustrating.
I tried Simply Being not long after in the middle of a workday that had gone haywire. I was surrounded by email-toting gadgets that, I was sure, were loading important messages from colleagues.
I grabbed my iPhone and opened Simply Being, and the screen offered four options for "guided meditation for relaxation and presence." I chose the 5-minute option, and left the 10-, 15- and 20-minute options for another day.
I then chose music, rather than nature sounds, to accompany the narrative, and I tweaked the volume of each so the narrative was clearly audible.
I was braced for a narrator who had the sort of whispery, saccharine tone that's as relaxing as a Sawzall on a steel pipe, but fortunately, the narrator, Mary Maddux, used an approach that didn't sound like a parent cooing a baby to sleep.
Maddux's husband and co-developer of the app, Richard Maddux, composed the admirable soundtrack.
After five minutes I was nearly asleep.
Not everyone will respond to a given narrator's voice, so another good choice is Mindfulness Meditation, which is written and narrated by Stephan Bodian, the author of "Meditation for Dummies."
Bodian's narrative was thorough, relaxing and well pitched for a meditation novice like me. There is no music or sound accompaniment, but there is more content to the app than in Simply Being.
Users can choose meditations of 5, 10, 15, 20 and 30 minutes, or a simpler relaxation narrative of 10 minutes.
A guide also offers audio tips for finding the best meditation position, for instance, and there is a text-based checklist of eight factors to improve the experience.
About an hour after nearly falling asleep to Maddux's voice, I did the same with Bodian's voice.
That drowsiness was partly due to a bout of insomnia the previous night. Lying awake at 3 a.m., I tried Brain Wave ($2 on Apple), which features binaural electronic tones against the backdrop of nature sounds. According to the app's description, it requires earbuds or earphones to work properly.
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while on business travel in western Leyte, scouting for a place to stay in ormoc city. visited a couple of places but this one is highly recommended. place is clean, decent, safe and has friendly staff. will be back when i travel with my family.
Own or manage this property? Claim your listing for free to respond to reviews, update your profile and much more.


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Ortho Memory Foam Pet Bed
Item # WX2-282875SOLD OUT
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Ortho Memory Foam Pet Bed. Soothe a tired dog's aches and pains. BIG BUCKS OFF!
High loft, super-soft foam conforms like a dream to your favorite 4-legged friend! The perfect throne for someone who's been by your side through thick and thin. Top-notch support helps relieve the stress of arthritis, hip dysplasia, sore joints and more. Offered in two sizes to get a better match for your specific dog. Give Rover a rest for BIG BUCKS OFF!A better Pet Bed:
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State Color and Size, as available in the Shopping Cart.


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|Meet the new addition to Sonic X OC world
|Meet the new addition to Sonic X OC world
A RISING HERO Ch.3Meanwhile in the X-Mansion...A RISING HERO Ch.3 by HyperGirl95
"Hey, Jean! Come and look here." Scott told Jean Gray. Scott was standing in front of a big monitor looking at a giant blip that just appeared on the map.
"Did you find something, Scott?" Jean asked.
"Yeah. Looks like a red signal." Scott answered.
"A red signal?"
"And it appears to be coming from Illinois."
"We have to tell Professor Xavier about this, Scott."
The next day at school...
"Did you see how Deadpool killed those men on StarClip? It was pretty brutal, but awesome." A boy was talking in the corridor during recess.
"I think you need to see a doctor. He Killed those men without mercy and then post his insane videos online. They confirmed that video will be removed earlier today from the site, because it's far too inhuman." the friend of the boy said.
Then the two boys walk past Eleanor and her two close friends, Helen and Cage.
"What is all the hype today
A RISING HERO Ch.2A RISING HERO Ch.2 by HyperGirl95
At school...
"I heard this mutant can control the weather and can make it snow, or rain, or whatever, whenever she wants" classmate1 of Ellie's was talking.
"Yes, there is such a mutant and her name is Storm from X-Men. Do some research before you talk about someone famous." classmate2 said.
"Won't it be great if we could invite at least one of those X-Men in our town? I mean, think about it. Every other town in the area will be jealous of us if we invite a professional mutant." classmate1 said.
"Just what do you mean by 'professional'?" classmate2 criticized.
"Hey, Ellie. You ok?" classmate1 asked Eleanor a bit worried.
"Huh." Ellie snaped out "What? Is lunch break over?".
"You seem a bit off today, Ellie. Have you forgotten to sleep again?" classmate1 asked.
"Who? Me? No. Not at all."
"You said you had an accident at home this morning. Do you still feel any pain?" classmate2 asked.
"No. Not at all. I feel great." Ellie raises her hands to show that nothing is wrong with her, only for
A RISING HERO Ch.1A RISING HERO Ch.1 by HyperGirl95
Some people say that "If you're born with a gift, then one day the people will appreciate you very much.". As opposed to this sentence, rises the question: "Will people appreciate your gift because of the good you do? Or the bad you do?". In the Marvel Universe, both things seem to be more balanced. There are just as many supervillains as superheroes. The Marvel Universe is famous for having around 8000 mutants (both villains and heroes). Weaker villains are being controled by stronger villains. Unexperienced heroes are being tutored by skilled heroes. And some mutants prefer to work only if they receive payment afterwords for their work. So in such a vast and powerful world, is it somehow possible for an ordinary mutant to suddenly become noticed by heroes, villains and other mutants out there... even if your mutant powers don't seem that much impressive? Well, we're about find that out.
KND Operation S.O.C.H.I. - Chapter 1KND Operation S.O.C.H.I. - Chapter 1 by HyperGirl95
Kids Next Door Operation: S.O.C.H.I.
"Kids Next Door! Battle Stations!" yelled Numbuh 1 in the middle of a battle. Some of the biggest enemies of the Kids Next Door were in this battle - Sticky Beard, Mr. Boss, Toiletnator, Crazy Cat Lady and many others.
"I'm gonna pound all these into a pile of dust." Numbuh 4 implied.
"And I'm gonna beat the tulips out of them. Get it! Tulips." Numbuh 2, while inside a giant robot, only no one was laughing. "How come everytime Numbuh 5 makes a joke, everyone laughs, but no one ever cares about my jokes?"
"Numbuh 5, come in! I need you to get a ship here this instant!" Numbuh 1 ordered Numbuh 5 on the phone.
"Numbuh 5 will be there any minute." Numbuh 5 answered.
"Numbuh 3! Come in! I need you to be ready, because Numbuh 5 will be here any moment with the ship." Numbuh 1 told Numbuh 3. "..." only nothing came from the oth
I'm a digital artist-hobbyist. My goal is to show my art to the world and to become a better digital artist and learn to do CGI art one day.
and a Pixiv account -> www.pixiv.com/users/5513593
|Help me receive more points so I can donate them to help other artists.


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'Brewers on Deck' aims for another record
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20 percent payroll cut. No #2 starter. Profits over winning.
Boycott.Hide replies
which #2 starter did you want them to get/overpay?
The first one is right. The second one is up for debate. The third one is flat wrong. If that was the case, the owner wouldn't have spent more than $100 m last year on Marcum and Wolf, both of whom where outdone by rookies called up later. Spending lots of money is no guarantee of winning. Just ask the Yankees. Or the Red Sox. If the owner wanted money he would do what the Marlins have done.
Been boycotting since the last strike.See no reason to change now.
How's that been working out for you?
"We thought it was spreading the players a little too thinly," said Schlesinger. "As much as we'd love to go upstate, we're going to have a lot more ability to impact and interact with folks by doing it at the Delta Center."
The story of our lives if you live in the Northwoods. I will be making the trek south several times this year for the Brewers....but I really don't mind.Hide replies
It seems to me that they had a caravan AND an on deck-type event in the past. To say what they are doing now serves the fans better is self-serving and not really accurate. They decided to save the money spent on the caravan and I'm sure they also wanted to avoid the poor weather that often accompanied the caravan. Cost saving measures trump just about everything these days so that's become the norm, but you can't make a case that it serves the fans better when so many won't now get the chance to see players/coaches as they had been able to do before.
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9 Halloween Crafts and Halloween Recipes for Parties
Bonus: Get our newsletter & special offers for free. We will not share or sell your email address. View our Privacy Policy
DIY Johnny Appleseed Costume
By: Kristin from peapodcreations.blogspot.com
We are adding the project to your Holiday Projects.
The project was added to your Holiday Projects.
Click here to view your Holiday Projects.
How adorable is this DIY Johnny Appleseed Costume? If you're looking for ideas for easy homemade Halloween costumes, this is one that your little boy will enjoy! He'll love parading around with a pot on his head and you'll have a blast taking pictures of this cute Halloween costume! This homemade Halloween costume idea is easy to make with thrift store finds and other scrap fabric you have around your house. Your child will have so much fun with this Halloween craft for kids.
Estimated Cost: $11-$20
Time to complete: In an evening
Primary Technique: General Crafts
Difficulty Level: Easy
If you're looking for more Halloween costume ideas, download our FREE eBook: 23 Halloween Crafts for Kids: Homemade Halloween Costume Ideas and Spooky Decor!
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Loo & Chilli
Best and Worst Foods to Eat When You're Sick
Posted February 19th, 2014 @ 7:26am
No matter how hard you try to avoid getting sick, the sniffles are still hard to escape. The next time you get sick...keep in mind which foods you SHOULD and SHOULDN'T be consuming.
According to The Huffington Post, here's a list of the BEST and WORST foods eat when you're SICK:
1. Hot Tea...it can soothe a sore throat.
2. Citrus fruits can boost the immune system and accelerate your recovery.
3. Spicy foods can relieve congestion.
1. Foods high in sugar and fat can suppress the immune system.
2. Drinking milk can produce more mucus.
3. Acidic food can upset your stomach.
photo credit: CHRISSPdotCOM via photopin cc


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From architecture to quantity surveying and construction to civil and mechanical engineering, many of our courses are accredited by professional bodies and developed with industry. You'll gain the skills and knowledge that reflect emerging technologies and meet the needs of today's employers.
Our student bloggers give you behind-the-scenes access to life as a student, from starting university as a fresher through to graduation.Read our student blogs
What's it really like to study with the Faculty of Science & Technology? Our students share their experiences of their courses and university life.


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Oracle April 2016 PSU and Proactive BPs are there
By Mike Dietrich-Oracle on Apr 21, 2016
Hurray, it's Patching Day!
Sounds a bit like D-Day But April 19, 2016 the most recent April PSUs (Patch Set Updates) and BPs (Bundle Patches) got released.
Find all the necessary information with the below links:
The important change in the April PSU/BP release:
The database patch for "Engineered Systems and Database In-Memory 18.104.22.168" luckily got renamed into "Proactive Bundle Patch 126.96.36.199". That is not only a rebranding but it should express that we would like to encourage you to apply the Bundle Patches instead of the PSUs. Simple reason is that the BPs will contain optimizer fixes.
In the MOS Note: 2102148.1 (Patch Set Update and Critical Patch Update April 2016 Availability Document) you'll find a section 3.1.4 linking to the database patches.
This is the recommended one for Oracle Database 22.214.171.124:
- Database Proactive Bundle Patch 126.96.36.199.160419 (Apr2016) Patch 22899531,
But right now it is available for Linux-x86-64, zLinux and Intel Solaris only. Not sure when the others will get released. Please find links to the regular PSUs and other ports and releases such as 220.127.116.11 and Windows etc in the above MOS Note: 2102148.1.
This is the list of fixes included in this Bundle Patch:
- MOS Note 1937782.1
126.96.36.199 Bundle Patches for Engineered Systems and DB In-Memory - List of Fixes in each Bundle
I will download it right now and patch my HOL environment.
And as usual don't forget the most recent version of opatch (Patch 6880880).


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This happens with Mordor too. I am trying it in the map "Black Gate"
This member has provided no bio about themself...
This happens with Mordor too. I am trying it in the map "Black Gate"
I have two questions about editing the game files. Since sometime before 3.2 they removes the Gondor Cavalry Militia from the campaign, but its still recruit able in custom battles. How can I add this unit back into the campaign? Secondly, they also at one point had forts around Minas Tirith in the Rammas Echor. Any way I can add this back in too or not? I am using the most recent MOS 1.6.1 if that helps. THANKS IN ADVANCE!
On a side note I was really surprised that they even removed the forts inthe first place considering they are in the lore and they were manned during the War of the Ring.
Two questions. Thanks in advance!
Anyone have any idea if this mod is compatible with Realistic Needs and Diseases? They have a patch for version 11, but I really want that mod and I am not sure if I can run v12 with the V11 patch or if I need a patch at all.
Secondly, I currently have V12 installed. When V13 comes rolling out will it be save game compatible or will I have to start a new character. I am really just holding out on my new play-through so I can install V13 when it comes out.
I have the version 12 and I found a balrog near a swamp, but it looks nothing like the one posted. It has a dragon like head and it looks nothing like the epic one shown here. Also I am having trouble finding the vast majority of the monsters added my this mod at all. What am I doing wrong? I am sure I Installed this correctly and have both the BSA and ESP in my data folder. Is there a Level requirement for each monster or something? I am currently level 45 and have yet to see the vast majority of the creatures this mod adds. ANY help at all would be appreciated! Can't wait for version 13!
Maybe this is stupidity talking, but could we do anything like they did in this case?
It said they paid like 100 dollars or so per year for a license. just saying that if its only 100 dollars a year then I will be more than happy to help out. I know that paying that must forever is retarded, but once the mod is out there its out there.
Hey guys, I know that this isn't a support forum, but I am at my wits end here. I am terrified to install this mod because im afraid it will stop working or not work at all. I installed Medieval 2 Total War Gold edition and I installed the crusades expansion (updated to version 1.05). However when I start my normal Medieval 2 Total War it says that its version 1.02. I know you have to have all the patches set up in order to play this mod. When I try to update my M2TW to version 1.03 it says that it is already at that version???? Just wondering if anyone else has this problem and if the mod is still playable.


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Grand Hyatt Istanbul, Istanbul
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What's around
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Grand Hyatt Istanbul, Istanbul
Hotel Info: 866-539-8122from $124
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At a glance
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Required at check in
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Nearby Five Star Istanbul hotels
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Recently reviewed hotels in Istanbul
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Special features
Gaia Spa has massage/treatment rooms. Services include deep-tissue massages, hot stone massages, massages, and facials. The spa is equipped with a sauna, a steam room, and Turkish bath/hammam.
The spa is open daily. Guests under 16 years old are not allowed in the spa.
DiningGazebo - This poolside cafe serves lunch and light fare. Guests can enjoy drinks at the bar.
Mezzanine - Onsite lobby lounge.
Grand Hyatt Istanbul, Istanbul's small print
Also known as
- Grand Hyatt Istanbul
- Grand Hyatt Istanbul Hotel
- Hyatt Istanbul Grand
- Istanbul Grand Hyatt
- Grand Hyatt Istanbul Hotel Istanbul
- Hyatt Istanbul
- Istanbul Hyatt Regency
Guests under 16 years old are not allowed in the spa.
Optional extras
Self parking costs EUR 7.00 per day
Valet parking costs EUR 10.00 per day
Rollaway beds are available for EUR 48 per night
Buffet breakfast is offered for an extra charge of EUR 30 per person (approximately)
Babysitting/childcare is available for an extra charge
Airport shuttle service is offered for an extra charge of EUR 80.00 per vehicle (roundtrip)
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.
Is the description of this hotel not correct? Tell us


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The striker, 30, has scored 17 goals this season in 38 appearances, but was left out of the Millers' damaging 2-1 defeat at Morecambe on Saturday, much to the anger of some fans.
Evans put that omission down to poor form and has refused to say whether he will be picked for Tuesday's must-win clash with Exeter.
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"Daniel Nardiello knows I pick a team to win a game. He'll find out whether he is playing at 6.15pm on Tuesday."
- Sports & Recreation
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From Our Editors
Snack on tasty pub fare at The Wilds Golf Club, a local favorite. With this restaurant's wide selection of refreshments available, you can tap into the drink menu early in the evening. The Wilds Golf Club's happy hour is filled with food and beverage deals. If dining outdoors is your idea of a good time, you'll love the gorgeous patio seating at The Wilds Golf Club.
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That's just the way it is
what a dummy !!
Come on! DO you expect VMW to just keep going up without pausing??Just look at the valuation!! The numbers are not blowout and they are not enough to sustain the current price. This will be red tomorrow!!Sell the news...dummy.
AH is the time to sell. VMW beat, but of course they were expected to beat. Now the question tomorrow morning is valuation. I think that this will pull back in the morning, if not later in AH
FU losers. You short today after hours and then tell us to sell. You're a gambler and you deserve to lose. Of course it will pull back a little. You prob don't know tech. Do you know what virtualzation is. Didn't think so. Keep shorting I need the money. Have fun.


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Birthday Gifts For Her
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Polaroid Cube Mini Lifestyle Action Camera
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Beaches By Gray Malin
Everyone's favorite luxury photographer is back — this time with a coffee table book full of all his best aerial work. If you're longing to take her on a tropical vacation but the budget won't quite allow it, this book of wonder may just be the next best thing.
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Related Readings
- Anniversary Gifts for Her
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After watching this minute by minute for a few quarters I knew this couldnt hold a new 52 week high. I still love the stock but I havent fallen in love with it, KORS is a fickle biotch and should be traded as such. I will get back in but I think we retest 60 before heading to 70. The company is solid and the growth is obvious but after the fireworks today I feel we will go back to the same old trading pattern and I want to take advantage of the dips and new highs to scalp some easy money.
I think upgrades will push this to 70 later this week. Thoughts? I'm holding March 16 calls $60.
Every leg up after earnings has followed more highs... just saying.
Sentiment: Strong Buy
You beat me to the board by about 40 seconds with the same topic...more or less. Congrats on getting out and booking a nice profit. Absolutely nothing wrong with that.
Sentiment: Sell


text: Remainders: Partridges and Pear TreesDoree Shafrir12/15/06 6:10pmFiled to: RemaindersJann WennerMen's JournalYouTube2EditPromoteDismissUndismissHideShare to KinjaToggle Conversation toolsGo to permalinkJann Wenner fires Men's Journal deputy editor Ben Court. Also, newsstand is down 40 percent since Wenner took over as editor-in-chief. [Jossip]College tours, WB style. [IvyGate]Catch up on all those YouTube videos everyone's been talking about. [BWE]Reply2 repliesLeave a reply


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Sounds Like: Ernest J. Lee Music - GameChangers, Jay Z, Lil Wayne, Drake, D12
Label: Red Tape/David's Dance
Manager: Minstrel's Consulting Firm
Bio: GameChangers are a group of Hip Hop Artists & Producers from Detroit, Michigan. The conglomerate was formed in July 2012 for the purpose of Producing, Recording, Performing, & Marketing upcoming artist who have the drive & passion to succeed in the music arena! The first Mixtape, titled "Big Talk...See Full Bio
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In Illinois licensure by the State Department of Public Health is required by statute of all hospitals giving maternity service. To qualify for a maternity license the hospital must comply with a number of regulations established by the Division of Maternal and Child Hygiene in conjunction with medical and hospital advisory groups. Among the requirements for licensure are those dealing with segregation of the obstetric unit, adequate physical arrangement, trained personnel, essential equipment, approved technics and acceptable records. Included in the item of records is the requirement of submission to the Division of Maternal and Child Hygiene of a monthly report which shows the number of mothers and infants cared for, the type of delivery, the operative procedures employed, the incidence and types of complications encountered, the frequency of abortions and ectopic gestations and the number and causes of stillbirths and neonatal and maternal deaths. These reports are given careful
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|Memory & Compatibility Features
|Internal Memory
|Compatible Image Format
|Memory Card Supported
|SDHC / SD (Maximum - 32 GB) (Not Included)
|Functional Features
|Slideshow, Thumbnail
|Model Name
|Landscape, Portrait
|Display Features
|Display Size
|6 inch
|Display Type
|Aspect Ratio
|Display Resolution
|480 x 800
|Viewing Area
|74.88 x 129.24 mm
|6 Months
|179 g
|Power Features
|Power Consumption
|DC (5V, 600mA)
|Power Requirement
|DC (5V, 600mA)
|Additional Features
|Remote Controller
|Additional Features
|6 inch LCD, Landscape and Portrait Placement, Calendar, Clock, Slideshow Feature
|In the Box
|Power Adapter, Digital Photo Frame
Please Note: All products sold on Flipkart are brand new and 100% genuine
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Nagesha H S
Feb 10, 2015
worst product
Jan 4, 2015
DigiFlip DF001 6 inch Digital Photo Frame- Candid review
Madhu Chigullapalli
Sep 26, 2014
Good Mid range photo Frame
Saleesh S
Aug 25, 2014
Best value for money Photoframe in India
Prasanna Nandurkar
Aug 18, 2014
Good Gifting Item
'Top Reviews' lists the most relevant product reviews only. Show ALL instead?Expand all Reviews
Binay%20Kumar Pandey
Apr 27, 2013
Value for moneyif you are looking for a no nonsense photo frame, this is the one to go for. It does the job done, no extra features like mp3 player or video support, its a plain simple photo frame. And thats what I wanted. The only con is its viewing angle from below. I put it on self, and sitting at sofa, the images are not as clear as they are from standing view. So, try to place it at a lower level, like on table or phone stand etc. if it is placed higher than 5 ft, and you are looking at it from 2.5ft (sitting at sofa), the images are dark, and not clear.
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Aug 21, 2013
After using it for 1 yearIn this budget it is the best deal....only one thing that it uses SDHC card only.
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Apr 1, 2014
Depends!!!Well we have purchased this product to gifted someone eventually we ended with something else. No doubt it has everything what described, but they should have elaborate the specs a bit more.
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A good photo-frame at this pricePros -
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worst productit shopped working with in 4 months.... and bad customer support as well. I would have give 0 if rating allowed it.
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DigiFlip DF001 6 inch Digital Photo Frame- Candid reviewHi All,
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Good Mid range photo FrameThe frame build quality is really good glad it did not look cheap, the overall picture quality more than satisfactory. I was worried about the pic quality, luckily it turned out be better than expected. It has all the features as in branded one's but less price. The shipping was done really fast, thanks to the seller. Hope this product lasts long,../Overall happy with product
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A new ratings tool has led to more games than ever being refused classification, but advocates say this is just a fraction of the massive list of 150,000 games now classified for the first time.
The Classification Board will review the ratings given to 12 released video games after a request from the South Australian attorney-general.
The Australian Classification Review Board has announced a review of banned game Saints Row IV.
The edited version of the troubled game has passed the Classification Board, garnering an MA15+ rating.
Rockstar's latest Grand Theft Auto game passes muster with the Classification Board, getting an R18+ rating.
The zombie survival game has received approval from the Classification Board for sale in Australia.
The Australian Government's Classification Board, which determines ratings on video games and decides if they can be sold in the country, lays down the ruling.
Yesterday, Saints Row IV became the first game hit by the R18+ laws, the Classification Board follows up by giving the same treatment to State of Decay.
Naughty Dog's post-apocalyptic thriller scores itself an adult rating from the Australian Classification Board.
Australia's classification board has weighed into the Grand Theft Auto "Hot Coffee" sex debate, opening their own investigation into the controversial mod.


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Matt Damon and Jimmy Kimmel Go to Couples Therapy Again. Does It Work This Time?
- 03:22 PM, Jul 26
NYC Premiere of "Daybreakers"
Photo credit: Janet Mayer / PR Photos
To fit your screen, we scale this picture smaller than its actual size. The original picture size is 600x589 pixels and this photo has been viewed 3312 times since January 07, 2010


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A man accused of killing his mother with a baseball bat is undergoing a forensic examination.
In criminal court on Tuesday public defender Charles Herman asked the court to reset James Marlow Jr.'s next court appearance to Sept. 27 so the tests could be completed.
With no objections raised by prosecutors, Criminal Court Judge Shayne Sexton allowed the postponement.
Prosecutors had previously filed a notice with the court that if Marlow was convicted of the first- degree murder charge they would seek that he be imprisoned for life with no possibility of parole, according to court records.
As supporting factors for the request, Marlow's prior conviction for a "violent felony" in which he physically attacked his then wife and the "heinous, atrocious, cruel" manner of his mother's death were presented to the court.
In June police found the body of Sue Marlow inside her home. A baseball bat was found in two pieces near her.
Her son, James Marlow, Jr. was arrested and charged in connection with her death.
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