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This article is sponsored by a research based pharmaceutical company
Getting to the heart of diabetes
Researcher aims to reduce heart disease in people with obesity and diabetes.
Rosalind Stefanac Special to Postmedia
Therapeutic Spotlight
What causes heart disease in people with diabetes? Thomas Pulinilkunnil (pictured above) of Dalhousie University, and his research team at Dalhousie Medicine New Brunswick in Saint John, N.B., are working to find out. By identifying new biomarkers (substances that act as a kind of early warning system for trouble or stress in heart muscle cells), Pulinilkunnil says researchers can develop future treatment options that could potentially improve the function of these cells to stop them from getting damaged.
How did you get involved in researching diabetes and the heart?
My parents and their siblings all have diabetes so I've seen the impact of this disease personally, which was a strong motivator for me to pursue diabetes research. This disease affects many systems in the body (eyes, skin, nerves) but the primary reason people die from diabetes is due to complications of the heart. In fact, most of my family members with chronic diabetes have now developed heart issues.
What have you discovered so far?
If insulin is working properly, then glucose [sugar] can get into the heart for energy. When insulin doesn't work properly, the heart starts borrowing energy by burning fat. Researchers have determined that [depending too much on fat for energy, rather than glucose,] is contributing to heart issues in people with diabetes. [One of the problems is] the failure of lysosomes—the heart cells' 'garbage cans.' We discovered that, in people with diabetes, the heart accumulates more 'garbage' because the [lysosomes] do not work as well as they should, which makes the heart cells less efficient over time until the cells die. This eventually leads to heart failure.
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We're trying to figure out exactly why these heart cells get damaged and whether there are specific cell markers we can identify so we can restore them. My lab is working on a small but important part of the puzzle.
You run the lab jointly with your wife [Petra Kienesberger, an assistant professorin the Department of Biochemistry, Dalhousie University]. What's the best part of being married to a fellow diabetes researcher?
The best part is our ability to collaborate. We complement each other personally and professionally. We review and critique each other's research progress and career development.
"Dr. Pulinilkunnil's research illustrates many components of research that has an impact—diving deep into the cells to understand what is going wrong when they are damaged by diabetes, seeking out chemical markers that can signal and track that damage, and working collaboratively both in a local team and as part of a larger community of scientists committed to finding innovative solutions." – Dr. Jan Hux, President, Diabetes Canada
Thomas Pulinilkunnil at a glance
Became the first applicant from New Brunswick to receive Diabetes Canada's Scholar Award and Operating Grant (2016)
Appointed operational research director, Dalhousie Medicine New Brunswick (2013)
Joined the Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, as assistant professor (2012)
Completed two post-doctoral fellowships, at the University of Alberta (2009) and at Harvard (2006)
Earned his Ph.D. from the University of British Columbia (2005)
Obtained a Masters in Neuropharmacology, National Institute of Pharmaceutical Education and Research, Punjab, India (1999)
Visit diabetes.ca/research to read about the research projects and awards funded by Diabetes Canada.
How can you help us fund research that changes lives? Donate now!
Reprinted with permission of Diabetes Dialogue, Diabetes Canada, 2018
This story was created by Content Works, Postmedia's commercial content studio.
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Own a Mac? It's time to update your software
Attention at the most recent Apple event was squarely focused on products, particularly the new iPad Pro range and Apple's new location tracking device, the AirTag. On the software front, iOS 14.5 has stolen all the headlines as it increases user privacy by blocking invasive ad tracking on iPhones and iPads.
Far less publicised has been the release of some updates for MacOS which runs on Apple's iMac and MacBook computers. While people have been eagerly updating their iPhones, they may have overlooked their computers – and that could be a serious mistake.
Dealing with a zero-day exploit
A new update has been released for MacOS Big Sur (11.3) and, somewhat unusually, for the two previous operating system versions (Catalina and Mojave). These updates address a number of security issues, the most important of which is a zero-day exploit that could leave your computer wide open to hackers and malware.
MacOS is designed to be highly secure, making it as hard as possible for hackers to break into your computer. One core protection is Gatekeeper, a security feature that checks every item of software you ever download and install is legitimate and safe.
However, the developers of the Shlayer trojan had found a way to bypass Gatekeeper so that the malware could install itself undetected. This zero-day exploit was so successful that around 10% of all Mac computers were suspected to have been infected by the Shlayer trojan before security researchers realised there was a problem.
A very, very important update
MacOS updates usually contain a number of patches to address important yet obscure, low level security vulnerabilities – as does MacOS 11.3. But because this latest Big Sur version fixes a significant issue with Gatekeeper, it is even more important that you download and install it as soon as possible. The longer you leave your computer unpatched, the longer you are at risk of being infected by Shlayer or other Mac malware.
Not running MacOS Big Sur? You should still check to see if there are updates available for your Mac because the Gatekeeper exploit also affects previous versions of the operating system.
Simply click the Apple logo in the top left-hand corner of your screen and select About This Mac. A small window will pop-up telling you which version of MacOS is installed. Click the button labelled Software Update… and your computer will see if there are any new patches that need to be installed.
If you want MacOS to install updates automatically in future, tick the Automatically keep my Mac up to date checkbox on the Software Update screen. Your computer will then download updates when they are available and install them overnight ensuring MacOS is kept up to date – and that the installation process doesn't interrupt when you are using the device.
And as always, keep an eye on the Panda Security blog for the latest news about threats and updates that will help you keep your Mac safe.
Panda Security specializes in the development of endpoint security products and is part of the WatchGuard portfolio of IT security solutions. Initially focused on the development of antivirus software, the company has since expanded its line of business to advanced cyber-security services with technology for preventing cyber-crime.
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redpajama_set_name: RedPajamaCommonCrawl


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Q: Can we do grpc calls inside an AWS Lambda func? I am trying to call the stable diffusion API from an AWS Lambda and I get the following error :
[INFO]  2022-09-21T22:17:51.365Z        Opening channel to grpc.stability.ai:443
[INFO]  2022-09-21T22:17:51.368Z        Channel opened to grpc.stability.ai:443
START RequestId: 01d0e435-90b5-4739-a740-20180586e331 Version: $LATEST
[INFO]  2022-09-21T22:17:51.370Z    01d0e435-90b5-4739-a740-20180586e331    Sending request.
E0921 22:17:51.514530074      13 ssl_transport_security.cc:1378] Handshake failed with fatal error SSL_ERROR_SSL: error:1000007d:SSL routines:OPENSSL_internal:CERTIFICATE_VERIFY_FAILED.
I'm setting up the grpc host with : os.environ['STABILITY_HOST'] = 'grpc.stability.ai:443'
Do you have an idea on how to fix this ?
Thanks

redpajama_set_name: RedPajamaStackExchange


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Trump and Pence take power
Nick Duffy January 20, 2017
Donald Trump and Mike Pence have been officially sworn in as President and Vice President of the United States.
The billionaire reality star and his political running mate took their oaths of office to officially succeed Democrats Barack Obama and Joe Biden.
As Trump and Pence take office, the GOP are now in full control of both the executive and the legislature for the first time since 2005.
The news means little chance for the Democrats to scupper Republican attacks on LGBT rights, with Obama previously using executive powers to defend equality from advances in Congress – something Trump has pledged not to do.
The President has not released a policy plan on LGBT rights, and also has no policy plan on HIV/AIDS.
However last year's Trump-backed GOP Platform contained some of the most anti-LGBT provisions in decades, attacking same-sex adoption and parenting and opposing a ban on 'gay cure' therapy, while lawmakers have drawn up bills affirming 'religious freedom' exemptions from anti-discrimination laws.
Once a moderate on LGBT issues, Trump has wholesale adopted of a number of hardline evangelical policy planks.
One of the new President's only direct policy pledges it to sign the Republican-backed First Amendment Defence Act, a law that would permit forms of anti-LGBT discrimination on the grounds of religion.
In a speech to Catholic interest groups, Mr Trump confirmed he would not veto the law, which bans the government from taking any "action against a person on the basis that such person believes or acts in accordance with a religious belief or moral conviction that marriage is or should be recognised as the union of one man and one woman".
The broadly-written law would part-legalise religious discrimination against LGBT people in all sectors, from employment to retail to healthcare, banning the government from intervening.
In passing FADA, Trump and Pence would be required to repeal Barack Obama's 2014 executive order that extended LGBT anti-discrimination protections to federal contractors.
Mike Pence confirmed this intention, pledging to pare back President Obama's orders on LGBT rights so that "the transgender bathroom issue can be resolved with common sense at the local level".
Likewise, the Republicans assuming control confirms that the Democrat-backed Equality Act – a bill that would amend the Civil Rights Act of 1964 to finally outlaw discrimination based on gender identity and sexual orientation on a federal level – is now effectively dead in the water.
Donald Trump's plan for the Supreme Court also raises questions of an impact on LGBT rights.
As President, he is likely to be responsible for filling two or three seats on the highest court in the US, where most LGBT rights battles have been decided by a narrow 5-4 majority.
During the Presidential debates, Trump confirmed that he would appoint justices in the mould of the late Antonin Scalia, who opposed the decriminalisation of sodomy and penned a blistering dissent against the equal marriage ruling.
A public shortlist of Supreme Court candidates released by Mr Trump features only anti-LGBT conservatives, after the hopeful said he would "consider" using his appointments to overturn equal marriage.
If an anti-LGBT majority is built up on the Supreme Court, a harmful precedent on LGBT rights could be established for decades, not just for four years.
There are many issues that may end up before the court – from transgender rights, to anti-discrimination protections, to ramifications from the 2015 same-sex marriage ruling – which could be set back.
Mr Trump has affirmed his support for local state anti-transgender laws, though he does not have a declared national policy on the issue.
A hardline evangelical who has not supported a single LGBT reform across nearly two decades in politics, VP Pence has one of the worst records on equality of any President or Vice President in recent memory.
The Governor of Indiana stirred up international outrage in 2015 when he signed Indiana's controversial 'Religious Freedom Restoration Act', giving businesses the right to discriminate against gay people on the grounds of religion.
Pence claimed the law was intended to "protect" organisations from having to provide services for same-sex weddings, saying: "I support the freedom of religion for every Hoosier [Indiana citizen] of every faith.
"The Constitution of the United States and the Indiana Constitution both provide strong recognition of the freedom of religion but today, many people of faith feel their religious liberty is under attack."
Last year appeared unable to answer when asked whether it should be legal to fire people because of their sexuality.
In a clip, Pence was asked "Yes or no: do you believe gay and transgender people should be able to be fired from their jobs just for that reason only?"
After an awkward ten-second silence, Pence attempted to stall, responding: "It's a great privilege to be your Governor."
Fudging a response, he said: "My position as I expressed in the state of the State address is that we are a state with a constitution, and as you know… that constitution has very strong safeguards for freedom of conscience and freedom of religion."
Just a few months ago Pence confirmed plans to roll back Barack Obama's executive protections on LGBT rights, so that "the transgender bathroom issue can be resolved with common sense at the local level".
He said: "This is such an example of an administration that seems to have… there's no area of our lives too small for them to want to regulate, no aspect of our constitution too large for them to ignore.
"Donald Trump and I both believe these questions can be resolved with common sense at the local level."
"These issues are resolved in the state of Indiana whenever they come up, and they should be resolved, for the safety and wellbeing of our children first and foremost, their privacy and rights, and with common sense. Donald Trump and I simply believe all of these issues are best resolved at the state level, by communities."
He added: "Washington has no business intruding on the operation of our local schools. It's just one more example of the heavy hand of this administration, and Donald Trump and I will stand by that common-sense people that when it comes to our kids, and the operation of our schools, those decisions should be made at the local level.
"Washington DC has no business imposing its bill and its values on communities around the nation."
Governor Pence previously suggested that HIV prevention funding be drained in order to fund state-sponsored 'gay cure' therapy.
On a 2000 Congressional campaign website, he wrote: "Congress should support the reauthorisation of the [HIV funding] Ryan White Care Act only after completion of an audit to ensure that federal dollars were no longer being given to organisations that celebrate and encourage the types of behaviours that facilitate the spreading of the HIV virus. Resources should be directed toward those institutions which provide assistance to those seeking to change their sexual behaviour."
Pence has never walked back the claim.
An investigation also found that Pence approved extreme anti-LGBT articles when he was the head of the Indiana Policy Review journal in the 1990s.
In an item published under his editorial tenure in the December 1993 issue, Pence's journal criticised The Wall Street Journal for taking part in a job fair for gay journalists – suggesting that "gaydom" was a "pathological condition", and arguing that gay journalists would be biased in their coverage because of their sexuality.
It claimed: "The more extreme of the gay movement consider themselves members of a sexual determined political party."
Another edition published in 1993 attacked Bill Clinton for reforms to permit closeted gay people to serve in the army.
It claimed: "Homosexuals are not as a group able bodied. They are known to carry extremely high rates of disease brought on because of the nature of their sexual practices and the promiscuity which is a hallmark of their lifestyle."
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Nick Duffy - December 16, 2020


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Antiplatelet therapies: An overview
Gundu H R Rao PhD
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA; Nuwill Research and Innovations, Bengaluru, Karnataka, India
Gundu H R Rao
Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
The role of blood components including platelets, in initiating inflammation, endothelial dysfunction, atherosclerosis, thrombus formation, thrombus growth, and acute vascular ischemic events, is well established. Given this recognized role played by platelets, there is a considerable interest in understanding the physiology and function of platelets, as well as in the development of novel platelet function-inhibitory drugs. The generation of the second messengers, calcium mobilization, shape change, adhesion, aggregation, contraction, release of granule contents, thrombus development, thrombus growth, and formation of hemostatic plug at the injured vessel surfaces, in brief, constitute platelet activation. Some of the known compounds that inhibit platelet activation include inhibitors of arachidonic metabolism (cyclooxygenase-1 inhibitors; aspirin, ibuprofen, etc.), adenosine diphosphate receptor antagonists (P2Y 12 inhibitors), adenylyl and guanylyl cyclase stimulators, calcium antagonists, and GP11b/111a receptor antagonists. Since platelets have multiple mechanisms of achieving in vivo activation, it is difficult to design a novel drug that offers total protection for developing acute ischemic vascular events, without compromising coagulation mechanisms. Given this complexity, any aggressive antiplatelet therapy results in increased bleeding episodes. Having said that, we feel that there is a great window of opportunity for developing novel antiplatelet therapies. There is also scope for the development of fixed-dose combinations for the primary and secondary management of chronic diseases such as hypertension, heart disease, and type-2 diabetes.
Keywords: Antiplatelet therapies, aspirin, clopidogrel, fixed-dose combinations, P2Y 12 inhibitors, platelet activation, platelet pharmacology, ReoPro
Rao GH. Antiplatelet therapies: An overview. J Clin Prev Cardiol 2016;5:130-7
Rao GH. Antiplatelet therapies: An overview. J Clin Prev Cardiol [serial online] 2016 [cited 2022 Jan 18];5:130-7. Available from: https://www.jcpconline.org/text.asp?2016/5/4/130/192696
Atherosclerosis is a chronic, complex, inflammatory disease of the blood vessels, which leads to the narrowing and hardening of the arteries. [1] Thrombosis is another associated multifactorial disease that causes reduction and blockage of the flow of blood to the tissues, causing ischemia and tissue injury. Together, these vascular diseases leading to heart attacks and stroke are the leading causes of morbidity and mortality worldwide. [2],[3] A variety of risk factors contribute to the pathogenesis of these diseases. Some of the well-known risk factors include smoking, inflammation, endothelial dysfunction, hypertension, diabetes, repeated injury of the vascular tissues, elevated levels of low-density lipoproteins, low levels of high-density lipoproteins (HDL), visceral adiposity, and sedentary lifestyle. Some of the newer emerging risk factors include increased levels of fibrinogen, elevation of circulating activating factor, circulating endothelial cells, increased stress, depression, decreased levels of Vitamin B 12 , Vitamin D, elevated blood phosphorous, C-reactive protein, platelet microparticles, platelet hyperfunction, and hypercoagulability. Since the time Framingham trials listed the predictors of risk (http://www.framinghamheartstudy.org/risk) (age, diabetes, smoking, systolic blood pressure (BP), total cholesterol, HDL cholesterol, and body mass index) for acute vascular events, there has been a great interest in reducing modifiable risks with appropriate intervention. In spite of decades of research in this field, the role of platelets in the initiation of inflammation, vascular dysfunction, atherosclerosis, ischemic heart disease, and stoke is not very well defined. In this overview, an attempt is made to provide some evidence to support the hypothesis that platelets play a very significant role in the promotion of events leading to acute coronary and cerebrovascular events. [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18] Unlike other reviews on the subject, no attempt will be made to catalog the results of all the clinical studies. On the other hand, we will try to explain why we have not reaped the benefits of antiplatelet therapy and shed some lights on some novel approaches. [8]
Platelet Physiology
Blood platelets interact with a variety of soluble agonists such as epinephrine and adenosine diphosphate (ADP), many insoluble cell matrix components, including collagen, laminin, and biomaterials, used for the construction of invasive medical devices. [1] These interactions stimulate specific receptors and glycoprotein-rich domains (integrins and nonintegrins) on the plasma membrane and lead to the activation of intracellular effector enzymes. The majority of the regulatory events appear to require free cytosolic calcium. Ionized calcium is the primary bioregulator, and a variety of biochemical mechanisms modulate the level and availability of free cytosolic calcium. [13],[14],[15] Major enzymes that regulate the free calcium levels via second messengers include phospholipase C, phospholipase A 2 , and phospholipase D, together with adenylyl and guanylyl cyclases. Activation of phospholipase C results in the hydrolysis of phosphatidyl inositol 4, 5 bisphosphate (PIP 2 ) and formation of the second messengers such as 1, 2-diacylglycerol and inositol 1, 4, 5 trisphosphate (IP 3 ) [Figure 1].
Figure 1: Structure of inositol trisphosphate (1P3). Activation of phospholipase C results in the hydrolysis of inositol bisphosphate and generation of the second messengers such as diacylglycerol and inositol trisphosphate
Diglyceride induces the activation of protein kinase C, which plays a crucial role in signal transduction for a variety of biologically active substances (Nishizuka Y: Nature 308, 693-698, 2016). Inositol trisphosphate mobilizes cytosolic calcium from internal membrane stores. Elevation of cytosolic calcium stimulates phospholipase A 2 and liberates arachidonic acid. Free arachidonic acid is transformed to a novel metabolite, thromboxane A 2 , by fatty acid synthetase (cyclooxygenase-1 [COX-1]). Thromboxane A 2 is the major metabolite of this pathway and plays a critical role in platelet recruitment, granule mobilization, and secretion. [13],[14]
Secretory granules contain a variety of growth factors, mitogens, and inflammatory mediators. Secretion of granules promotes p-selectin expression on the platelet membrane. Furthermore, activation also promotes the expression of acidic lipids on the membrane and tissue factor expression, thus making these cells pro-coagulant. Fully activated platelets can modulate the function of other circulating blood cells such as leukocytes, monocytes, macrophages as well as vascular endothelial cells. Agonist-mediated stimulation of platelets promotes the expression of an epitope on glycoprotein 11b/111a receptors. Activation of this receptor is essential for the binding of circulating fibrinogen. Fibrinogen forms a bridge between individual platelets and facilitates the thrombus formation. Von Willebrand factor (vWF) binds platelet GP1b1X complex only at high shear rate unlike fibrinogen, which can bind platelets at low shear [Figure 2].
Figure 2: Agonist-mediated activation of platelets results in the mobilization of cytosolic calcium. Cytosolic calcium levels are modulated by the second messengers such as cyclic adenosine monophosphate and cyclic guanosine monophosphate
Upregulation in signaling pathways will increase the risk for clinical complications associated with acute coronary events. Downregulation of signaling pathways may precipitate bleeding diathesis or hemorrhagic stroke. Based on this knowledge about various activation mechanisms, the current antiplatelet drugs are being developed for therapeutic applications. [14],[16] Having said this, I would like to mention here that aspirin is one of the most researched drugs in the world, and it was used for the prevention of cardiovascular and cerebrovascular diseases, long before its mechanism of action was researched and the results were published by Professor John Vane in 1971. According to Clinical Pharmacist (September 2014), an estimated 700-1000 trials are conducted each year. As far as its use as an antiplatelet drug is concerned, Antithrombotic Trialists (ATT) Collaboration has done meta-analysis of all clinical trials of aspirin and summarized their findings. The results of these studies will be discussed along with the other newer antiplatelet therapies.
Clinical Conditions Needing Antiplatelet Therapy
Cardiovascular disease (CVD) is the leading cause of death, accounting for 17.5 million deaths per year that is expected to exceed 24 million by 2030. Worldwide prevalence of stroke was 33 million in 2010, with some 17 million people with the first stroke. Stroke is the second leading cause of death with 12 million deaths worldwide. Given these statistics from the American Heart and Stroke Association data, it is clear that antiplatelet therapies play an important role in the management of these diseases. Having said that, we should give credit to the significant role primary prevention has played in the reduction of morbidity and mortality. Nearly, half of the decline in coronary artery disease (CAD) deaths has been attributed to population-wide risk reduction and another half due to intervention with medical therapies specific to risk factors. Antiplatelet therapies play a significant role in the risk reduction strategies. [19],[20]
Pharmacological Approaches for the Development of Antiplatelet Drugs
Major pharmacological approaches for the prevention of platelet activation include the use of compounds that inhibits the release of arachidonic acid (Vitamin E), development of receptor antagonists for potent agonists (thromboxane receptor antagonists), COX inhibitors (aspirin, indomethacin, and trifusal), stimulators of adenylyl cyclases (adenosine, PGE 1 , and PGI 2 ) and guanylyl cyclases (nitric oxide), calcium chelators, calcium antagonists, and calcium channel blockers [Figure 3].
Figure 3: Major pharmacological approaches include the development of drugs that inhibit cyclooxygenases, receptor antagonists, and modulators of cyclases
Before discussing studies related to the major antiplatelet therapies, for the sake of providing readers some knowledge of the type of antiplatelet studies that have been explored before, we will list a few examples for each class of platelet function-inhibitory drugs. [14],[15],[16] COX inhibitors include aspirin, phenylbutazone, ibuprofen, fenoprofen, fluribuprofen, naproxen, butylhydroxyanisole, butylated hydroxytoluene, and diphenylamine. Thromboxane synthetase inhibitors include benzydamine, imidazole congeners, 9,11-azo-13oxa-15 hydroxyprostanoic acid, and 9,11-azoprosta-5-13dienoic acid (U-51605). Thromboxane receptor antagonists include vapiprost (SN309), 13 azaprostanoic acid, isoprostane (8epi-PGF 2 alpha), and (3-pyridinyl) alkanoic acids. Stimulators of cyclases include aCyclases; PGE 1 , PGI 2 , adenosine, forskolin, coleonol gCyclases; nitric oxide, nitroglycerine, nitroprusside, Sin-1, nitrosoglutathione, and free radicals. Cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitors include dipyridamole and related compounds such as RA233, RA433, VK744, VK774, methylxanthines, theophylline, caffeine, papaverine, and aminophylline. Serine protease inhibitors include heparin, hirudin, low molecular weight heparins, and synthetic biosimilars. Calcium antagonists include cAMP, cyclic guanosine monophosphate, verapamil, nifedipine, diltiazem, quin-2AM, BAPTA-AM, mepacrine, and trifluoperazine. Studies from our laboratory as well as that of others have demonstrated that none of these agents are capable of effectively blocking platelet interactions with vessel wall or with cell matrix components. [11] In addition, we have to remember that in vivo platelet activation is accomplished by a variety of small molecules, enzymes, peptides, proteins, and cell matrix components. Just blocking one receptor or one pathway will not be able to inhibit platelet activation in acute clinical conditions. [14],[15],[16]
Clinical Complications Needing Antiplatelet Therapies
Clinical applications of antiplatelet drugs include conditions such as CAD (acute myocardial infarction, unstable angina, and re-occlusive restenosis), cerebrovascular disease (transient ischemic attack, complete stroke, and carotid-endarterectomy), peripheral vascular disease (peripheral arterials disease and peripheral venous disease), small vessel disease, and situations where thrombus formation needs to be prevented on medical implants, artificial surfaces, preoperational conditions, and before and during cardiac and cerebrovascular interventional procedures. [18],[19],[20],[21],[22],[23],[24],[25],[26],[27]
One of the great success stories of modern day discovery of a drug on evidence-based science is the development of GP11b/111a antagonists. Professor Barry S. Coller and his associates did extensive work in the development of a monoclonal antibody (10E5) that blocked fibrinogen binding to platelets. Experiments that led to this discovery and the clinical studies that helped them to develop a potent antiplatelet therapy make a superb story in the modern day drug discovery initiatives. We were fortunate to have Prof. Coller as our chief guest at the SASAT-1996 conference in Bengaluru. The GP11b/111a receptor complex numbers between 60,000 and 80,000 copy per platelet and play a critical role in fibrinogen binding and aggregation of platelets. The clinical data supporting the use of these classes of inhibitors were first established with abciximab (EPIC and EPILOG trials) and eptifibatide (IMPCT 11 and ESPIRIT) trials. Both were found to achieve significant improvements in reducing the mortality in patients undergoing percutaneous coronary interventions (PCIs). [21],[22],[23],[24],[25],[26],[27] Glycoprotein 11b/111a inhibitors are antiplatelet drugs that are commonly used in treating patients who have unstable angina, certain types of heart attacks, and in combination with angioplasty with or without stent placement. These drugs are given in combination with heparin or aspirin to prevent clotting before and during invasive cardiac and cerebrovascular procedures. Specific inhibitors of this class of drugs in use include abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat). These drugs are usually administered as intravenous injections or IV infusion during hospitalization.
What are some of the concerns related to the use of this class of drugs in antiplatelet therapies? Currently, use of these types of drugs is limited because of the need to administer them by constant intravenous infusion. Since it is not easy to reverse their effect, there are chances of increased bleeding if the dosage is not well within the required limit. There is also some concern about immunogenicity. The second-generation drugs of this class are the group of synthetics that target a GP11b/111a recognition site for an Arg-Gly-Asp sequence found in fibrinogen. When these classes of drugs occupy the receptor site, GP11b/111a is no longer functional as the aggregation promoting receptor. There is continued effort to develop orally active arginine-glycine-aspartic mimics for therapeutic applications. There is a window of opportunity for synthetic chemists to develop novel organic molecules, which can compete for this active site on the platelet membrane and provide an alternate for ReoPro-like molecules, which can be used only by IV route and as such have limited clinical application.
Another class of drugs that were developed on the basis of available scientific evidence is ADP receptor antagonists. Since the time studies by Hellem (1960) observed that small molecules from red cells caused platelets to adhere to the glass and aggregate, there is considerable interest in the development of ADP receptor antagonists. [28],[29],[30],[31],[32],[33],[34],[35],[36] Clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) was a randomized, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of acute vascular events. CAPRIE steering committee concluded that long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin. [30],[35]
Clinical Trials of Antiplatelet Drugs
Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing clinical vascular complications. Data for aspirin as a drug of choice for the primary prevention strategies come from ATT' Collaboration, which evaluated 95,456 patients in six clinical trials. [21] The current ACC/AHA guidelines recommend the use of low-dose aspirin for primary prevention. [22] Both aspirin and clopidogrel as the drugs of choice have been quite effective. [30],[31],[32],[33],[34],[35],[36],[37],[38] The ATT was set up to provide updated information about the benefits and hazards, among particular types of patients, of antithrombotic therapy. In the 2002 analyses, 200,000 high-risk individuals in 287 studies were compared. Aspirin was the most widely studied antiplatelet drug. Indirect and direct comparisons suggested that doses of 75-100 mg daily were at least as effective as higher daily doses. In the 2009 analyses, 95,000 low-risk individuals in six primary prevention trials were compared. In the primary prevention trials, the absolute risk of a serious event was an order of magnitude less than in the secondary prevention trials. In the secondary prevention trials, aspirin is of substantial benefit. It reduces nonfatal events by much more than it would increase major extracranial bleeds (BMJ: 2002:234:71-86, lancet 2009; 373:1849-60). In an earlier article, Sudlow and Baigent (ao GHR: Handbook of Platelet Physiology and Pharmacology, 1999 Kluwer Publication) reviewed all the available randomized trial evidence for the effects of antiplatelet therapy in the treatment and prevention of major vascular outcomes as summarized by the ATT Collaboration in 1994. The 2002 ATT analyses showed that aspirin or some other antiplatelet regimen was of clear net benefit for those who have occlusive vascular disease. For primary prevention, however, the balance between risks and benefits was less clear. [31],[32],[33],[34]
Given the fact that ATT Collaboration does not discuss the controversial area of aspirin and clopidogrel resistance, I have briefly discussed this phenomenon. In recent years, several studies have reported the existence of a strange phenomenon of resistance to these drugs. [17],[18] However, if one looks at these studies, one can see the flaw in these studies. Aspirin, for instance, is an irreversible inhibitor of COX, an enzyme, which converts substrate arachidonic acid to active metabolites, prostaglandin endoperoxides. The bioactive molecules are further converted to thromboxanes, which are the real agonists that induce platelet activation. In our experience of four decades, we have never found anyone whose platelet COXs are resistant to the action of aspirin. [17] However, we have demonstrated that if platelets are first exposed to short-acting ibuprofen, those platelets are resistant to the action of aspirin. [13] Majority of studies, describing aspirin resistance, have based their conclusion on results obtained by functional studies using various platelet agonists other than arachidonic acid. Similarly, clopidogrel studies also should be done, using the specific agonist ADP, to titrate platelet aggregation response, postclopidogrel treatment. Having said that, we would like to bring the attention of the readers to the observations in several clinical studies, in which those individuals, who have increased urinary metabolites of thromboxane, in spite of aspirin prophylaxis, are at risk for developing acute CVD events. Given these reports, it is important to customize the antiplatelet prophylaxis with functional studies as well as by monitoring urinary metabolites.
A new meta-analysis of clopidogrel clinical trials has shown that patients with either one or two loss-of-function CYP2C19 alleles, undergoing PCI on normal doses of clopidogrel, have an increased risk of cardiovascular events, compared with noncarriers. In these studies, the researchers explain that the CYP2C19 enzyme plays a key role in clopidogrel metabolism, and the carriers of reduced function variants in the CYP2C19 gene have lower active clopidogrel metabolite levels and diminished platelet inhibition. The findings of this collaborative meta-analysis demonstrate that common genetic variants in the CYP2C19 gene are associated with almost one in three patients not receiving ideal protection from ischemic events, when treated with the standard doses of clopidogrel for PCI. Given how widely clopidogrel is used to treat patients with CVD, determination of the optimal antiplatelet treatment doses or regimens for individual patients is needed to tailor the therapy appropriately. The total knowledge base on this topic now shows a definite increased risk of stent thrombosis and other cardiac events in the carriers of CYP2C19 loss-of-function alleles. It is widely known that poor platelet function suppression is associated with poor outcomes. [18]
To customize antiplatelet therapy of the two most commonly used antiplatelet drugs (aspirin and clopidogrel), one needs to do the following studies. For aspirin prophylaxis, determine the platelet aggregation response to arachidonic acid and determine the ability of aspirin-treated platelets to generate thromboxane or monitor urinary metabolites of thromboxane. For clopidogrel prophylaxis, determine the ADP-mediated platelet aggregation response or determine CYP2C19 functional alleles. Alternately, use new clopidogrel (Plavix) point-of-care assay for the rapid determination of antiplatelet activity (Bansal et al.; Trauma 2011;70:65-9). However, various guidelines published by major professional societies do not advocate such studies for the optimization of standard of care with antiplatelet therapy. Lack of an easy-to-do assay for monitoring platelet function limits the validation/optimization of antiplatelet therapies. There is a great need for the development of a point-of-care assay to monitor the status of circulating blood in terms of its thrombotic state or otherwise, similar to monitoring of the effect of anticoagulation therapy with INRs (Rao GHR: Stroke: 2009;40:2271-72). We at the University of Minnesota have validated a platelet reaction-monitoring device, which uses shear-induced activation of platelets and clotting time (Rao GHR: New point-of-care methods for monitoring antiplatelet therapy. A symposium Sponsored by Eli Lilly and Company: XX1 st Congress of the International Society on Thrombosis and Hemostasis, Geneva, Switzerland, 2007) [Figure 4].
Figure 4: Platelet reactivity monitor uses a drop of fresh blood to monitor shear-induced activation and clotting time. Disposable cassettes with capillary are used to generate flow and required shear force. Courtesy: Blood Biocompatibility Laboratory, University of Minnesota
Based on the results of 11 clinical studies, an extensive guideline has been developed and published recently on the duration of dual antiplatelet therapy (DAPT) (DAPT: Aspirin plus a P2Y 12 inhibitors; clopidogrel, prasugrel, or ticagrelor) in patients with CAD. Among P2Y 12 inhibitors, cilostazol, ticagrelor, and cangrelor are direct-acting drugs, and prasugrel and clopidogrel are prodrugs. When it comes to the clinical application of DAPT for studies of long duration for an additional 18-36 months after drug-eluting stent placement, there was an absolute decrease in late stent thrombosis and ischemic complications. [37] As far as DAPT for coronary artery bypass graft (CABG) was concerned, it was associated with a significant lower vein graft occlusion at 1 year versus antiplatelet monotherapy, but with no such improvement in arterial graft patency. Of course, major bleeding was more frequent with DAPT compared to monotherapy. Aspirin remains the drug of choice for antiplatelet therapy for patients with acute coronary syndrome (ACS). DAPT recommendation beyond a minimum recommended period was associated with increased bleeding and thereby offsets the benefits of DATP. [39],[40],[41] Therefore, careful monitoring of patients and customization of therapy are essential.
DAPT with aspirin and P2Y 12 inhibitors are the antiplatelet therapy choices worldwide for the care of ACS patients and those undergoing coronary interventional procedures such as PCI or CABG. These classes of antagonists inhibit only two specific pathways of platelet activation and minimally affect other pathways of platelet activation. These limitations may explain why even patients with DAPT experience recurrent ischemic events. Given these observations, currently, two oral thrombin receptor antagonists (PAR-1) are under clinical evaluation. [38],[39] From time to time, several other agents that target various platelet signaling pathways have been developed and evaluated in Phase 1 and Phase 2 trials. They include glycoprotein V1 antagonist (6B4-Fab antibody), serotonin receptor inhibitor (saprogrelate, APD791), prostaglandin E receptor antagonist (DG-041), nitric oxide donors (LA846, LA419), nitric oxide substrate, L-arginine, and phosphatidylinositol 3-kinase inhibitors (TGX-221). Prostaglandin/thromboxane receptor antagonists such as GR32191, ifetroban, and sulotorban had disappointing results in Phase 1 and Phase 2 clinical trials. Antiplatelet drugs that are in preclinical studies include inhibitors of platelet adhesion; vWF (Mab, aptamer), GP1b/V/1X (peptide, MAB), GP V1 (Mab, small molecule), collagen (protein) P13K inhibitors, intracellular targets; cytoplasmic tail of Beta3-integrin, and tyrosine kinase inhibitors (Src, Syk). Dual antiplatelet therapy has become the standard of care in the management of a variety of platelet-related clinical complications. However, emerging antiplatelet therapies are aimed at developing more potent novel drugs, which would offer better protection by reducing ischemic events, without increased bleeding. Currently, prasugrel, ticagrelor, cangrelor, oral thrombin antagonist SCH 530348, and elinogrel are undergoing extensive testing worldwide. We have made no attempt to review the development of oral anticoagulants. Readers are urged to refer to recent reviews on this topic for additional information. [42],[43],[44] As mentioned in the introduction, this is not a comprehensive review on this subject. Readers are urged to refer to the current guidelines and reviews by the experts. [34],[35],[36],[37],[38],[39],[40],[41],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56]
The Ministry of Health and Family Welfare, India, has banned recently over 350 fixed-dose combinations (FDCs) as unsafe or ineffective. On the other hand, there are currently several ongoing international clinical studies with various FDCs for the management of hypertension and type-2 diabetes. For hypertension, a combination of benazepril plus amlodipine or hydrochlorothiazide has been tested. For the management of type-2 diabetes, the fixed-drug combinations include metformin with sulphonylurea, thiazolidinedione, dipeptidylpeptidase-4 inhibitor, or meglitinide as well as thiazolidinedione-sulphonylurea. [57],[58] Professor Salim Yusuf of Population Health Research Institute of Ontario, Canada, has hypothesized that a combination of four drugs (aspirin, B-blocker, a statin, and an angiotensin-converting enzyme inhibitor) could reduce CVD events by 75% in those with vascular disease. [50] Wald and Law have proposed a polypill containing three BP-lowering drugs for different classes with each, at half doses, aspirin, a statin and folic acid, for all individuals with established CVD and older than 55 years without CVD and have estimated that this approach will reduce CVD events by 88% and stroke by 80%. [51] The Central Drugs Standard Control Organization (CDSCO), India, has approved 41 FDC formulations for type-2 diabetes. This approval by the CDSCO has resulted in 500-marketed brands. According to an article in the Lancet (Valerie E, Pollock AM: Doi.org/10.1016/52213-8587 (14) 70239-6), most of the FDCs sold in India have not been shown to be safe and effective for the treatment of diabetes.
Various national and international health organizations such as the WHO, National Institutes of Health, USA, National Heart, Lung and Stroke, UK; Centers for Disease Control, USA, have advocated the development and validation of different FDCs. [50],[51],[52],[53] For a comprehensive review on this subject, readers are urged to refer to the work of Lonn et al. and associates. [50] In their overview on this subject, they conclude, "On the basis of available data on the individual component drugs, the polypill could potentially be widely used in secondary prevention and in selected high-risk individuals without CVD (e.g., those with hypertension or diabetes with additional risk factors). " The question that arises from this need for a cost-effective medication for managing "at risk" individuals and lack of robust clinical trial data on FDCs is how do we find an acceptable way to validate the comparative safety and efficacy of these FDCs? Authors of the Lancet article on FDCs conclude, "None of the metformin FDC trials meet WHO guidelines for approval as FDCs and recommended criteria for efficacy and safety. With such large volumes of metformin FDCs in the India market, this inadequate control is deeply worrying."
The role of platelets in the pathogenesis of inflammation, atherosclerosis, thrombosis, and stroke is well recognized. Variety of agonists are capable of mediating platelet activation including shear force in the circulating blood. [11],[59] Activation of platelets by agonists initiates a series of biochemical events leading to the formation of second messengers, elevation of cytosolic calcium, shape change, contraction, release of pro-aggregatory components, and formation of hemostatic plug for the arrest of bleeding at the injured sites. Since the activation of GP11b/111a receptors and fibrinogen binding is considered the common pathway for aggregation, thrombus formation, and growth, several effective antiplatelet therapies have been developed related to this mechanism of activation. Similarly, antiplatelet therapies also have been developed using ADP receptor antagonists. As we have explained earlier, platelets are activated by a variety of external stimuli, and as such, there is a need to develop antiplatelet therapies that can offer better protection than these two inhibitory pathways and yet will not promote bleeding. There is a great window of opportunity for the development of novel antiplatelet therapies including FDCs. [60]
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Having the right pieces of décor around the fairy garden is always a fun and simple way of adding some visual interest and realism to the space. This Green Wheelbarrow is a nice touch that should fit in quite well with many types of fairy garden out there. It has a red wheel with white spokes, and the green looks like it has been made from wood. It's a fun addition to your garden, and there are plenty of places where you can use it.


text:
Party Reform: The Interim Peers List, is it fit for purpose?
By Sue Doughty | Tue 27th August 2013 - 11:52 am
Tim Farron, our Party President has long championed concerns about how democratic the Lib Dems really are and how can we do better. Federal Executive has now set up the Democratic Reform Group which I chair. Our first task has been to take a hard look at the Interim Peers List and we have published a consultation paper on this together with organising a meeting at Glasgow to consult members about improvements to the process. The Interim Peers list is an group of people elected by Conference Representatives from which the Party Leader can make nominations to the House of Lords.
We still want to see a democratically elected second chamber but need support from the other main parties to change things. Peers tend to be older than MPs although this delivers experience, we have not been successful in bringing in a retirement system that works. Indeed, only the leader can nominate Lib Dem members under the current system and even then we never know how many places are coming. We can't change this.
What Lib Dems can do is to look at how the Interim Peers List works and if we can improve it in terms of transparency and democracy. Should votes to the list be by Conference Representatives only or should all members have a vote? How can we improve regional representation? Former Parliamentarians (English, Euro, Scots and Welsh) are all automatically members of the list but former council and group leaders are not although in recent years Nick has taken care to recruit from the latter highly experienced sector especially outside the South East. Should there be an upper or lower age limit to be on the list? And of course, how far the leader should ensure that Lib Dems in the Lords are more representative of other underrepresented groups.
We want Lib Dem members to read our paper which explains more on the background to the list, and to the basis of nomination to the Lords. We are asking your views on a number of questions and need your feedback by 4th October. We can then come back with a motion to Spring Conference.
Improving democracy within the party doesn't just stop there. If you think that there are other areas of internal party management which need fixing we want to hear from you.
Our fringe meeting "Is the Peers List fit for Purpose" will be on Saturday 14 September at 20.15 in the main conference centre. Our paper is at here. Feedback to [email protected]
* Sue Doughty chairs the FE Working Group on Democratic Reform. She was formerly the MP for Guildford
Read more by Sue Doughty or more about autumn conference 2013, featured, house of lords or interim peers list.
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Chris 27th Aug '13 - 11:56am
Surely it's not worth expending effort on improving this list unless the leader can be induced to take some notice of it when nominating peers?
Geoffrey Payne 27th Aug '13 - 1:19pm
I have to admit that when I voted as a conference representative for the interim peers list, I actually thought I had the power to vote for lib dem members who would go on to become peers. So much better I thought than the leader placing yes men and anonymous party donors into the chamber. Then I found out that the leader could ignore that and put in whoever he wants regardless. What a strange system we have, good to see it is being fixed. But how did we get the system that we currently have in the first place? I can't imagine the party ever voted for that.
Richard Shaw 27th Aug '13 - 1:22pm
Surely it's not worth a leader taking notice of the list until it's worth using?
In other words, given that we cannot mandate use of the list and that, to my knowledge, it has been largely ignored by all Lib Dem leaders since its introduction then the onus is on reforming the list so that its use is always clearly in the best interest of the wider Party, so that it can't easily be sidelined as being either unworkable, undemocratic or generally irrelevant.
I personally would like a model based on the selection of our Euro list candidates, with each region having a list of would-be Peers and with each region getting a share of the number of new peers based on regional membership numbers. Importantly, like the Euro list, this list would be chosen by the whole membership and not just those lucky few at Conference, and therefore a lot more credible and harder for Leaders to sidestep.
David Evans 27th Aug '13 - 2:06pm
@ Richard & @Sue
It's the leader that is the problem (and past leaders are all as bad as each other), not the process.
But until we get a party that is less deferential to its leader and has the courage to stand up for its values within the party as much as it is prepared to stand up for its values outside the party, things will not change. Ultimately it will need a party that is prepared to insist leaders do as they are told on occasions, rather than just let them do as they like and then let them off when they bluff it out.
However, after three years of watching our party and its principles being cut to pieces by its leader and seeing long serving members leave as the only principled thing to do, I fear it will never happen.
Actually Sue, one further query. In your article you say
"The Interim Peers list is a group of people elected by Conference Representatives from which the Party Leader can make nominations to the House of Lords."
When the peers list was first introduced, was it made up on the basis that
It was a list from which the Party leader can make nominations,
It was a list from which the party leader should make nominations, or perhaps
It was a list from which the party leader must make nominations.
Tony Greaves 27th Aug '13 - 8:53pm
"it has been largely ignored by all Lib Dem leaders since its introduction"
Not so. The first couple of lists of new peers were very much based on the Interim Peers Panel. (I declare an interest in the first of those lists, nominated by Charles!)
It was on the basis of a request to the Leader (on the grounds that constitutionally and legally the party could not insist) but there was a clear expectation that nominations would come from the list other than (1) one per list who could be chosen by the Leader – known in those days as "Charlie's Choice" and (2) former MPs. The latter was meant to be only for the Dissolution lists but has been stretched to include former MPs and other parliamentarians (Scotland, Lords, EP) without much complaint; also to apply at any time which is not what was originally intended.
The simple fact is that Leaders since Kennedy have largely ignored the list and have disregarded the wishes of the party as expressed at Conference. Any reform will need to gain the agreement of the Leader to adhere to what the party requests and requires.
I stand corrected re Charlie.
Caracatus 28th Aug '13 - 9:54am
Well I can't think that this was the most urgent thing in need of reform. It would be great to introduce some e-democracy into the party. A website with user names and pass words surely is not too much to ask. Even if results were only consultative it would be a start. Tony Greaves hits the nail on the head, and the leader of the Lib Dems since Kennedy have behaved appallingly.
Sue Doughty 28th Aug '13 - 10:21am
Many thanks for the comments one and all. I do hope you will also write in to us as well as there is some useful background in the paper.
As you rightly point out, the system relies to an extent on the leader at the time. There is also the issue of people who could not be elected to the list because they needed to be strictly non political such as Tim Gardner but became available around the same time as the we were allocated some places and who have provided splendid expertise.
@caracatus As a new group we had to start somewhere. We also want to look at One Member One Vote and e-democracy would usefully sit here. We are concerned however that the party does not have a strong list of member's emails and of those we have, the read rate is really low. The reality is that our members now communicate with the party and with each other through a wide variety of ways – e news, facebook, twitter, phone, face to face and print. We suspect that very few people use all, and certainly Facebook is a marmite issue within the party. All suggestions would be really helpful.
Gareth Aubrey 28th Aug '13 - 11:53am
It would helpful to have the basis on which we cannot impose a mandate set out, as I'm sure there must be a way around it. My suggestion would be that any nomination made from outside the Panel (and allowing the exception Sue mentions about restricted persons) would trigger a vote of no-confidence in the Leader at the following Conference; I accept that no Leader would ever lose such a vote, but equally, I doubt any Leader would risk such a vote even taking place…
I'm sorry Sue, the system relies "entirely" on the leader at the time.
Unless and until that is accepted and addressed, you will be wasting your time,
Tony Dawson 28th Aug '13 - 5:50pm
Unfortunately, knowing that the Leaders tend to ignore these lists, a lot of very good people in the party who would make excellent LIBERAL working peers do not even put their names forward. Within the list, though, are still people considerably more suitable than those who have been chosen.
Amalric 29th Aug '13 - 12:54am
It is a shame that the questions do not reflect some of the areas Sue says she wants to consult on. Examples of these are: former council and group leaders, age limits. Also there are no questions regarding restricting the leader's power and making the leader accountable to whatever Federal Conference decides. There is no discussion of whether former MPs should only be eligible for dissolution honours.
The paper also reads as if it has already been decided to go for one member, one vote and then ensure that most of those elected to the list are former MPs, former members of the Scottish and Welsh assemblies and the European Parliament.
James Graham 29th Aug '13 - 11:02am
There are more than enough worthy people on elected part of the interim peers list at the moment, although I'd accept that you would probably struggle to find ten people. You could do a lot better than one however.
It doesn't help, however, that a) the leadership tips a nod to its mates and indicates that they will just ignore the list anyway and b) that they cancelled the elections last year even after the House of Lords reform bill had been abandoned. Of course if you undermine the list's status it will lead to weaker candidates.
What this working group will have to contend with is the visceral hostility to the interim peers panel from both the people who hover around the leadership (whoever it may be) and fully sign up to the idea that a "strong" leader should be able to appoint whoever they want, and the deeply anti-democratic instincts that dominate the Lords parliamentary party itself. The current system gives them about as much leeway as it is possible to have while still having elected people on the panel, but they still ignore it. Tighten the rules and they will simply ignore it even more and insist they can't be "mandated" to do anything they don't want to.
Little Jackie Paper
Daniel Walker 1 - UK isn't a member state. 2 - Montenegro 2006 independence referendum....


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Madison je hlavní město státu Wisconsin v USA. V roce 2010 činila populace 233 209 obyvatel, což Madison činí druhým největším městem ve státě Wisconsin, hned po Milwaukee, a 77. největším městem v USA. V Madisonu mimo jiné také sídlí University of Wisconsin-Madison.

Historie
Madison byl založen roku 1836. Bývalý federální soudce jménem James Duane Doty tehdy zakoupil více než tisíc akrů (4 km²) bažin a lesů na šíji mezi jezery Mendota a Monona, s úmyslem vybudovat nové město.

28. listopadu 1836 byl Madison vybrán jako hlavní město oblasti, a to i přesto, že dosud existoval pouze na papíře. Důvodem byla jeho poloha mezi novými a rostoucími městy okolo Milwaukee na východě a starším Prairie du Chien na západě, a také mezi vysoce obydlenou oblastí olověných dolů na jihozápadě a Green Bay (nejstarším městem Wisconsinu) na severovýchodě. Madison byl pojmenován podle jednoho z Otců zakladatelů USA, Jamese Madisona, který roku 1836 zemřel.

Základní kámen wisconsinského kapitolu v Madisonu byl položen roku 1837, zákonodárný sbor se v něm poprvé sešel roku 1838. Když se roku 1848 stal Wisconsin státem, zůstal Madison i nadále jeho hlavním městem. Téhož roku v něm byla založena univerzita (University of Wisconsin-Madison). Na železniční síť byl Madison napojen roku 1856. Roku 1856 byl Madison povýšen na město; tou dobou v něm žilo 6 863 obyvatel. Během Americké občanské války jej armáda Unie používala jako základnu pro Wisconsin. Takzvaný Camp Randall byl využíván jako výcvikový tábor, vojenská nemocnice a jako zajatecký tábor pro vojáky Konfederace. Poté, co válka skončila, byl tábor přičleněn k území univerzity. Roku 1917 byl na jeho místě vybudován stadion Camp Randall.

Ve 20. století pokračoval Madison v růstu a stal se druhým největším městem Wisconsinu. Počet jeho obyvatel vzrostl více než desetinásobně.

Geografie a klima
Město se nachází uprostřed okresu Dane County ve středním jižním Wisconsinu, 123 km na západ od Milwaukee, 195 km na sever od Chicaga. Zcela obklopuje menší města Madison a Monona, stejně jako vesnice Maple Bluff a Shorewood Hills. Hraničí se svým největším předměstím nazývaným Middleton, dále s městy Sun Prairie, Fitchburg a s vesnicemi McFarland, Verona a Waunakee.

Z celkové plochy města, 219,4 km², tvoří 177,9 km² země a 41,5 km² voda.

Madison je někdy nazýván Městem čtyř jezer, a to díky čtyřem jezerům na řece Yahara: jedná se o jezero Mendota ("Čtvrté jezero"), jezero Monona ("Třetí jezero"), jezero Waubesa ("Druhé jezero") a jezero Kegonsa ("První jezero"). Jezera Mendota a Monona se nacházejí přímo na území Madisonu, jezera Waubesa a Kegonsa nedaleko od něj, v jižním směru. Páté, menší jezero jménem Wingra se rovněž nalézá ve městě, avšak není spojeno s řekou Yahara. Centrum města se nalézá na šíji mezi jezery Mendota a Monona.

Řeka Yahara, protékající Madisonem, je asi 70 km dlouhá a vlévá se do řeky Rock River, a ta následně do Mississippi.

Celý jižní Wisconsin má mírné, vlhké kontinentální podnebí. To je charakterizováno proměnlivým počasím a velkým sezonními teplotními výkyvy – v zimě se teploty nacházejí pod bodem mrazu, se středními, někdy značnými sněhovými srážkami; vysoké teploty v létě často dosahují horních hranic v rozmezí 30–35 °C. Běžnými jsou také vysoké hodnoty vlhkosti vzduchu.

Demografie

2010
Podle sčítání lidu z roku 2010 zde žilo 233 209 obyvatel.

Rasové složení
 78,9% Bílí Američané
 7,3% Afroameričané
 0,4% Američtí indiáni
 7,4% Asijští Američané
 0,0% Pacifičtí ostrované
 2,9% Jiná rasa
 3,1% Dvě nebo více ras

Obyvatelé hispánského nebo latinskoamerického původu, bez ohledu na rasu, tvořili 6,8% populace.

2000

Podle sčítání lidu v roce 2000 měl Madison 208 504 obyvatel, 89 019 domácností a 42 462 rodin. Hustota zalidnění byla 1169 obyvatel na km². Ve městě se nacházelo 92 394 bytových jednotek, průměrně tedy 519,5 bytových jednotek na km².

Z 89 019 domácností bylo 22,1% takových, v nichž žilo alespoň jedno dítě mladší 18 let, 37% tvořily manželské páry, 7,8% obývala žena bez manžela a 52,3% nebylo rodinného typu. 35,3% všech domácností bylo tvořeno jednotlivci a v 7,1% žil osamoceně člověk ve věku 65 let nebo starší. Průměrná domácnost byla tvořena 2,19 osobami a průměrná rodina byla tvořena 2,87 osobami.

Obyvatelstvo města bylo tvořeno ze 17,9% osobami ve věku pod 18 let, z 21,4% osobami ve věku od 18 do 24 let, z 32,2% osobami ve věku od 25 do 44 let, z 19,3% osobami od 45 do 64 let a z 9,2% osobami ve věku 65 let nebo staršími. Věkový medián měl hodnotu 31 let. Na každých 100 žen žilo ve městě 96,6 mužů. Na každých 100 žen ve věku 18 let a vyšším žilo ve městě 95 mužů.

Příjmový medián na jednu domácnost ve městě měl hodnotu 41,941 USD, příjmový medián rodiny byl na hodnotě 59,840 USD. Muži měli příjmový medián v hodnotě 36,718 USD, naproti tomu ženy 30,551 USD. Důchod na hlavu byl ve městě 23,498 USD. Okolo 5,8% rodin a 15% obyvatel žilo pod hranicí chudoby, včetně 11,4% z těch, kteří byli mladší 18 let, a 4,5% z těch, kteří byli ve věku 65 let nebo starší.

V městské aglomeraci Madisonu v roce 2003 žilo 526 742 lidí, což ji činilo druhou největší ve státě, hned po Milwaukee. Rovněž v okrese Dane County roste počet obyvatel nejrychleji v celém Wisconsinu. Za každé desetiletí přibývá přibližně 60 000 lidí.

Osobnosti města
 Frank Lloyd Wright (1867–1959), architekt
 Thornton Wilder (1897–1975), spisovatel a dramatik, trojnásobný nositel Pulitzerovy ceny
 John Bardeen (1908–1991), fyzik a elektrotechnik, dvojnásobný držitel Nobelovy ceny
 Gena Rowlandsová (* 1930), herečka
 Howard M. Temin (1934–1994), biolog, držitel Nobelovy ceny
 Tyne Daly (* 1946), herečka
 Chris Noth (* 1954), herec
 Eric Heiden (* 1958), pětinásobní olympijský vítěz v rychlobruslení a cyklista
 Bradley Whitford (* 1959), herec a scenárista
 Phil Hellmuth (* 1964), profesionální hráč pokru

Partnerská města
  Ainaro, Východní Timor, 2001
  Arcatao, Salvador
  Bac Giang, Vietnam
  Cuzco, Peru
  Camagüey, Kuba, 1988
  Freiburg im Breisgau, Německo, 1986
  Managua, Nikaragua, 1987
  Mantova, Itálie, 2001
  Obihiro, Japonsko, 2006
  Vilnius, Litva

Odkazy

Reference

Externí odkazy

Města ve Wisconsinu
Hlavní města států v USA

redpajama_set_name: RedPajamaWikipedia


Here we will explain how to place bet on baseball.
To pace bet on baseball, please choose baseball from the left of the screen and choose which league to bet.
Then you can choose which match to bet.
The default betting type is "Money Line" in which you will expect which team to win.
Let's see how to bet on baseball. Here we will bet on BAL vs Orioles match.
You can see bet slip on the left of the screen.
Mostly same as other sports, but the difference is "Pitcher Action" in the middle of the screen. From here, you can choose the condition of your bet. When you choose must-start selections, your bet will not be valid unless the match start with the pitcher. If you choose "action" your bet is valid regardless of the first pitcher.
Here we will explain betting types of baseball in bet365.
In Game Lines you can choose most popular betting types; Money Line, Game Totals and Run Line.
In Money Lines, you will expect which team to win.
In Game Totals, you will expect total scores of both tem at the end of the match.
In Run Line, you will expect the winner with decided handicap.
You will choose the winner or score from three choices.
You will expect which team will lead at the end of the first innings.
You will expect if there will be any run in the first innings.
You will expect total runs at the end of the first innings.
You will expect total hits at the end of the first innings.
You will expect which team will have hits most.
You will expect the first score will be made in the top or not.
You will expect the first hit will be in top or not.
You will expect the first score will be made in the bottom or not.
Here you will expect which team will score the decided number first.
You will expect the total scores of both teams will be higher than the decided score or not.
You will expect which team will lead at the end of the decided innings.
You will expect the match will go to extra innings or not.
You will expect which team will score the first point.
You will expect which team will score the last point.
You will expect if the first scored team will win or not.
You will expect the total scores of the match from bands.
Here you will expect the result with each handicaps. The rules of betting are same as the original ones.
You will expect which team will score more.
You will expect the result of first four innings and last four innings.
You will expect which team will and with what difference.
You will expect whether there will Solo/2-run/3-run/Grand Slam or not.
You will expect the total scores will be odd number or even number.
You will expect the total scores by fourth top innings is higher than the rest of the innings.
You will expect the total hits is higher than the decided number or not.
You will expect which team will have more hits.


Daimler AG announced in April 1993 that it would build its first passenger vehicle manufacturing facility in the United States. This decision emphasized the company's globalization strategy and desire to move closer to its customers and markets. In September of 1993, after an extensive, six month site selection process, the company chose Tuscaloosa County, Alabama, as the location for its $300 million plant. Mercedes-Benz U.S. International, Inc. (MBUSI) was formed to fulfill the goal of producing the Mercedes-Benz M-Class Sport Utility Vehicle for the worldwide market.
MBUSI created a new corporate culture, based on teamwork and open communication. The combination of German & American team members, with experience from U.S. and Japanese automakers, as well as from Mercedes-Benz, made the "melting pot" in terms of its practices, procedures and corporate culture.
In 1993, original projections were for 65,000 M-Class vehicles to be built at the Tuscaloosa plant each year. Because of overwhelming demand, MBUSI invested an additional $80 million in 1998 and 1999 to expand the plant and increase annual production by 20% to 80,000. During the first eight years of production, some 350 vehicles a day came off the line, in two shifts.
In 2011, Daimler announced plans for another $1.5 billion expansion for the production of the C-Class, which began production in 2014, and the new GLE Coupe was available starting as a 2016 model.
As a result of the worldwide success of the M-Class (now called the GLE SUV), Daimler AG has continually invested, expanded, and more than tripled production at MBUSI. We build the M-Class, GL-Class, the GLE Coupe for USA and the world, and the C-Class for North America.
As of today, Daimler AG has invested over $4.5 billion and continues to invest in MBUSI in Tuscaloosa County, Alabama. MBUSI is responsible for more than 22,000 direct and indirect jobs in the region, and has an annual economic impact of more than $1.5 billion. MBUSI is also the state's largest exporter, with more than $1 billion in exports each year to countries throughout the world.
In 2016 annual production was over 300,000 units. Roughly two-thirds of the components used in MBUSI-built vehicles come from North American suppliers, and about 30 first- and second-tier suppliers are now located in Alabama. We distribute to 135 markets worldwide with 60% for export.
Besides body, paint and assembly shops, also located on the Tuscaloosa site are a comprehensive training facility, a visitor center, a childcare and a health and wellness center. The Mercedes-Benz Visitor Center, which houses entertaining exhibits detailing the history of Mercedes-Benz—including its products, technology, and commitment to safety—is open to the public.


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Red Tourism in China
ChinaCultural Anthropology March 29, 2016 - No comments
A review of Production, Transmission, and Consumption of Red Tourism in China: A Model of the Circuit of Red Heritage and Tourism, by Shengnan Zhao.
In 2010, Hu Jintao paid homage to the site of the Gutian Conference where, eight decades earlier, the CCP had given Mao control of the Fourth Red Army. During the visit, a snake slithered across Hu's path, an event that tour guides later claimed was an auspicious omen. Two years later, villagers from nearby Rongwu launched a bid to build a massive shopping mall where they currently lived. In exchange for a slice of the profits, they were ready to tear down their homes and move to the backside of their hill. What connects these two incidents is a circuit of political hierarchies, guanxi networks, economic incentives, sanctioned histories, and superstitious folktales that together comprise red tourism—the repackaging of Maoist heritage for tourist consumption. In China, the CCP has injected billions of RMB into sites like Gutian, hailing the resultant rise in tourist traffic with much fanfare. "The scenery of red tourism forms a provocative stage for the establishment of nationhood," writes Shengnan Zhao (p. 215). While previous research has focused on textual analyses of memorial sites and the political contexts behind them, Zhao studies how these narratives are transmitted and consumed by their target audiences. Combining observational fieldwork with quantitative analysis, her dissertation evaluates the structures of tourism from the ground up, bringing into focus the local officials, tour guides, and tourists who reinterpret the stories they are fed.
Each main chapter offers a different perspective on the tourism circuit: production, transmission, and consumption. In the first part, Zhao examines how government patronage has shaped red tourism in Gutian. Local officials mediate between the lofty goals of Beijing and the needs of local villagers, forming a feudal hierarchy governed as much by informal guanxi relations as it is by institutional power. In this system, celebrity endorsements are particularly important. When Jiang Zemin visited the site in 1989, a CCTV performance troupe in 1999, and Hu Jintao in 2010, central funding and tourism grew exponentially. As a result, local officials are incentivized to continuously build, demolish, and then rebuild the same infrastructure that will attract further grants from Beijing, a so-called process of "red washing." Facades of adjacent homes are retiled, hotels hang Red Army-themed plaques in their rooms, and the main road is strictly regulated to minimize traffic jams and pollution. These projects have mixed benefits for the local economy. While central funding provides a powerful stimulus, Zhao finds that tourism in Gutian has been neither profitable nor sustainable. Simple decisions must be approved by multiple layers of bureaucracy, leaving local officials feeling disempowered. Farmers have been displaced from their land, but there are few opportunities for service-sector employment. The villagers of Rongwu, who agreed to have their homes razed in order to build a shopping center, are unlikely to find private investors to back their plans. Zhao argues that the centrality of "celebrity endorsements" to tourism development has given Gutian generous injections of funding, but it has also paralyzed more ambitious projects, deprived the local government of its autonomy, and multiplied bureaucratic inefficiency.
The second part explores how tour guides mediate between government objectives and the interests of tourists. Distinguishing between unsalaried tour guides and contracted site interpreters, Zhao probes the dual staffing system that underlies Gutian's tourism apparatus. Whereas tour guides derive their income from tips and shopping commissions, site interpreters enjoy the relative prestige and job security of working for the public service (shiye danwei). Interpreters are trained by museum historians, subjected to a series of tests and, to mitigate the boredom of memorized rhetoric, are encouraged to research and craft their own narratives. These structural disparities and power inequalities, Zhao argues, shape the narratives that are told at the tourist sites. As freelancers, tour guides often rely on folk tales and superstition to retain the attention of their clients—some even recount stories of Mao's illegitimate children, or the auspicious myth that autumn leaves never fall on the conference site. Site interpreters, on the other hand, are forbidden from telling these stories. As their primary function is to give tours to high-level officials, they are also often reluctant to take on tourists, who they perceive as aggressive and entitled. "The more you talk, the less feeling you have. Sometimes you only feel that your lips are moving," one interpreter said (p. 132). Among tour guides and site interpreters alike, Zhao finds little use of humor, drama, interaction, and other oral techniques that may capture the imaginations of the tourists.
In the third part, Zhao turns to the experiences of the tourists themselves. Who participates in red tourism, and what do they gain from it? Data from 241 surveys were clustered according to the primary activities that tourists pursued onsite—political education, nature appreciation, entertainment, and a mixture of the above. These four behavior patterns were then compared to the motives of the visitors, their ability to recall political and non-political content, their impressions of the site, and their support for the CCP. Only 11% of tourists were purely interested in political activities; those interested in leisure, nature, and local Hakka culture came away with few changes to their political outlook. Members of the CCP or Communist Youth League did not behave very differently than their non-political counterparts. And in a series of focus groups, Zhao found that visitors had mixed perceptions of nationalism and red heritage. While most tourists seemed to appreciate the sacrifices made by early revolutionaries, what also mattered was that the current administration deliver on its promises: "The government deserves being loved by us only if the government makes people satisfied," one tourist said (p. 180). Some even thought that the political aspects of Gutian were secondary to its excellent fengshui. Zhao observes, "Visitors were not pure political pilgrims or amateur political scientists who practiced passionate worship or sought a detailed understanding of communist heritage" (p. 208). Despite the ideological goals of Beijing, tourists consume red culture as utility-maximizing agents, as fenghsui pilgrims, and as family vacationers whose political orientations are as varied as their reasons for traveling.
Tourism is one of the most direct ways to politicize heritage, Zhao writes (p. 213). If Gutian is to become an economically sustainable, ideologically compelling destination for its visitors, then the CCP needs to hone its strategies (p. 227). It needs to use media displays and interactive storytelling to maximize engagement, and it should conduct further market research in order to gauge the secondary interests of tourists. Yet Zhao's work reveals that some of the deepest problems with Gutian are structural: tour guides are underpaid, local officials are disempowered, development is not yet profitable, and tourists' political opinions are often shaped by current government performance, not the rhetoric of the past. Her dissertation contributes to a growing trend in East Asian area studies that brings anthropological insights to the study of politics. Rather than a one-way transmission of ideology from Beijing to the grassroots, Zhao echoes Richard Johnson's model of meaning-making as a circuit. Like Johnson, she holds that symbolic and social relations are authored and modified by multiple actors. With her attention to the agents of red tourism and her sensitivity to the structures that shape their behavior, Zhao offers us a compelling, detailed portrait of the CCP's biggest domestic PR campaign—both its lofty hopes and its bureaucratic underbelly.
Rachel Wong
rachelwong@post.harvard.edu
Fieldwork conducted in 2012 at Gutian Conference Memorial Museum (Fujian, China)
Arizona State University. 2014. 266pp. Primary Advisor: Dallen Timothy.
Image: Photo by Author.
Tags:2014 Dissertation, Arizona State University, China, Dallen Timothy, Tourism
Modern Fatherhood, Nationhood, and Globalization in Japan
Burmese Buddhist Political Thought


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Microsoft and Nook redo their agreement; no Microsoft e-reader in the works
It looks like the Nook Windows 8 app may be superseded by a Microsoft reading app. But the planned Nook Windows Phone app is seemingly tabled.
By Mary Jo Foley for All About Microsoft | March 13, 2014 -- 14:04 GMT (07:04 PDT) | Topic: Windows
On March 10, Microsoft and Nook Media updated their agreement forged two years ago, according to a new 8-K filing by Barnes & Noble.
Under terms of the amendment, Nook Media is allowed to discontinue distributing the Nook Windows app and to cease work on its Windows Phone app. Ouch.
There seemingly is a replacement app coming for the Nook Windows app, however. It is rather confusingly named "Microsoft Consumer Reader."
This is not a dedicated e-reader, I hear from my sources. (Such a device from Microsoft has been rumored in the past). Instead, I think this is just the name for one of Microsoft's coming e-reading apps.
There seem to be at least two of these apps in the works. The Microsoft Office Reader app , which company officials showed off last year at an employee meeting, will provide users with access to digital content, PDFs and textbooks, according to leaks.
The Xbox team also is believed to be readying a reading app. It's not clear whether this is the same or different from the Office Reader.
In at least one -- and maybe both Readers -- Nook will likely be providing access to some of the digital content.
It's a good bet that a version of this Microsoft Consumer Reader will be available on Windows Phone, too. See this tweet from Nook Customer Care (via @mikebaz).
Update: That tweet seems to have been deleted. Here's what it said:
I asked Microsoft what the "Microsoft Consumer Reader" is and was told by a spokesperson: "We are always looking for ways to evolve and innovate on our app experiences for customers. We have nothing further to share at this time."
Here's exactly what the 8-K says:
"Pursuant to the Amendment, NOOK Media LLC ("NOOK Media") and Microsoft agreed to co-branding within the Microsoft Consumer Reader for reading content delivered by NOOK Media. The Amendment also provided that subject to certain conditions NOOK Media would be permitted to discontinue distributing the NOOK Windows app and will cooperate in good faith with Microsoft to transition users to the Microsoft Consumer Reader. Microsoft and NOOK Media also agreed to updated revenue sharing to address this possibility. The Amendment also permits NOOK Media to cease efforts with respect to a Windows phone app."
The two companies have also updated their revenue-sharing terms as part of this amendment, but aren't disclosing the particulars.
In April 2012, Microsoft invested $300 million in a new Barnes & Noble subsidiary, initially known as Newco, and later renamed "Nook Media." Nook Media is the part of B&N that made Nook readers and also included the digital/College businesses from Barnes & Noble. The agreement was part of an Android patent-settlement dispute between Microsoft and Barnes & Noble.
At the time of that announcement, it seemed a Nook Windows Phone app was definitely going to figure in a big way.
So it's now looking like Microsoft's $300 million investment is going to end up being all about Nook digital content. And that's about it.
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