text:
Q: Updating D3 chart resulting in duplicate charts I am having a hell of a time trying to update JSON data going to a D3 histogram after a button click.
While I solved the button click to update issue, the D3 javascript is now appending one chart per button click, resulting in duplicate charts instead of simply updating the data.
I understand that the click event is calling append() in the D3 code every time it is triggered, but how can I get around this so there's only one chart with updated data per click?
console.log('chart.js loaded');

$(document).ready(function() {

  var vimeoVideoId = $('p#vimeoVideoId').text();
  var api = 'http://localhost:3001/videos/' + vimeoVideoId + '/json';

  function initData() {
    $('#all-notes').click(function() {
      getData();
    });
  }

  function getData() {
    $.getJSON(api, draw);
  }

  function draw(json) {

    data = json;
    var duration = data.duration;

    var timeToSec = function(data) {
      notes = [];
      // convert min:sec to seconds
      for(i=0; i < data.notes.length; i++) {
        var min_sec = data.notes[i].timecode;
        var tt = min_sec.split(':');
        var seconds = tt[0]*60+tt[1]*1;
        notes.push(seconds);
      }
      return notes;
    };

    noteTimes = timeToSec(data);
    console.log(noteTimes);

    // Formatters for counts and times (converting numbers to Dates).
    var formatCount = d3.format(",.0f"),
        formatTime = d3.time.format("%H:%M"),
        formatMinutes = function(d) { return formatTime(new Date(2012, 0, 1, 0, d)); };

    var margin = {top: 10, right: 20, bottom: 30, left: 20},
        width = 550;
        height = 285;

    var x = d3.scale.linear()
        .domain([0, duration])
        // .domain([0, d3.max(noteTimes)])
        .range([0, width]);

    // Generate a histogram using twenty uniformly-spaced bins.
    var data = d3.layout.histogram()
        .bins(x.ticks(50))
        (noteTimes);

    var y = d3.scale.linear()
        .domain([0, d3.max(data, function(d) { return d.y; })])
        .range([height, 0]);

    var xAxis = d3.svg.axis()
        .scale(x)
        .orient("bottom")
        .tickFormat(formatMinutes);

    var svg = d3.select("#chartSet").append("svg")
        .attr("width", width + margin.left + margin.right)
        .attr("height", height + margin.top + margin.bottom)
      .append("g")
        .attr("transform", "translate(" + margin.left + "," + margin.top + ")");

    var bar = svg.selectAll(".bar")
        .data(data)
      .enter().append("g")
        .attr("class", "bar")
        .attr("transform", function(d) { return "translate(" + x(d.x) + "," + y(d.y) + ")"; });

    bar.append("rect")
        .attr("x", 1)
        .attr("width", x(data[0].dx) - 1)
        .attr("height", function(d) { return height - y(d.y); });

    bar.append("text")
        .attr("dy", ".75em")
        .attr("y", 6)
        .attr("x", x(data[0].dx) / 2)
        .attr("text-anchor", "middle")
        .text(function(d) { return formatCount(d.y); });

    svg.append("g")
        .attr("class", "x axis")
        .attr("transform", "translate(0," + height + ")")
        .call(xAxis);
  }

  initData();

});

A: To handle creation and updates, you will have to reorganize how the draw function is written.
function draw(json) {

   // Initialization (few wasted CPU cycles)
   // ...

   // Update hook
   var svg = d3.select("#chartSet").data([data]);

   // Enter hook
   var svgEnter = svg.enter();

   // Enter cycle
   svgEnter.append("svg")
      .append("g")
      .attr("transform", "translate(" + margin.left + "," + margin.top + ")");

    // Update cycle
    svg
        .attr("width", width + margin.left + margin.right)
        .attr("height", height + margin.top + margin.bottom);

    // Exit cycle (not really needed here)
    svg.exit().remove();

    // Update hook
    var bar = svg.selectAll(".bar")
        .data(data)

    // Enter hook
    var barEnter = bar.enter();

    // Enter cycle
    var barG_Enter = barEnter
                        .append("g")
                        .attr("class", "bar")
    barG_Enter
        .append("rect")
        .attr("x", 1);

    barG_Enter
        .append("text")
        .attr("dy", ".75em")
        .attr("y", 6)
        .attr("text-anchor", "middle");

    // Update cycle
    bar.attr("transform", function(d) {
        return "translate(" + x(d.x) + "," + y(d.y) + ")"; });

    bar.select("rect")
        .attr("width", x(data[0].dx) - 1)
        .attr("height", function(d) { return height - y(d.y); });

    bar.select("text")
        .attr("x", x(data[0].dx) / 2)
        .text(function(d) { return formatCount(d.y); });

    // Exit cycle
    bar.exit().remove();

    // Enter cycle
    svgEnter.append("g")
        .attr("class", "x axis")
        .attr("transform", "translate(0," + height + ")")
        .call(xAxis);

    // Update cycle
    svg.select('g.x.axis')
        .call(xAxis);
}

This classical enter-update-exit pattern is improved upon in this article on making reusable graphs. This answer draws heavily on that pattern.
With a slightly better implementation which uses closures, you will be able to save the few CPU cycles wasted on initialization each time.

A: You can either create the SVG outside the function that you call when the button is clicked, or check whether it exists and only add it if it does not exist. That is, something like
var svg = d3.select("svg");
if(svg.empty()) {
    // code for appending svg
}

The same thing applies to the block of code at the end of your function that appends the x axis. For the bars, all you need to do is handle the update and exit selections in addition to the enter selection, i.e. set the dimensions and potentially remove elements based on the new data.

redpajama_set_name: RedPajamaStackExchange


For the super thrifty, of course, there is the option of bringing in a good old fashioned mug and a cafetière.
Claer Barrett is the editor of FT Money; ; Twitter: @Claerb.
To get your caffeine (regular or decaf) fix in the capital, discover the best aafes promo code june 2015 coffee shops in London below.Sign In, sip a cup of magic, caramel Brulée, Peppermint and Toasted White Chocolate seasonal flavors are here.Paul also has a loyalty card (.So which is the best buy and what kind of return on investment could coffee lovers potentially obtain?The Starbucks basic reusable cup costs 1 and it looks.Better, then, to invest in a cup with a stoppable, leakproof lid thats robust enough to survive the rigours of commuting and being repeatedly stuffed into a handbag.Only available in the US, it is controlled via a smartphone app and can be customised with a 24 carat gold halo lid and a recharging coaster.A solution for a problem that few of us experience, you would have to be seriously wired to think that buying one of these was a good idea.From Instagrammable flat whites to the wave of artisan coffee pop-ups, London has enjoyed something of a love affair with real, good coffee in the past few years.
Ecoffee, are another option at around.
The cheapo Starbucks cup will pay for itself after four discounted coffees in the chain, or two in rivals Pret and PatVal.
Costa, Starbucks and Paul, the French sandwich chain, all offer a discount of 25p.
If you sink 10 into a sturdier reusable cup, it will take 20 coffees to pay back (assuming the 50p discount).The dedicated coffee enthusiast could substantially boost their investment returns by playing coffee arbitrage.How many coffees it will take to earn back the value of your investment also depends on the type of cup you choose.KeepCup (bright mix and match colours, cork thermal bands and choice of a glass costway com discount code or plastic cup) ranging from 10.For the hipster in your life, theres the.How is this possible?So, as well as being better for the planet, using a reusable cup could also be better for your bank account.Contigo (between 20 and 30 depending on size and colour) are guaranteed leak-free, and will also keep your coffee warm for hours.But your future investment returns also depend on its lifespan.Some of my contacts on social media complained that the cups cracked easily.But heavier, non collapsible cups with intricate locking systems such as the.However, Pret and Patisserie Valerie offer the most generous discount of 50p per hot drink to those who bring their own cups (Pret will soon start selling its own ).Anxious to boost their green credentials, most of the big coffee chains offer discounts of up to 50p per hot drink to encourage consumers to bring their own reusable vessels.Then replace the thermal lid, walk back to your work kitchenette, and top up with free boiled water and milk there.
La Carte Noire ) with a free coffee and croissant when you sign up, then your tenth coffee free.
If you drink five coffees a week or 260 cups a year after youve paid for the reusable cup, you could save a cool 120.
But you are still spending rather a lot of money on coffee.


text:
UW-Madison: Government spending bill funds major research initiatives
Mar 14, 2022 | BioForward Member News
The House passed a 2022 spending plan on Wednesday evening, which will fund the federal government through September. The $1.5 trillion-dollar bipartisan appropriations package provides significant funding for University of Wisconsin-Madison initiatives and includes other provisions to boost college affordability and federally funded research. The bill will now be sent to the Senate, where it is expected to pass soon.
"This legislation provides crucial funding for cutting-edge university research and projects, and will improve health, drive innovation and create a more prosperous Wisconsin," said UW–Madison Chancellor Rebecca M. Blank.
"We applaud Wisconsin's congressional leaders for their commitment to funding research and programs that invest in the future of our state and university. Congressman Mark Pocan and Senator Tammy Baldwin, both members of the Appropriations Committee, were particularly instrumental in crafting this legislation and championing priorities for UW–Madison and the state of Wisconsin."
UW-Madison programs received more than $80 million in the spending bill. Some of the funded initiatives include:
•$39.7 million: To build the new Plant Germplasm Facility
•$15 million: Center on Exposome Studies in Alzheimer's Disease and Related Dementias
•$10 million: Institute for Rural Partnership
•$5 million: Center of Excellence for Extreme Events in Structurally Evolving Materials
•$5 million: Center for Unmanned Aircraft Systems (UAS) Propulsion
•$5 million: PANTHER — a biomedical research program addressing traumatic brain injuries
•$2 million: Agricultural Genome to Phenome Initiative
•$1.2 million: Next Generation Scanning High-resolution Interferometer Sounder (S- HIS)
•$1 million: Retirement and Disability Research Consortium
•$500,000: Odyssey Project
•$174,000: Small Business Accounting Projections Clinic
•Up to $10 million for research and development on 2 stroke opposed piston engines
UW–Madison's Office of Federal Relations – located in the university's Washington D.C. office – worked closely with campus stakeholders and Rep. Pocan and Sen. Baldwin to secure support for these critical new investments.
Read the full press release here

redpajama_set_name: RedPajamaCommonCrawl


text:
Bill Clinton: free trader
The former President is giving some business to Scotland. Not all Americans are pleased:
Staff at Netherfield Visuals, in Midlothian, were at the centre of a debate about the US economy - a key issue in the race for the White House.
While Democrat candidates complain that too many American jobs are going overseas, the party's last president has indirectly awarded Netherfield Visuals a contract worth £600,000 to make cabinets for his forthcoming presidential archive.
I'm not quite sure what to make of this:
With more than 2.4 million jobs lost as a result of free trade since George Bush took office in 2001, the loss of manufacturing and IT jobs and contracts abroad has become a major issue.
The current administration hasn't been all that positive towards free trade - remember the tariffs suddenly imposed on steel and timber imports? In some ways the previous regime was friendlier to trading freedoms, but that won't stop populist Democrats spouting economic nonsense in the presidential election campaign.
As Bastiat made clear back in the 19th Century:
Free trade, Bastiat explained, would mean "an abundance of goods and services at lower prices; more jobs for more people at higher real wages; more profits for manufacturers; a higher level of living for farmers; more income to the state in the form of taxes at the customary or lower levels; the most productive use of capital, labor, and natural resources; the end of the "class struggle" that . . . was based primarily on such economic injustices as tariffs, monopolies, and other legal distortions of the market; the end of the "suicidal policy" of colonialism; the abolition of war as a national policy; and the best possible education, housing, and medical care for all the people."
Free trade doesn't "lose" jobs; it allows some jobs to be replaced by others, to the long-term benefit of mankind.
Incidentally, I rather thought that Bill Clinton was too involved in other matters during his presidency to have amassed enough reading material to fill a £600,000 bookcase.
Malky returns
I'm glad to see that Sir Malcolm Rifkind is on his way back to Westminster, having been selected for the safe Conservative seat of Kensington and Chelsea. Although a bit too much on the side of the State for my liking, he does seem to be an honest and gentlemanly kind of guy, unlike so many of the gang now in power.
I once met Sir Malcolm at the magazine section of Borders in Edinburgh and had a brief chat. I pointed him in the direction of the American libertarian publications, Liberty and Reason. Maybe he has picked up some useful ideas from them.
Sir Malcolm echoes Michael Howard's recent remarks on the role of Scottish MPs:
SIR Malcolm Rifkind has come out in support of the idea of Scottish MPs being prevented from voting on English-only issues, saying the present situation is no longer sustainable.
Quite correct of course, but a minefield for a Labour party that is so often dependent on the votes of MPs from north of the border. As I have written before, the only workable solution is for all four parts of the UK to be self-governing and self-financing with a fee being sent to the UK government to cover the few functions that need to be handled centrally. Other than defence and foreign relations, little else comes to mind.
With effect from today readers wishing to access the opinion section of the Scotsman will need to register with the paper. I believe that this will also apply to the Edinburgh Evening News and, no doubt, Scotland on Sunday. Unfortunately, it appears that you need to log in each day, unlike the Daily Telegraph system that automatically recognises your details when you access their site.
The commenting system appears to be offline at the moment. I have e-mailed Haloscan and hope to have the comments back shortly.
(In the meantime, if you have any comments to add please send them to me by e-mail indicating which post you are writing about. I should be able to add them when the system is working again.)
Goodness me. Jerry Hall was busy last night:
WHEN Jerry Hall opined that a woman should be a cook in the kitchen, a maid in the living room and a whore in the bedroom, it was clear she was open to playing a multitude of roles.
But last night the Texan beauty outstripped her own advice by completing a challenge to portray six different characters in six different stage shows in a single night.
This was Jerry's schedule:
7:40 pm - Her Majesty's Theatre (Phantom of the Opera)
8:04 pm - Palace Theatre (Les Miserables)
8:35 pm - Aldwych Theatre (Fame)
8:55 pm - Phoenix Theatre (Blood Brothers)
9:25 pm - Theatre Royal (Anything Goes)
10:09 pm - London Palladium (Chitty Chitty Bang Bang)
By a most extraordinary coincidence this bears an uncanny resemblance to my own plans for Day 1 as First Minister for Scotland after my appointment by popular acclamation:
7:00 am - 103 of Scotland's 129 MSPs are dismissed for late arrival at work.
9:00 am - I meet the Chief Constables of Scotland's Police Forces and demand plans for the removal of political correctness from their organisations and the introduction of a radical new policy: catching burglars. Some officers do not return by the 9:20 deadline and proceed directly to the dole office.
10:00 am - Presentation to a group of taxpayers of the first free share certificates in the newly privatised Scottish Schools PLC. Tax consumers do not receive any certificates.
11:00 am - (You must understand that we are looking a little into the future) - An official ceremony is held to celebrate the victory of Kilmarnock Football Club in the final of the Champions' League.
3:00 pm - The First Minister addresses staff and shareholders at the Global Bank of Scotland Edinburgh Royal Infirmary.
10:00 pm - Large crowds cheer the First Minister as he arrives at Holyrood. In the world's most successful Internet auction, the rubble from the Scottish Parliament building has been pre-sold for £1,000 million, thus giving a profit of £5 to the Scottish taxpayer.
10:30 pm - Her Majesty walks across from Holyrood House and graciously presses the button that explodes the ghastly monument to socialism and bureaucracy.
11:00 pm - The Queen returns to the Palace with lady members of the cabinet to watch a repeat of EastEnders while the First Minister and the rest of the cabinet (accompanied by the Duke of Edinburgh) go on a mega pub crawl.
Any more bids please?
Last week it was costing £420 million. Now it's gone up to between £425 and £430 million. What can I possibly say?
Getting the right result
The first item on last night's Channel 4 News was a very lengthy investigation into America's new computerised voting machines. I hardly think that this was the main news story yesterday, but Channel 4 never misses any opportunity to have a go at President Bush, and here was a chance. We were told that hackers could gain access to these new machines and deliver the November election to the Republicans. Well, that may be so. But why mention only the GOP? Hasn't Channel 4 heard of the numerous suggestions of Democratic gerrymandering? That wouldn't fit the agenda though, would it?
Jon Snow also expressed dismay at the size of the President's $100 million election fund. The implication was that it would be so much better for America to use the severely constricted British election funding system.
But Mr Bush's election stash has been raised voluntarily from people's own pockets. No taxpayer is forced to fund the Republican campaign. I would draw your attention to the BBC Accounts for 2003. I note with astonishment that the Corporation has an income of £3,532 million. No viewer could deny that the BBC's output is strongly favourable to the Labour government and its chances of re-election. Radio 5 Live alone costs some £53.8 million – almost the same sum as George Bush's campaign fund – and Radio 5 is overwhelmingly leftist. The BBC's relentless pro-Blair propaganda makes President Bush a mere amateur in the election funding business.
(By the way, who's going to fund the BBC's £1 billion pension fund deficit? I suspect that it's you and me – the poor old taxpayer. We're not going to see Greg Dyke or his successor out on the streets selling the Big Issue.)
Is this accurate reporting?
Fred Goodwin is one of Scotland's most successful businessmen and has recently enjoyed a huge pay rise.
But have a look at the headline in the news report:
Goodwin to take home £3.5m in pay and bonuses
The article goes on to say that:
ROYAL Bank of Scotland's Fred Goodwin has been paid about £3.5 million in salary and bonuses for guiding the company to its record results last year - catapulting him ahead of the pack as the country's best-paid chief executive.
Unless I am very much mistaken, our Fred has "taken home" more like £2.1 million after paying something in the order of £1.4 million in income tax. Now most of us could probably get by on £2.1 million without too much bother, but I do find it rather worrying when business reporters make mistakes like this. All too often journalists ignore the effects of tax and state benefits when comparing standards of living. Let's leave this kind of headline to the Scottish Socialists.
In praise of Labour MPs
That's not a headline you're likely to read here too often, but in this instance it is justified. A group of Scottish Labour MPs has come out against the state funding of "faith schools":
In an interview with Holyrood Magazine, Dr Moonie, a former defence minister, called for the immediate withdrawal of state funding.
He said: "There should be no state-funded faith schools. Providing faith schools is not the job of the state, as religion has nothing to do with education.
Dr Moonie is not alone:
The group opposed to denominational education also includes Calum MacDonald, the Western Isles MP and former Scottish Office minister, Ian Davidson, the chairman of the Scottish Labour group of MPs, Malcolm Savidge, the Aberdeen North MP, and Frank Doran, the MP for Aberdeen Central.
The Catholic Church is upset:
Peter Kearney, a Catholic Church spokesman, said he was extremely angry over the MPs' comments.
"It's a pity that these past-their-sell-by-date politicians didn't have the courage of their convictions to express their views when facing the electorate. I think it is telling that they use the twilight time of their careers to drop such inflammatory bombshells.
"And to say the taxpayer subsidises faith schools is unfounded because Catholics pay their taxes as well."
I entirely agree that these politicians, like all socialists, are "past-their-sell-by-dates" and have been silent on this issue when facing the electorate. Nevertheless, the operation of two parallel state school systems is a form of subsidy that necessitates higher taxation than would otherwise be required. Let's end this nonsense now. Of course, the best solution is the privatisation of all schools, Catholic and secular.
This post is a test
The Herald
When shall we see their like again?
I took these two photographs in Edinburgh on the way for a lunchtime beverage.
Richard Cobden and John Bright were the leaders of the Anti-Corn Law League, which achieved its goal in 1846 thus leading to the most successful period in Britain's history.
A map of the area can be found here
The Scottish Parliament fiasco - part 998
So, it's gone up by another £19 million. I wrote some time ago that I expected the final cost of the building to be £500 million and I see no reason to alter that forecast. What's really extraordinary about the latest news from the Inquiry is this:
Mr Fisher told the hearing the true cost of the project had been suppressed for "political reasons" for several years. Twice MSPs voted to back the project, in 1999 and 2000, and on both occasions the true estimates were kept from them by civil servants.
The inquiry was shown a memo from Mr Fisher in 2000, in which he recorded how he had been told by Barbara Doig, the civil servant in charge of the Holyrood project, that it would be "inappropriate for political reasons" to release his cost estimates.
Why on earth are civil servants making political judgments? I thought that elected MPs and MSPs made policy and civil servants carried it out. I sincerely hope that heads will roll at the end of this affair with custodial sentences and loss of pension rights for those found guilty.
Don't mention the war!
I heard a funny story last night from Struan Stevenson MEP. You may recall that last year's EU Intergovernmental Conference ended in failure because the Poles "voted the wrong way". Good for the Poles, I say.
The German reaction was somewhat different. A German diplomat was heard haranguing a Polish colleague with the words: "How could you do this after all that we Germans have done for Poland?"
Where's Basil Fawlty when we need him?
Jenny Hjul remembers her driving test in North London
I remember mine (plural) as if they were yesterday, the one I passed particularly. It was late on a dismal December afternoon when I eventually returned to base with the examiner, the north London rush-hour having scuppered his timetable.
I had my first experience of driving when my mother took me to a friend's house that had a long driveway. I was able to drive the maternal car forwards five feet and then backwards five feet without having a license as this complex operation didn't necessitate the use of the public highway. I then started driving lessons. At the time I was working in the West End of London and Lesson One was during my lunch hour. The school was in Charing Cross Road. "First we shall drive round Trafalgar Square," said the instructor! Traffic was a little lighter in the seventies. A few lessons later and I was learning to perform hill starts in Hampstead.
At this time I shared a flat with a workmate who had already passed his test but had never been to Scotland. We went for a weeklong trip and I was able to get in some useful driving practice in the Highlands. Nevertheless, Trafalgar Square hadn't prepared me for reversing 200 yards along one of those single-track roads with a lorry coming the other way.
I then took the test - in South London. Big mistake. I'm really more of a North London guy and, apparently, I didn't pay enough attention at the approach to a crossing.
After some more lessons, I booked for another test but told nobody about it. I just needed a day's holiday from work. This test was in Southgate - North London. All went well until I got back to the test centre and switched off the engine. A huge column of steam emerged from the front of the car.
"Do you want the good news or the bad news," the inspector enquired.
"OK, what's the bad news?"
"Your car is totally f.....d"
"And the good news?"
"You've passed the test, but if the car had broken down before we had finished, I would have had to have failed you."
"That's OK - it belongs to the driving school!"
After the driving instructor added some water, the car restarted and I was able to drive back in triumph.
Well, actually it was a Ford Cortina.
The travelling blogger
Thanks to Samizdata for this map. It shows where I have been in Europe:
create your own visited european countries map or write about it on the open travel guide
And in the US:
create your own visited states map or write about it on the open travel guide
The Council Tax (Part Two)
So, the Scottish Socialists' policy would result in national bankruptcy. What though of the other parties?
The Liberal Democrats want "the rich" to pay more, but not on the same scale as the SSP.
The Nationalists say that:
The SNP want a fair and transparent funding system for local government, which should include a taxation system based on the ability to pay.
Labour is spinning away as expected.
The Tories do seem to understand that the level of spending is a problem:
"The average increase in Council Tax this year is 5%. Contrast that with Tory proposals in Councils where Conservatives were able to offer an alternative and the rise would have been halved to just 2.4%
But why should there be any increase at all?
Graeme Brown gets it:
What is this tax being spent on? The government spin is that it is needed for services. But we know services haven't improved by 90 per cent in ten years. Perhaps the real reason is that we are bailing out the generous and badly-managed council pension funds with their massive bogus ill-health retirements.
Exactly. As I wrote here:
Let's have a really good look at all those inflation-linked local government pension schemes that seem to allow early retirement for an amazing number of bureaucrats. Private sector pensions have been savaged by this government. Why don't we change the terms of public sector pensions to reduce the benefits to the average enjoyed by folk in the private sector? If that were to be done I bet that council tax could be cut instead of increased.
While we're at it, let's get rid of some of those twenty-five-grand-a-year council outreach workers who concern themselves with the vast, one-eyed, vertically-challenged, trans-gendered, multi-hued community of refugees who have apparently come to Scotland from even more socialist parts of the planet. Let those folk work for a living. I mean the refugees of course - the outrageous outreachers are beyond hope of economic redemption. Council tax finances a mere 25% of local government expenditure. Cut spending by one eighth and we could halve council tax at a stroke.
The Council Tax (Part One)
I can't say that I am too surprised by the results of this poll:
Seven out of 10 Scots think council tax is unfair and should be scrapped, according to a survey.
The System Three poll found that 77% of Scots believe it should be replaced by a tax based on ability to pay.
The poll was commissioned by the Scottish Socialist Party who have plans of their own:
There would be five ascending rates of SST (Scottish Service Tax) based on income.
* Rate 1) Nil. All income under £10,000 is exempt from Scottish Service Tax.
* Rate 2) 4.5 per cent. All income between £10,000 and £30,000 will be taxed at a rate of 4.5 per cent.
* Rate 3) 15 per cent. All income between £30,000 and £50,000 will be taxed at a rate of 15 per cent.
* Rate 4) l8 per cent. All income between £50,000 and £90,000 will be taxed at a rate of 18 per cent.
* Rate 5) 20 per cent. All income above £90,000 will be taxed at a rate of 20 per cent
The comrades have identified winners and losers under this scheme:
Laurie, a self-employed actor, lives with her teenage son in a Band C tenement property in Edinburgh. Last year, she earned just under £10,000. Her Council Tax bill, including a 25 per cent single person's discount is £667.50. Under the Scottish Service Tax she would pay NOTHING. Saving: £55 a month.
Good news for "Laurie", then.
What about "Frederick"?
Frederick is one of Scotland's highest paid chief executives, earning £1,200,000 last year. He lives in a Band H property in Edinburgh with his partner and their children. Their current Council Tax bill is £2,002. Under the Scottish Service Tax they would pay £233,100 a year. Loss: £19,258 a month.
Of course the taxes collected from Frederick and his ilk are meant to pay for most council expenditure. The fact that Frederick will have left the country taking his company and his most productive employees with him may well cause a slight financial hiccup in the glorious People's Scotland. But, hey, we can't make an omelette without breaking a few eggs, can we? And anyway, cash flows and balance sheets are outmoded bourgeois concepts that should have been done away with long ago.
(I don't suppose that "Frederick" could be the boss of the Royal Bank of Scotland.)
My political career
Spring-cleaning has unearthed this document:
As far as I recall, I got 199 votes - the second highest out of some 30 candidates across London. I didn't get elected, but the Greater London Council was eventually abolished.
A pity about the missing apostrophe.
Dangerous thoughts
Each week in the Spectator Ross Clark writes his Globophobia column in which he surveys "world restrictions on freedom and free trade". I won't link directly to this week's article, as I fear that registration is now required to read the Spectator online.
Mr Clark examines the forthcoming entry into the EUSSR of the ten new member states and discusses the impact of immigration from those countries into the UK.
There is a quite obvious third way which has been given no consideration at all: let willing Lithuanians come to work here but don't pay them a bean in benefits.
So what's the problem with that? The difficulty is that all those "Lithuanians" without entitlement to benefits would, of necessity, have to work, and work hard. A disproportionate number of them would therefore become successful as employees and, in particular, as entrepreneurs. That in turn may well cause some of us to ask why so many British people don't want to work and are perfectly happy to spend a lifetime on welfare. More sophisticated folk might even think that the true purpose of the welfare state is to provide voting fodder for politicians who themselves serve no useful economic purpose. That would never do. Surely it's far better to bar the new immigrants completely or put all 70 million on the dole as soon as they arrive at Dover.
Apartheid in Scotland
The French Parliament has banned the wearing of headscarves in state schools. Now, there's a similar development in Germany:
The dominant party in the western German state of Hesse on Tuesday proposed legislation that would ban Muslim civil servants from wearing headscarves, a measure that goes further than three other states' proposals to outlaw the veil for public school teachers
This sort of thing doesn't go on in Scotland, does it?
Actually, we have our own homegrown religious conflicts in Scottish schools:
Scotland's first mixed-faith secondary school campus has been hit by fresh controversy following news that the headteacher of the Catholic school at the complex was ordered to take down religious artefacts.
Marion Docherty received an e-mail message from Midlothian council's director of education, instructing her to remove items from a wall in a shared corridor in the £33 million building.
The situation is utterly ridiculous. We have two separate state school systems in Scotland - one Catholic and the other "non-denominational". Two of these schools in the Midlothian town of Dalkeith now share a common campus but the whole arrangement has been plagued with trouble from the start. There was even talk of teachers having to use separate toilets. Unsurprisingly, Muslims now want their own state schools.
I note this afternoon that Edinburgh City Council is about to spend £550 million on school redevelopment. Now I wonder if this has anything to do with the cost:
Designs for the school buildings involved have still to be drawn-up, but it is expected that Forrester High and the neighbouring St Augustine's RC High, which already share some facilities, will be housed in a shared campus.
It's that religious duplication again - at the taxpayers' expense. Why not merge these two schools completely? No wonder our council taxes have just been increased by well above the rate of inflation.
The state shouldn't be in the education business, but as long as it is why should we be asked to fund two or goodness knows how many more brands of "faith" school.
The headscarf problem in France is also the result of state-run education. Let's privatise all schools. Then they can set their own rules - at their own expense.
Today's letters ..
.. in the Scotsman include this one from Andrew Duffin who explains that our bodies belong to us and not to the state.
Andrew also drew my attention to Roy Bradley's letter, which says:
If councils wish to increase local taxation above the rate of inflation, they should have to seek the approval of residents.
Approval should be given by taxpayers rather than "residents" according to Andrew. That's right, and when we consider that no one who is on welfare or who is working for the public sector pays any tax just how many taxpayers are there other than the readers of this blog?
Metropolitan bias
It looks as though the BBC is not interested in any Scottish applications for the position of "chair". Oh well, I suppose that rules out my friend.
A population swap?
Professor Duguid makes some useful points about the plans to bring more immigrants into Scotland:
It would enable the government to avoid addressing the scandal of Scotland's huge number of fit, unemployed people on welfare
I have no problem with people coming here who are willing to support themselves. The Herald (no direct link to the article) has a story today about a Latvian couple that have been told to leave the UK even although they can probably be here legally after 1st May. They don't want to live at the expense of the taxpayer and are keen to work:
They are both enthusiastic about the prospect of working, having been denied the opportunity since they came to Britain three years ago. Mr Suhotskis, who worked in the building trade in Latvia, buying and renovating properties, said he would find it easy to get a job in Glasgow.
So why is it "easy to get a job in Glasgow" when 20% of the city's population is on welfare? I say: Ship out all those fit, unemployed people in Glasgow to Eastern Europe and replace them with hard working and entrepreneurial folk from the Baltic countries.
To the Department for Culture, Media and Sport
I have seen your recent advertisement for the position of BBC Chair.
I am very interested in this challenging opportunity and in particular the salary of £81,320 pa. You will see from my photograph that I am uniquely qualified for this job and look forward to going to London for an interview. You can probably arrange for me to be delivered by Federal Express at little cost.
Taxes up again
This time it's the council tax:
COUNCIL taxes across Scotland are set to rise by an average of 5 per cent, according to the Scottish Executive.
Andy Kerr, the finance minister, said estimates submitted by local authorities indicated an above-inflation rise in most council areas.
And he said he would have "very grave concerns" if any local authority exceeded these figures when new levels are announced on Thursday.
I read elsewhere today that inflation is now running at 1.3% under the government's latest definition. Shouldn't a 5% tax increase cause Mr Kerr "grave concern", not to mention the 15% in poor old Moray? I certainly think so and will make a modest suggestion. Let's have a really good look at all those inflation-linked local government pension schemes that seem to allow early retirement for an amazing number of bureaucrats. Private sector pensions have been savaged by this government. Why don't we change the terms of public sector pensions to reduce the benefits to the average enjoyed by folk in the private sector? If that were to be done I bet that council tax could be cut instead of increased.
The football crisis
It looks like Heart of Midlothian will be selling their ground in Edinburgh and moving to the Scottish Rugby stadium at Murrayfield. To say that fans are unhappy would be an understatement:
With Hearts currently attracting an average home gate of around 12,000 this season, there has been real concern among supporters over what the atmosphere will be like in the cavernous bowl of Murrayfield with its capacity of 67,800.
Posters like this one are regularly displayed at Hearts games. Robinson is the current boss.
I must say that the planned move seems to be rather hasty as well as being tremendously unpopular with the fans:
This, despite a proposal from leading shareholder and property developer Robert McGrail to buy the stadium and rent it back to Hearts and a wide-ranging business plan from his brother Peter which would lead to a new Tynecastle as the focal point of a new multi-sports complex in a regenerated Gorgie.
One thing is certain: we don't need politicians getting involved in Scottish football.
But, of course, they are:
With Livingston, Motherwell and Dundee football clubs all forced into administration, Mr MacAskill is to sponsor a debate on how the Scottish Parliament might support the game.
MacAskill states:
"This is not a question of public money - there can be no bail-out - but we can look at the strategic direction and structure of the sport."
But we don't expect consistency from MSPs, do we?
Mr MacAskill called for money to be put into the sport via other development programmes.
"The Executive currently puts cash into youth development. I believe that opens up the opportunity to link this money to internal reform and play a proactive role in helping football through this crisis."
That sounds like a bail-out to me.
I think that football should consider the system used in the US. The team that does worst in the league gets first pick of the best players in the next season. That way we get competitive games that people will pay good money to watch. I'm not suggesting that politicians should lay down such a law but that the sport's governing body should change the current situation in which Scotland has two clubs with multi-millionaire players and all the other clubs being on the verge of bankruptcy.
Asked on the Daily Reckoning discussion board:
Question: What recent event most clearly shows the extent of Globalization?
Answer: Princess Diana's death.
Consider: An English princess with an Egyptian boyfriend crashes in a French tunnel, driving a German car with a Dutch engine, driven by a Belgian who was drunk on Scottish whisky, (check the bottle before you change the spelling) followed closely by Italian Paparazzi, on Japanese motorcycles; treated by an American doctor, using Brazilian medicines. This is sent to you by an Australian, using Bill Gates' American technology, and you're probably reading this on one of the IBM clones, that use Taiwanese chips, and a Korean monitor, assembled by Bangladeshi workers in a Singapore plant, transported by Indian lorry-drivers, hijacked by Indonesians, unloaded by Sicilian longshoremen, and trucked to you by Mexican illegals.
I am impressed by the correct spelling of "whisky".
So what do you know about economics?
My wife Pam has just taken the economics quiz on the Mises Institute website. She is rightly proud of achieving the excellent score of 87%:
Pam insists that the only economics book she has read is Economics in One Lesson by Henry Hazlitt - and that was some 15 years ago. This either demonstrates what a good book Hazlitt wrote or that Pam really has been listening to my ravings over the years.
I'm a Politician, Get Me Out of Here
Here is an extract from the Liberal Democrat 2001 General Election manifesto:
The Right to Know
Individuals should have the right to know as much as possible about decisions taken by government and in the Scottish Parliament.
And yesterday in the Inquiry into the Scottish Parliament Building fiasco we discovered that:
And Lord Steel revealed that he had deliberately kept crucial information on this dispute back from MSPs, information which could have persuaded some to vote against the project and stop it in its tracks.
And who is this Lord Steel? The former leader of the Liberals!
Big Brother alert
Andrew Duffin has drawn my attention to this letter in today's Scotsman.
As Andrew says:
Given that the reason we have a shortage of housing is very largely "the planning system", this letter is a really classic case of "the answer to state interference is more (and more determined) state interference"
Note Mr Bookbinder's use of the weasel term "social housing". Are privately owned houses "unsocial"?
The Bank of England has raised interest rates to 4%. Contrary to what the media has been reporting over the last few months not everyone in Britain is in debt. Someone is doing the lending to all those indebted folk - of whom Gordon Brown is the champion. It's good that the lenders are to be compensated a bit more fairly.
Is it safe to vote?
Or is there any point in voting? Thomas DiLorenzo thinks not. Writing about the USA he says:
But America was not founded as a democracy. It was a constitutional republic. The whole purpose of the Constitution, James Madison wrote in Federalist #10, was to control "the violence of faction," by which he meant democracy. That's why, until the Lincolnian "Civil War Amendments" were added to it, every part of the Constitution was a prohibition of some kind of governmental power or activity. Democracy was made into a "civil religion" by Lincoln and subsequent generations of Lincolnites who have successfully overthrown the constitutional republic of the founding fathers.
These constitutional prohibitions or limitations are all but ignored today, of course. The Constitution does not provide for the central government to get involved in education, let alone sending a man – and untold millions or billions of dollars – to Mars.
Mr DiLorenzo concludes that he should not vote:
That's why it is unpatriotic to vote. Being patriotic in America means being devoted to the Constitution, if not the natural rights philosophy that motivated much of it. Since neither of the major political parties has any interest whatsoever in enforcing the constitutional limitations on the state, they are all traitors to the Constitution (with one lone exception, Congressman Ron Paul).
But is it safe to vote? I have voted in every election in which I was entitled to participate. I once travelled several miles across London by bus to vote in a local council bye-election in which there was absolutely no chance of a change in party control. The turnout was about twenty percent. It has always seemed the right thing to do for someone interested in politics. Now I am not so sure.
We know that British ballot papers have a reference number that is logged against the voter's individual code. If the state wishes to know how we vote, it can. Surely that wouldn't happen here. A few years ago I would have said no. Now I'm not so certain. As reported over on Samizdata:
Home Secretary David Blunkett wants new anti-terrorism laws to make it easier to convict British terror suspects.
He has discussed lowering the standard of proof required by a court and introducing more pre-emptive action.
Possible plans, revealed on his six-day trip to India and Pakistan, also include keeping sensitive evidence from defendants and secret trials before vetted judges.
As David Carr commented:
The truly frustrating thing here is that not only is Big Blunkett unlikely to be opposed to any meaningful degree (the Conservatives are already weighing in on his side) but his ripping up of our last remaining bulwarks of civil liberty is probably going to make him more popular. That is because civil liberties are unpopular. They are merely the boring obsession of pot-smoking hippies and wishy-washy do-gooders; a shielding sanctuary behind which terrorists and child-molestors can hide from justice.
I wouldn't be at all surprised if this awful government were to start checking how we have voted, although it's fairly obvious that I wouldn't vote for them in a million years. Spoiling one's ballot paper might draw even more attention than voting the "wrong way". Perhaps I've voted for the last time, but I'll still stay up on election night to enjoy seeing the smug smiles removed from the faces of some unexpected losers.
Are we free?
Here is another call for greater Scottish fiscal autonomy:
ROBERT Crawford, the former chief executive of Scottish Enterprise who resigned ten months ago following pressure over allegations of mismanagement at the quango, last night gave his backing to greater fiscal powers for Scotland.
I too agree with a movement towards fiscal responsibility for Scotland and there is a good document on this subject available as a pdf file ("Paying Our Way") from the Policy Institute's website.
Fiscal autonomy does not necessarily imply national independence, as Mr Crawford explains:
"I think the argument is a broader one than nationalism versus unionism. It's a very sophisticated argument. You can get US states which have got far more powers in the economy than presently exist in Scotland and they happily exist in a federal system."
US states certainly do have far more freedom to manage their own affairs than does the Scottish Executive. Indeed, in some respects American states have more independence than does the UK government. Texas can decide whether or not it wants the death penalty. Florida is free to levy a sales tax and to decide the rate of such a tax. It can also decide not to have a sales tax. Washington has no say on these matters. The UK has no such freedom. EU rules forbid us from restoring the death penalty. Brussels also insists that we impose VAT and that it must be within certain tax bands.
Let's devolve power away from the mega-state down to the people, or at least to local politicians whom we can keep an eye on.
News from Houston
I don't understand American football but I liked some of the Superbowl ads that were shown last night. Especially the Budweiser Clydesdale Donkey.
Standard Life
Some time ago I read an article about outsourcing - it may well have been by Peter Drucker who writes wisely on this topic. The message was that outsourcing is a very useful business tool but that an organisation should never outsource its core activity.
Standard Life is thinking about outsourcing its handling of complaints:
Standard Life said it is considering outsourcing the handling of "mis-selling" complaints from its endowment mortgage holders in an attempt to hit a strict deadline set by City watchdog the Financial Services Authority for dealing with complaints.
In my opinion that would be a grave mistake. Standard Life has suffered from a huge amount of adverse publicity over the last few years and especially in recent months. Restoring its good name should be the number one priority for Standard's executives. Such a task should not be outsourced and indeed I would suggest that all members of the organisation's top management spend a few hours each week manning the phones and speaking to real live customers. Regaining the members' trust is surely the core activity at the present time.
I believe that Standard Life should have been more wary of the very high stock market values that pertained a few years ago and it should have scaled back its exposure to equities at that time. I notice that Standard is now being criticised for selling shares when the market is "recovering". I'm not so sure. It seems to me that valuations are still far too high and Standard may well now be correct in at last reducing its exposure to the stock market.
Oh what a tangled web ...
My Member of Parliament is Alistair Darling. In today's Sunday Times (registration may be required outside the UK), Mr Darling writes about calls for Scottish MPs to be barred from voting on "English" matters in the House of Commons:
It would go against the grain of our constitution to have two classes of MP. When constituents send their representative to parliament they expect them to represent their interests. MPs are not restricted exclusively to constituency matters but are free to speak, and vote, on all matters brought before parliament.
Of course MPs are not restricted to speaking about "constituency matters", and rightly so. But Mr Darling has a problem. There are already two classes of MP. An MP representing an English seat can speak and vote on UK concerns such as foreign policy and levels of taxation. So too can Mr Darling as MP for Edinburgh Central. An English MP can speak and vote on health and education policies affecting his own constituents. Mr Darling cannot do so because health and education policies for Edinburgh are devolved to the Scottish Parliament. He is a different sort of MP. What Mr Darling can do is speak and vote on health and education in so far as it affects English voters and that is a constitutional outrage.
Mr Darling points out that some apparently "English" legislation nevertheless has a Scottish impact:
Take the question of the current Higher Education Bill. While variable fees, as a devolved matter, will not apply to Scottish universities, many Scots attend universities in England and, indeed, a significant proportion of the Higher Education Bill will apply in Scotland. It is hardly surprising, therefore, that Scottish MPs are interested in these proposals. The idea of Scottish MPs participating in scrutiny of some bits of a bill and then withdrawing for others would be unworkable and absurd.
I'm sorry but that won't do. Many Scots attend universities in the United States. Does that mean that Mr Darling should be able to vote in the House of Representatives? I think not. The coming of devolution means that is absolutely necessary for Westminster legislation to be firmly and fairly split into English and UK categories with Scottish MPs having no say on English laws.
Here's another problem identified by Mr Darling:
Even more fundamentally, it would make a nonsense of the way in which we choose a government and hold it to account. There is no separation of the legislature and executive in the UK. If we had two classes of MPs we could be faced with the prospect of a government elected for the UK unable to deliver its programme for parts of the UK. A government with a majority in the UK but not in England.
It is quite wrong for any party to be talking about implementing a programme for all parts of the UK from Westminster - Scottish domestic policies are devolved and are legislated from Edinburgh. Mr Darling doesn't seem to grasp the necessary implications of the devolution settlement.
The current situation is the creation of Mr Darling's own party and does indeed logically imply an eventual movement to either federalism or independence. For myself, I chose federalism. To those who reject federalism as being unworkable because of the dominance of England in the UK state, I reply that the problem goes away when government is reduced to its (arguably) legitimate function of protecting the people against those who initiate force or fraud.


text:
Q: How to beautify pagination URL in laravel 6.x I have a website where I used pagination . But the url is making pagination url such as
http://website.com/user?page=2

But I want to beautify it as
http://website.com/user/2

I am using laravel 6. how can I make it to do?

A: Pretty Laravel Pagination
There is no official way to beautify laravel pagination code. So I make my own code and Finally it is working.
Goal
www.website.com/user?page=1 → →→→ www.website.com/user/1
Step1:
In route :
Route::get('/user/{page?}', 'MainController@index')->where('page', '[0-9]+')->name('areasearch');

*

*where('page', '[0-9]+') this code is to maintain that page parameter will accept only numeric value.

*{page?} here ? question mark is for making the value optional.

Step2:
In MainController:
public function index(Request $request){
    if(isset($request->page) && $request->page<1)
        $page = 1;
    else
        $page = $request->page;
    $user = User::ALL();
    $data=$this->paginateArray(user,$page);
    $data=$data->setPath($request->url());
    return view('index')->with('data',$data);
}
public function paginateArray($user='', $page = 1)
    {
    $currentPage = $page;
    $user_collection = collect($user);
    $perPage = 50;
    $paginatedItems = new LengthAwarePaginator($user_collection->forPage($currentPage, $perPage) , $user_collection->count(), $perPage, $page);
    return $paginatedItems;
    }
public function paginate_with_custom_path($data)
    {
    $links = $data->links('pagination.paginator');
    $patterns = '#\?page=#';
    $replacements = '/';
    $one = preg_replace($patterns, $replacements, $links);
    $pattern2 = '#/([1-9]+[0-9]*)/([1-9]+[0-9]*)#';
    $replacements2 = '/$2';
    $paginate_links = preg_replace($pattern2, $replacements2, $one);
    return $paginate_links;
    }

Step3:
In view:
use App\Http\Controllers\MainController; $MainController= new MainController();
@extends('master')
@section('maincontent')
    {!!$MainController->paginate_with_custom_path($data)!!}
@endsection

That's all . We successfully made changes the url.


Towards the end of 2011, we found ourselves on an unexpected trip to Datça and its peninsula with friends and, in January, we wrote a post reflecting on the differences between Palamutbükü now and how we remembered it from eight years ago. Click the link to read about the beautiful Palamutbükü.
You can always expect Istanbul to feature heavily in any talk about travelling Turkey on this blog. In February, we wrote about our friend's ceramic shop, Istanbul Ceramic, which is in the Grand Bazaar (Kapalı Çarşısı). We're not big on shopping centres, historic or not, so a visit to our friend is the only time we venture into this world famous building. Click this link for more souvenir photos taken in Istanbul Ceramic.
Ahhh, once again, we're in Istanbul – well we declared our love for the city in our post, Istanbul – It's A Love Thing. In March, we told you all about our favourite place to sit and drink çay and smoke nargile when we're in the city. Read about Çorlulu Alipaşa Medresesi.
April saw us returning for a day trip to the Turkish UNESCO World Heritage archaeological sites of Letoon and Xanthos. Because it was so early in the year, we had the sites to ourselves. These are our posts on Letoon In Photos and a Xanthos Photo Tour.
This is the month where our travels took us out of Turkish borders. It meant a return to Istanbul at the end of April so that we could fly to Italy from the most impressive Sabiha Gökçen Airport. During our time in Italy, we were privileged to visit San Pietro, Italy's Kayaköy.
What's the rush? Why fly up and down Turkey, when you can feel the size of the country by making use of Turkey's excellent intercity bus network? In this post, we photographed and described the bus journey from Fethiye to Istanbul.
This is the month when we have most friends over to visit, so any explorations tend to be closer to home. The definite highlight of July was hiring a car with friends and driving along the mountain road to Kabak. This series of posts was really popular so it looks like a lot of us just fall in love with that area when we see it.
In August, we started to look back on some past travels that we hadn't really covered in any depth on the blog. We kicked off with past trips to the Bodrum Peninsula and reminisced about the huge boatyard at İçmeler and the rather smart marina at Turgutreis.
This was the month where we took ourselves off to explore the Turkey's third largest city after Istanbul and Ankara, the Aegean city of Izmir. On our return, September posts included Izmir Saat Kulesi and the views over the city from Asansör.
Any budding sailors out there? In October, we featured our first interview on the blog when we interviewed travel blogger, Dave Dean about private yacht charter in Fethiye.
We continued with our series of posts about our trip to Izmir (and we still have more to come). We were keen to stay in the city rather than take off to explore the highly popular environs because we like to get a real feel for a city. Our hike up to Kadifekale revealed a different side to Izmir and we soaked up the atmosphere of Alsancak at night with this series of photos of Izmir after the sun goes down.
Of course, November is when many around the world commemorate Remembrance Day. Our contribution to this was a look back on our trip to Italy and our emotional visit to the Polish war cemetery at Monte Cassino.
Well, December is all about looking back – which is what we've just done – and looking forward. What will 2013 bring with regards to travels around Turkey? Definitely another trip to Istanbul – well, of course. Other than that, we've got a good few ideas pencilled in – and time and money will determine which of those ideas come to fruition.
Thanks so much for following our random wanderings in, and out of, Turkey in 2012 and we'll have much more to come in 2013. Hope to see you on the other side. In the meantime, we're not done with 2012 just yet…Keep an eye out for our next post on our Turkish food highlights.
It's been great fun joining you on your travels this year. If we can't be in Turkey, it's a great escape joining you!. Can't wait to see where we're going next year!
Nice look back on a great year. Cheers!


Manuscript submitted December 22, 2009; resubmitted December 27, 2009; accepted December 27, 2009.
The diverse actions of the incretin hormone glucagon-like peptide (GLP)-1 include insulinotropic, beta-cell preservative, cardioprotective and vasodilatory effects. This spectrum makes GLP-1 an appealing therapeutic option for patients with type 2 diabetes. However, its rapid metabolism by the enzyme dipeptidyl peptidase (DPP)-4 renders it impractical. Incretin-based analogues have been developed to extend endogenous GLP-1 action (GLP-1 receptor agonists) and to hamper its degradation (DPP-4 inhibitors). Evidence suggests that GLP-1 receptor agonists and DPP-4 inhibitors have different pharmacodynamic and pharmacokinetic effects. For example, GLP-1 receptor agonists deliver supraphysiologic levels of GLP-1 analogues designed to resist inactivation by DPP-4, whereas DPP-4 inhibition conserves native GLP-1 resulting in concentrations within the physiologic range. Furthermore, GLP-1 receptor agonists induce glucose-dependent insulin secretion, beta-cell protection, and other extraglycemic benefits such as weight loss and improvement in markers of cardiovascular risk. In contrast, DPP-4 inhibitors are weight neutral and have modest effects on glucose control. DPP-4 inhibition is dependent on the availability of endogenous GLP-1, which appears to be adversely affected by type 2 diabetes and its progression. Therefore, DPP-4 inhibitors may be better suited for patients with mild hyperglycemia without comorbidities. This review examines the present understanding of the pancreatic effects of endogenous GLP-1, and the extrapancreatic actions it exerts on human bodily systems. Also, it analyzes available preclinical and clinical data on incretin therapies with respect to glycemia, lipids, blood pressure, and weight.
Glucagon-like peptide (GLP)-1 was first characterized as an incretin hormone. In the years after its discovery, diverse actions of GLP-1 were described. These include: 1. insulinotropic effects [1, 2], 2. neogenesis, differentiation, and preservation of pancreatic β-cells [3-7], and 3. cardioprotective and vasodilatory properties. The discrete mechanisms governing the latter two effects have not yet been fully clarified . Despite early encouraging results with intravenous infusion [9-11], native GLP-1 was determined to be an impractical therapeutic tool, due to its rapid extensive metabolism by dipeptidyl peptidase 4 (DPP-4) [12, 13]. Consequently, attempts to adapt GLP-1 to therapeutic advantages in the treatment of type 2 diabetes resulted in the development of GLP-1 analogues that protract endogenous GLP-1 action. Also, DPP-4 inhibitors have been developed to impede the enzymatic inactivation of the incretin hormone.
Current evidence suggests that GLP-1 receptor agonists and DPP-4 inhibitors have differential pharmacodynamic and pharmacokinetic effects. GLP-1 receptor agonists deliver supraphysiologic levels of GLP-1 analogues designed to resist DPP-4 degradation. Whereas, DPP-4 inhibition conserves native GLP-1, resulting in concentrations within the physiologic range . DPP-4 inhibitors are associated with weight neutrality and modest effects on glucose control (HbA1c reductions of 0.6% to 0.8%) . DPP-4 inhibition is dependent on islet function, which is adversely affected by type 2 diabetes and its progression . Therefore, DPP-4 inhibitors may be better suited for patients with early type 2 diabetes without comorbidities . DPP-4 inhibition is nonspecific; thus, it may compromise the function of additional peptide substrates such as GLP-2, glucose-dependent insulinotropic polypeptide, peptide YY, neuropeptide Y, growth hormone-releasing hormone, as well as various paracrine chemokines and immune system substrates [17, 18].
GLP-1 receptor agonist therapy supplements native GLP-1 with pharmacologic doses of GLP-1 analogues. The analogues are fully capable of binding to the GLP-1 receptor and inducing glucose-dependent insulin secretion. They also provide β-cell protection and other extraglycemic benefits, such as weight loss and improvements in markers of cardiovascular (CV) risk [1, 4, 7, 12, 19-21]. GLP-1 receptor agonists are designed to retain the β-cell-potentiating and -preserving properties of the incretin hormones, while incorporating resistance to inactivation by DPP-4 .
DPP-4 inhibitors have less robust antiglycemic and extraglycemic effects than GLP-1 receptor agonists. This may be explained by different GLP-1 plasma concentrations. Furthermore, DPP-4 inhibitors may convey humoral and neuroendocrine effects of GLP-1 by inhibiting GLP-1 degradation in various tissues. Another explanation may involve the potential bioactivity of GLP-1 (9-36), a rapidly produced metabolite of GLP-1. In animal models, GLP-1 (9-36) appears to have cardioprotective benefits independent of the GLP-1 receptor . It may be that agents of the incretin class are associated with substantial differences in circulating levels of GLP-1 (9-36) . Whether inhibition of DPP-4 has beneficial consequences independent of its antidiabetic effects remains to be demonstrated .
GLP-1 receptor agonists improve glycemic control by increasing glucose-stimulated insulin secretion and suppressing glucagon secretion . GLP-1 receptor agonists are associated with robust effects on glucose control (HbA1c reductions of 0.4% to 1.5%) as well as weight loss (~-3 kg) and other beneficial extraglycemic effects [25-33]. The insulinotropic effects of these agents have been amply demonstrated in large, placebo-controlled, clinical trials. GLP-1 receptor agonists promote weight loss by inhibiting gastric secretion and motility [34-36], which delays carbohydrate absorption and contributes to satiety by delaying gastric emptying [37, 38]. GLP-1 receptor agonists increase β-cell mass in rodents [39-43] and inhibit β-cell apoptosis in vitro and in vivo [44, 45]. While direct effects on β-cell mass cannot be quantified in humans, the results of these preclinical studies suggest potential protective effects on β-cell volume and morphology. Clinical evidence of effects on contractility, blood pressure, cardiac output, and cardioprotection in animals and humans, has also been reported [23, 46-50].
Ample preclinical and clinical evidence substantiates the need for a multifactorial risk-reduction strategy to address hyperglycemia and comorbidities in type 2 diabetes. Type 2 diabetes is highly correlated with dyslipidemia, hypertension, and a spectrum of cardiovascular and metabolic derangements. Adiposity increases the risk of type 2 diabetes [51, 52], and is often accompanied by a distinct pattern of plasma lipid abnormalities. Elevated triglyceride-rich lipoprotein levels, low high-density lipoprotein cholesterol (HDL-C) levels, and structural alterations of low-density lipoprotein cholesterol (LDL-C) cause a predominance of dense, highly proatherogenic particles . The dramatic increase in mortality in type 2 diabetes associated with cardiovascular disease (CVD) and comorbid adiposity underscores an urgent need to address these risk factors in type 2 diabetes [54-56]. The benefits of weight reduction in type 2 diabetes are evident. They include improved insulin sensitivity, restored β-cell sensitivity, enhanced β-cell capacity [57-59], a less atherogenic lipid profile , and reduced systolic blood pressure (SBP, -5 mmHg to -20 mmHg) . Weight reduction of as little as 5% to 7% from baseline has been shown to reduce the risk of developing diabetes mellitus by >50% in patients with impaired glucose tolerance .
The present review examines what is known about the pancreatic effects of endogenous GLP-1 and the extrapancreatic actions it exerts on the central nervous, gastrointestinal, and CV system (Figure 1) . It concludes with an analysis of the available preclinical and clinical data on incretin therapeutics with respect to glycemia, lipids, blood pressure, and weight.
Figure 1.	Glucagon-like peptide-1: pancreatic and extrapancreatic actions.	The various organs or organ systems affected by GLP-1 actions are depicted in the figure. In the pancreas, GLP-1 action causes short term effects that result in increased glucose-dependent insulin- and somatostatin secretion, increased insulin synthesis, and inhibition of glucagon secretion. Long-term effects of GLP-1 action on the pancreas include increased expression of genes that modify beta-cell function and survival in a beneficial way by inhibiting beta-cell apoptosis and stimulating beta-cell replication. In the stomach and intestine, GLP-1 slows motility resulting in delayed gastric emptying and a retardation of intestinal motility. In the CNS, GLP-1 is an important neurotransmitter for regulating appetite and eating behavior. GLP-1 promotes satiety and leads to reduced food intake. Additional long-term effects of GLP-1 on the CNS comprise an improvement of learning and memory, as well as a stimulation of neuronal cell survival and replication. In liver, adipose tissue and muscle, GLP-1 action causes increased glycogen synthesis and liogenesis. These effects are mainly mediated by the increase in insulin secretion and suppression of glucagon secretion mediated by GLP-1. In the heart GLP-1 improves left ventricular function and has preventive effects on ischemic damage of the heart muscle. Reproduced from Best Pract Res Clin Endocrinol Metab, Vol 18, Baggio LL, Drucker DJ, Clinical endocrinology. Glucagon-like peptide-1 and glucagon-like peptide-2, 531-554, 2004, with permission from Elsevier .
GLP-1 is a potent gut hormone that stimulates insulin secretion and inhibits glucagon release in a glucose-dependent manner. Therefore, it reduces postprandial glycemia without causing hypoglycemia. GLP-1 is present in two circulating molecular forms, glycine-extended GLP-1 (7-37) and GLP-1 (7-36) amide . Following secretion by enteroendocrine L-cells located primarily in the distal ileum and colon, GLP-1 (7-36) amide is rapidly degraded and inactivated by DPP-4 to its metabolite GLP-1 (9-36) [64, 65]. The half-life of intact circulating GLP-1 is less than 2 minutes in vivo .
Unlike other insulin secretagogues, GLP-1 promotes insulin gene transcription and messenger-RNA (mRNA) biosynthesis. Therefore, it has the capacity to restore depleted β-cell insulin . Studies in rodents and isolated human islets have shown that GLP-1 has insulinotropic effects on pancreatic islet β-cells by enhancing differentiation and proliferation and reducing apoptosis [3, 7, 67]. The peptide sequences of GLP-1 in rodents and humans, have been found to be identical, suggesting that those effects may occur in vivo in both species . In clinical studies, exogenous administration of GLP-1 has normalized β-cell responsiveness to glucose and restored both first- and second-phase insulin responses in patients with type 2 diabetes, regardless of disease severity [11, 69].
The inhibitory effects of GLP-1 on the pancreatic islet α-cell may occur indirectly through GLP-1-mediated stimulation of insulin secretion  or via direct interaction with GLP-1 receptors on α-cells . GLP-1 reduces α-cell insulin resistance in type 2 diabetes [72-74], thereby it helps inhibiting postprandial glucagon secretion [26, 75-77]. Additionally, GLP-1 is able to inhibit glucagon secretion from α-cells indirectly by stimulating somatostatin secretion from δ-cells. Somatostatin then binds to somatostatin receptor 2 on α-cells, leading to a decrease in glucagon secretion . Thus, GLP-1 elicits multiple actions resulting in glucose homeostasis and appropriate islet cell activity. However, the precise mechanisms of GLP-1 action (e.g. insulinotropic effects on pancreatic islets) independent of the insulin to glucagon ratio is not yet fully known.
GLP-1 exerts its actions through the engagement of structurally distinct G-protein-coupled receptors. These receptors are present in islet α-cells and β-cells and in regions of the central nervous system (CNS) that regulate diverse homeostatic functions, including gastric motility and glucoregulation [79-81]. Consistent with the distribution of GLP-1-receptor expression, GLP-1 inhibits glucagon secretion and gastric empting, and may reduce caloric intake [82, 83]. In the presence of food, GLP-1 may mediate gut-brain signaling from the gastrointestinal tract to GLP-1 receptors in the hypothalamus and brainstem. This constitutes a feeding control via neural and endocrine mechanisms .
The coordinated actions of GLP-1 in feeding and glucose homeostasis are evident at multiple sites. GLP-1 is a key regulator of appetite, food intake, body weight, and gut motility. It has been shown to inhibit food intake and promote satiety in normal, obese, or diabetic individuals [36-38, 85, 86]. In vivo studies suggest that GLP-1 exerts effects on fuel sensing; it was able to reduce food intake in Göttingen minipigs , and craving in rats , for simple carbohydrates and/or fat. Manganese-enhanced magnetic resonance imaging in fasted mice following exogenous-administered GLP-1 supports the observation that the anorexigenic effects of GLP-1 may be mediated via "nausea" circuits within the hypothalamus and brainstem . Collectively, the evidence indicates that the inhibitory effects of GLP-1 on gastric emptying and acid secretion involve vagus nerve stimulation and activation of GLP-1 receptors located in the CNS, and/or on the vagal afferent fibers that relay sensory information to the brainstem .
GLP-1 may also regulate bone metabolism, possibly through a calcitonin-dependent pathway . A study evaluated bone resorption in GLP-1 receptor knockout mice compared with wild-type mice. The investigators found higher urine levels of the bone resorption marker deoxypyridinoline and reduced thyroid levels of calcitonin mRNA transcripts in the knockout mice, but no evidence of a direct effect of GLP-1 on osteoclasts or osteoblasts . However, treatment with calcitonin effectively suppressed urinary concentrations of deoxypyridinoline in the knockout mice. The GLP-1 receptor agonist exendin-4 increased calcitonin gene expression in the thyroid of wild-type mice. These findings are preliminary and need confirmation and replication through in vivo studies.
GLP-1 receptors are widely expressed in CV, adipose, hepatic, and renal tissue [80, 81]. High-affinity GLP-1 receptors are present in autonomic nuclei that control CV functions [91, 92], and have been isolated in rodent and human cardiomyocytes, endothelial cells, and vascular smooth muscle cells [23, 93]. Although the specific localization and functional relevance of those receptors has not been completely defined, it is noteworthy that mice lacking functional GLP-1 receptors have structural and functional cardiac abnormalities. These include diastolic dysfunction, alterations in resting heart rate, heart wall thickness, and abnormalities in the ratio of heart weight to body weight . Stimulation of central GLP-1 systems has been associated with activation of autonomic regulatory neurons and increased heart rate and blood pressure [91, 92, 95]. In a recent study, GLP-1-receptor activation improved survival after myocardial infarction (MI) in the normal and diabetic mouse heart. This finding suggests that GLP-1-receptor activation is accompanied by effects on the modulation of mediators important for cardiomyocyte survival, including peroxisome proliferator-activated receptors (PPAR)-β/δ, heme oxygenase (HO)-1, Akt, and glycogen synthase kinase (GSK)-3β .
GLP-1 receptor agonists appear to have CV effects independent of the autonomic nervous system, and even independent of known GLP-1 receptor-linked pathways . Preclinical evidence suggests a novel two-pathway schema for the CV actions of GLP-1. One pathway depends on the GLP-1 receptor for glucose uptake, ischemic preconditioning, and mild vasodilatory actions. Another appears to involve GLP-1 receptor-independent effects on postischemic recovery of cardiac function and vasodilation [23, 48].
Recent studies suggest a role for GLP-1 as a cardioactive peptide, with demonstrable effects on contractility, cardiac output, arterial blood flow, and cardioprotection [23, 46, 48-50, 98]. At supraphysiologic concentrations, GLP-1 behaves as a molecular signal, linking CV and metabolic functions in vivo. Treatment with GLP-1 at supraphysiologic concentrations resulted in increased femoral arterial blood flow correlated with whole-body insulin-stimulated glucose utilization. In a murine model, a strong correlation was observed between glucose utilization and blood flow rates. This correlation was not observed in experimental conditions where brain GLP-1 signaling was abolished in GLP-1-receptor knockout mice, and even more selectively, in mice whose brains were directly infused with a GLP-1 receptor antagonist . GLP-1 has demonstrated an inotropic effect in dogs with heart failure [49, 100], and exerts salutary cardioprotective effects in patients with acute MI when administered as a 72-hour infusion following angioplasty . Clinical studies, involving patients with type 2 diabetes and comorbid coronary artery disease, have shown that GLP-1 infusion improved endothelial function , and blood pressure and cardiac function in the immediate postoperative state after bypass surgery . Recent in vitro studies indicate that GLP-1 attenuates tumor necrosis factor alpha (TNF-α)-induced expression of plasminogen activator inhibitor 1 (PAI-1) in vascular endothelial cells, suggesting a possible mechanism for observed ameliorative effects on endothelial dysfunction . Of salient interest, studies have shown cardioprotective and vasodilatory actions of GLP-1 independent of the proposed GLP-1-receptor pathway .
The beneficial effects of GLP-1 on CV parameters may also occur indirectly through GLP-1-mediated improvements in fatty free acid levels and glucose disposal. GLP-1 has been shown to stimulate lypolysis in rat  and human  adipocytes. In a small study of 20 patients with type 2 diabetes, a continuous 6-week infusion of GLP-1 produced reductions in fasting and 8-hour mean concentrations of free fatty acids . There is preliminary evidence that GLP-1 suppresses endogenous glucose production under fasting conditions independently of its action on islet hormone secretion . GLP-1 may also help to regulate glucose homeostasis via influencing islet cell hormone secretion and modulating gastric emptying. Also, it may have an impact on hepatic glucose production via stimulation of GLP-1 receptor in the arcuate . D'Alessio et al. have postulated that GLP-1 facilitates enhanced glucose disposal in peripheral tissues independently of its effects on islet hormone secretions (insulin and glucagon) . However, other studies have failed to demonstrate a GLP-1-mediated, insulin-independent effect on glucose disposal [107, 108].
Intravenous infusion of GLP-1 revealed renal-protective properties, including enhanced sodium excretion and reduction in hyperfiltration associated with kidney damage . The antihypertensive effects of GLP-1 observed in salt-sensitive Dahl S rats, coupled with reductions in renal and cardiac end organ damage, has been attributed to the GLP-1-dependent increase in salt and water excretion .
Recognition of the sustained insulinotropic and glucagon-lowering activity of GLP-1 has fostered interest in the use of GLP-1 receptor agonists for the treatment of patients with type 2 diabetes. GLP-1-based therapy could be especially valuable in patients with comorbid overweight/obesity and/or CVD. Observations elucidating a role for GLP-1 in the potentiation of glucose-dependent insulin secretion have been followed by clinical trials. They confirm the efficacy of GLP-1 receptor agonists in controlling the glycemic disorders associated with type 2 diabetes. Similarly, in vivo and small proof-of-concept studies confirming the extrapancreatic actions of endogenous GLP-1 have provided the rationale for investigations of the extrapancreatic effects of GLP-1-based therapeutics.
Exenatide (synthetic exendin-4) was originally identified during research for biologically active peptides in Gila monster venom . The drug has a 53% homology to human GLP-1  and a half-life of 2.4 hours. It must be injected within 60 minutes of morning and evening meals . In addition to potentiating effects on glucose-dependent insulin secretion, exenatide appears to have beneficial effects on indices of β-cell function [113, 114]. However, these benefits have not been sustained after discontinuation of the therapy . In three double-blind, placebo-controlled trials, patients with type 2 diabetes receiving exenatide added to conventional oral antidiabetics (metformin, sulfonylurea) experienced a mean weight loss ranging from 0.9 kg to 2.8 kg at 30 weeks coupled with reductions from baseline HbA1c of 0.40% (5 μg bid) to 0.86% (10 μg bid) [31-33]. In an open-label extension of a 30-week trial (n = 283), exenatide produced mean body weight reductions of 4.7 kg at week 104 (p < 0.001) ; HbA1c of ≤7% was achieved in approximately 50% of patients. In a subgroup of these patients, from whom homeostasis model assessment of β-cell function data were collected (n = 112), significant improvement (p < 0.01) was observed from baseline. Biomarkers of hepatic injury, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), progressively and significantly declined (p < 0.05 for both ALT and AST) from baseline to week 104. β-cell function was also measured in a 1-year trial, in which exenatide was compared with insulin glargine, in type 2 diabetes patients inadequately controlled on metformin. Exenatide-treated patients demonstrated significantly increased first- and second-phase insulin secretion (as measured by C-peptide secretion response to arginine during hyperglycemic clamp) compared with insulin glargine (p < 0.0001) . With respect to cardioprotective effects independent of weight loss, exenatide improved cardiac function and reduced infarct size in a porcine model of ischemia . In vivo results showed infarct-limiting action against ischemia-reperfusion injury in rat heart .
In clinical studies, exenatide is associated with modest improvements in lipid parameters across a range of changes in HbA1c values, including increased HDL-C concentrations (+4.6 mg/dl, +0.12 mmol/l), and reductions in triglycerides (-38.6 mg/dl, -0.44 mmol/l) and LDL-C (-1.6 mg/dl, -0.04 mmol/l). Improvement in lipid profiles occurred even in the absence of clinically significant weight loss . Blood pressure parameters were modestly improved, as indicated by reductions in SBP (-1.3 mmHg) and diastolic blood pressure (DBP; -2.7 mmHg). In the 82-week extension study, the largest reductions in weight relative to baseline were associated with the greatest baseline-to-end point improvements in SBP (-3.9 mmHg) and DBP (-4.4 mmHg) .
Reductions in CV risk factors were also observed in a post hoc analysis of patients who underwent exenatide therapy for at least 3 years in open-label extensions of 30-week, double-blind, randomized trials. These patients experienced a progressive weight loss from baseline (a mean of -5.3 kg at 3 years, p < 0.0001). Reductions in HbA1c observed at 12 weeks were sustained for up to 3 years (mean reduction, 1.0%). A subgroup of patients treated with exenatide for 3.5 years experienced reductions in triglycerides (12%, p = 0.0003), total cholesterol (5%, p = 0.0007), and LDL-C (6%, p < 0.0001), and an increase in HDL-C (24%, p < 0.0001) . As reported at the 2009 Annual Meeting of the European Association for the Study of Diabetes, a study of 56 type 2 diabetes patients randomized to 3-month treatment with exenatide or insulin glargine, showed exenatide to be significantly better than insulin glargine regarding the improvement of central hemodynamic biomarkers of CV risk (e.g., central pulse pressure and augmentation pressure; p < 0.05 for both measures) . Analysis of blood pressure reductions in the same patient group found that exenatide was associated with a significantly greater reduction in DBP, when tested versus insulin glargine (-4.85 ± 7.3 vs. -0.15 ± 9.7 mmHg for exenatide vs. insulin glargine, p = 0.038). A non-significant trend towards greater SBP reduction with exenatide versus insulin glargine was also reported . A 1-year extension study of a 30-week trial of once-weekly exenatide in type 2 diabetes patients with elevated baseline cardiometabolic values, reported significant reductions from baseline in SBP and DBP as well as LDL-C and triglycerides (p < 0.05 for all cardiometabolic parameters) .
Liraglutide is a once-daily GLP-1 receptor agonist with a 97% human homology to the native hormone . The key modification (an acyl side-chain addition and an amino acid substitution at position 34) facilitates albumin binding and self-association. By these modifications, the half-life of liraglutide is prolonged to approximately 13 hours, enabling once-daily administration [125-127].
In the Liraglutide Effect and Action in Diabetes (LEAD) trials (6 randomized, controlled phase 3 trials involving ~4500 subjects), liraglutide was associated with significant reductions in HbA1c, weight, SBP, and plasma lipids. In LEAD-3, a 52-week, double-blind, active-control, parallel-group trial, liraglutide monotherapy reduced HbA1c by 1.6% in patients previously treated with diet and exercise only, representing the drug-naive population . Significant weight reduction relative to insulin glargine (-3.43 kg; p < 0.0001) was seen in LEAD-5, accompanied by a significant reduction in waist circumference (-1.5 cm liraglutide vs. +0.89 cm glargine; p < 0.0001) . Dose-dependent weight reductions of up to 3.2 kg were observed in liraglutide patients in the 24-week, head-to-head trial of liraglutide or exenatide added-on to metformin or sulfonylurea or both (LEAD-6) . Weight loss was statistically similar in both treatment groups but numerically greater in the liraglutide group (-3.2 kg, liraglutide; -2.9 kg, exenatide; p = NS) . Liraglutide also had significantly greater reductions in HbA1c than exenatide (-1.1% vs. -0.8%, p < 0.0001) . Results from a 14-week extension of this trial demonstrated additional benefits in glycemic control (HbA1c -0.3%; p < 0.001), as well as a further reduction in SBP (-3.8 mmHg; p < 0.001), and additional weight loss (-0.9 kg; p < 0.001) in 186 patients who switched from exenatide to liraglutide .
Data from four clinical trials of liraglutide in combination with one or two oral therapies (metformin plus sulfonylurea or thiazolidinedione) achieved HbA1c reductions of 1.0% to 1.5% for liraglutide 1.2 mg (all reductions were significant vs. placebo), and 1.0% to 1.5% for 1.8 mg (all reductions were significant vs. placebo). Liraglutide 1.2 and 1.8 mg achieved HbA1c reductions of at least 1.0% regardless of whether it was used in conjunction with metformin, a sulfonylurea, or two oral therapies [27-30]. Additional results from the LEAD studies demonstrated that liraglutide combination therapy (metformin plus sulfonylurea or thiazolidinedione) produced SBP reductions from 4.5 mmHg (vs. insulin with metformin plus sulfonylurea) to 6.7 mmHg (vs. placebo with metformin plus rosiglitazone) [29, 30]. SBP reductions occurred within 2 weeks and after reductions in body weight, suggesting an ameliorative effect on blood pressure independent of weight loss . A meta-analysis of results from all six LEAD trials found significant improvements for liraglutide versus baseline in plasma concentrations of total cholesterol (-5.03 mg/dl, -0.13 mmol/l, p < 0.01), LDL-C (-7.73 mg/dl, -0.20 mmol/l, p < 0.0001), free fatty acids (-0.09 mmol/l, p < 0.0001), and triglycerides (-17.72 mg/dl, -0.20 mmol/l, p < 0.01) .
Liraglutide is also associated with action on other markers of CV and metabolic risk. It conferred cardioprotection and survival advantages over metformin after MI in diabetic mice, including reduction of cardiac rupture and improvement of cardiac output. The results suggested that liraglutide treatment modulated cardioprotective genes in the mouse heart, including PPAR-β/δ, HO-1, NF-E2-related factor-2, Akt, and GSK-3β . An in vitro investigation of liraglutide effects on markers of endothelial dysfunction found a significant inhibition of TNF-α or hyperglycemia-mediated induction of PAI-1, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human vascular endothelial cell lines . An exploratory analysis of a 14-week study of 165 patients with type 2 diabetes treated with liraglutide reported PAI-1 reductions of 29%; levels of B-type natriuretic peptide, a marker of left ventricular dysfunction, were reduced by 38% . These results support an earlier 14-week study that found a significant decrease in triglycerides (-22%) in patients with type 2 diabetes receiving liraglutide 1.9 mg; SBP was also reduced by 8 mmHg in these patients . These reductions in CV risk markers were accompanied by reductions in HbA1c from baseline of 1.45% (liraglutide 1.9 mg daily) and 1.40% (liraglutide 1.25 mg daily) versus an increase of 0.29% for placebo (p < 0.0001). The percentage of patients reaching target HbA1c goal of <7% was 46% with 1.90 mg liraglutide, and 48% with liraglutide 1.25 mg versus 5% for placebo. The 1.9-mg dose of liraglutide was associated with a mean weight loss of 3.0 kg at week 14.
Recent clinical trial data suggest that liraglutide may significantly reduce deposits of metabolically active visceral fat when compared with glimepiride/metformin combination therapy. A trend towards visceral fat reduction was observed in patients who received combination therapy with liraglutide and metformin (a 13%-17% reduction from baseline) compared with the glimepiride/metformin treatment group .
Antiexenatide antibodies have been found in 27% to 49% of patients treated with exenatide [31-33, 134, 135]. Of the 6% who developed high-titer antiexenatide antibodies, approximately half showed an attenuated glycemic response . Likely due to its closer homology to human GLP-1, liraglutide is associated with antiliraglutide antibodies in up to 13% of patients treated [27-30].
Nausea may be frequently observed with exenatide (incidence 3%-51%), although it typically subsides within 8 weeks of therapy initiation [31-33, 136]. Incidence of nausea is less frequent with liraglutide (11%-40%) and tends to abate within 4 weeks [25-30].
A number of cases of acute pancreatitis have been reported in patients with type 2 diabetes treated with exenatide. The exenatide product label cautions vigilance for signs and symptoms of acute pancreatitis . A claims-based safety surveillance system report assessing the risk of acute pancreatitis with either exenatide or sitagliptin found no risk differential between the two therapies . Currently available clinical trial data indicate that the incidence rate among subjects using liraglutide or a comparable product is in line with what one would expect in any type 2 diabetes population [25-30]. It is important to note that patients with type 2 diabetes have a three-times higher risk of developing pancreatitis than the general population . To date, the number of pancreatitis cases is not sufficiently high to determine whether there is an association between the development of acute pancreatitis and liraglutide treatment [139, 140].
In preclinical rodent studies, liraglutide induced calcitonin-producing cell (c-cell) hyperplasia, c-cell adenoma, and, at the highest doses, c-cell carcinoma. Similar findings did not occur in nonhuman primates at an exposure of 60-fold that of the human dose of 1.8 mg. The cumulative data suggest that rodent c-cells are sensitive to activation by GLP-1 agonists, but human and nonhuman primate c-cells not [139, 140].
In recent years, research into type 2 diabetes has generated a wealth of discoveries concerning the pleiotropic effects of GLP-1. The research initiatives revealed an activity profile beyond the stimulation of insulin secretion. The profile includes actions potentiating the secretory activity, proliferation and preservation of the β-cell, as well as cardioprotective actions.
GLP-1 appears to have broader biological action on the pancreas and on extrapancreatic tissues than previously expected. Indeed, the results of recent preliminary investigations suggest that the cardioprotective effects of GLP-1 may manifest via two distinct pathways. One dependent on the GLP-1 receptor for glucose uptake, mild vasodilatory effects, and ischemic preconditioning. Another is accompanied by actions on postischemic recovery of vasodilation and cardiac function independent of the GLP-1 receptor .
Limited data exist on the question whether GLP-1 receptor agonists affect strong end points such as CVD morbidity and mortality. However, it is evident that GLP-1 receptor agonists may have other CV, CNS, and gastointestinal consequences than DPP-4 inhibitors. The latter prolongs the activity of native GLP-1, but secretion and bioactivity is progressively impaired in type 2 diabetes. The pleiotropic effects of GLP-1 receptor agonists may benefit patients with type 2 diabetes with hypertension, dyslipidemia, and other risk factors for CV disease, such as overweight/obesity. Further studies in GLP-1 receptor agonists assessing surrogate parameters, and strong end point studies, are warranted to support promising but preliminary emerging evidence to date.
Disclosures (conflict of interests statement): The author is member of advisory boards for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Merck, Roche, and Takeda, and has also received honoraria from these companies for giving lectures.
Acknowledgments: The author thanks Rob McCarthy, PhD, of AdelphiEden Health Communications for providing medical writing and editorial support funded by Novo Nordisk.


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All Metronomes
A metronome is a device that produces a regular sound that marks the time of music and is used for study or for musical interpretation. There are mechanical metronomes consisting of a pendulum whose oscillations are regulated by the distance of a weight at the base of the pendulum rod. Each oscillation corresponds to a tempo of the measure. Ther...
A metronome is a device that produces a regular sound that marks the time of music and is used for study or for musical interpretation. There are mechanical metronomes consisting of a pendulum whose oscillations are regulated by the distance of a weight at the base of the pendulum rod. Each oscillation corresponds to a tempo of the measure. There are also electronic metronomes, which signal each time of the compass by flashing a'led 'and emitting an electronic click.
Korg Metronome MA 2
The Korg MA-2metronome is compact and contains all the basics, with a wide range of tempos and a rich variety of beats and rhythmic patterns. The MA-2 also shows the beat in an innovative way that makes the practice easier. The MA-1 is available in: blue and black or black and red. With sleek design and reliable functionality.
Boss Tuner and Metronome TU 30
The TU-80 tuner and metronome has for years been an essential tool for musicians and music teachers. With the TU-30, the BOSS offers the main features of the TU-80 with an even more compact size. All the basics are transported, including Accu-Pitch, various tuning modes and rhythm patterns, the ability to play reference sounds and more.
Boss Metronome DB 30 Dr Beat
Portable, reliable and fun to use, the Roland DB-30 helps musicians to practice, with a set of challenging features that seem hard to imagine in such a small size. Much more than just a simple metronome, you have a variety of rhythm patterns and timings to aid in your workout.
Korg Tuner Metronome TM 60
This Korg TM-60 metronome belongs to the TM series, which combines tuner and metronome on the same device. The TM-60 is the latest model in the series and features a larger display to show both tuner and metronome simultaneously. The battery life has also been drastically improved. With the new TM-60, you can enjoy rhythm training without having to worry...
Wittner Metronome MT41
Wittner Metronome 836 Piccolo Black
Wittner Metronome 886051 Mini Black
Wittner Piccolo Metronome Brown 835
Wittner Metronome 855131 Pyramid Walnut


Mark Dumm is a member of the first violin section of The Cleveland Orchestra. He joined the ensemble in 1985 and has served in several positions, including first assistant principal of the second violin section. Mr. Dumm was a member of the Saint Louis Symphony Orchestra for two seasons prior to joining The Cleveland Orchestra. In addition to violin, he plays guitar, mandolin, and banjo, and performs with the Orchestra on those instruments when they are called for. Mr. Dumm has appeared as soloist with The Cleveland Orchestra on several occasions, including performances of Saint-Saëns's Violin Concerto No. 3 and works by Corelli and Vivaldi during the 2001 Blossom Festival. Mr. Dumm has been involved in the production of numerous concert television broadcasts as well as the video recording of the Cleveland International Piano Competition.
A member of a musical family, Mr. Dumm began his studies with his father, Thomas Dumm, principal violist of the Saint Louis Symphony. He studied with Margaret Pardee at the Juilliard School and subsequently attended Indiana University, studying with former Cleveland Orchestra concertmaster Josef Gingold..