text:
Fighting McKenzie, the Anzac spirit and Australian values
Warwick Marsh
Australia has produced some amazing war heroes but none so remarkable, or popular, as Fighting McKenzie from World War I. Daniel Reynaud, author of the book 'The Man the Anzacs Revered' asked, "How did a wowser become an Anzac legend? And how did this legend become totally unknown today?"
William McKenzie served in both Gallipoli and France and was said to have been recommended for a Victoria Cross three times. Unfortunately, the recommending officers were killed in action before they could file their reports.
Known as 'Fighting Mac' William McKenzie enlisted as an Anzac chaplain, being a commissioned officer with the Salvation Army. He preached against booze, brothels, betting and bad language, but was Australia's most popular soldier after World War 1. After the Great War, everywhere Fighting Mac went, he was mobbed by adoring soldiers, their families and bereaved family members.
McKenzie was born in Lanarkshire, Scotland in 1869 and migrated to Australia in his teens in search of adventure. He gained a reputation as a good fighter while drinking and brawling in the pubs of Bundaberg. It was at a Salvation Army open-air meeting in Bundaberg that he began to see the light. He was particularly impressed with the testimony of two fellow Scotsmen who, like him, had been hardened drinkers, fighters and adept in the use of foul language. Their story of change touched him so deeply that he joined the Salvation Army and began a long period of ministry all over Australia, but particularly in the outback areas.
In August 1914, war was declared and Fighting McKenzie was one of 416,809 volunteers who served in the Armed Forces. The population of Australia was fewer than five million people at the time. On a country-by-country basis, Australia had more troops at war per head of population and suffered higher death rates and casualty rates, than any other country that fought in the First World War.
When McKenzie received his posting, it was not always received with open arms by his fellow soldiers. One Australian trooper exclaimed, "What the hell have we done to deserve this?" when he saw the chaplain's luggage which said, 'Chaplain, W. McKenzie, Salvation Army'.
McKenzie however, soon disarmed and endeared himself to the troopers; he began to organise singsongs and sporting events, such as boxing matches. The burly seventeen stone chaplain was a formidable boxer himself and the troopers found to their amazement that there was no Digger or Light Horseman aboard ship who could get the better of 'Fighting Mac' when it came to 'fisticuffs'. He was to remain undefeated in boxing matches throughout the war. Many a young trooper was sent crashing to the canvas – the result of a swift upper cut from Mac – after misjudging the fighting abilities of this huge man-of-God. But the burly chaplain was always quick to lend a helping hand to a groggy young Aussie 'Billijim' that he had just knocked to the ground. Often the first thing many a dazed young Anzac saw – as he regained consciousness – was a huge hand and a broad smile as 'Fighting Mac' helped him back to his feet. One dumbfounded young soldier responded with: "Are you sure you really are a chaplain?"
McKenzie quickly grew to love and admire these young men, describing them later as 'the finest fighting men in the world'."
(Extract from 'Fighting McKenzie Anzac Chaplain – Tribute to a Hero' by Col Stringer.)
When the troops reached Cairo, Egypt, Fighting Mac was deeply concerned about the brothels and gin dens of Cairo that preyed upon the young Australian soldiers. So much so, that he, with a fellow padre and a group of Anzacs went into the red-light district of Cairo and burned it to the ground. The following report was found in The Sun newspaper, 24 April 1972:
McKenzie thundered against Cairo's 'blighting evils'. After dragging out scores of men 'by the ears', he led an Anzac contingent in an onslaught against the vice dens. Armed with firebrands and sticks, they stormed through the streets setting the whole district ablaze. (The Battle of the Wazzir). Arab mobs fought back, but the Australians didn't even feel the resistance. Leaving the pavement littered with unconscious natives, the Australians withdrew to clash with the fire brigades. By enthusiastically slashing through every fire hose, McKenzie and his men, prevented the fires extinction and the area was razed to the ground.
An Australian officer wrote: "There are men back in Australia, valued citizens, loved husbands, revered parents – who would never have returned home had not Mac single-handedly challenged the hell-houses of the Wasa district in Cairo."
It was Easter Sunday 1915 when the Anzacs embarked for the Dardanelles. They landed at dawn on 25 April for what many of them thought was to be a great adventure. The 'great adventure' became Australia's greatest military defeat. The horror of the Gallipoli campaign claimed two out of three dead or wounded, such was the price they paid, and all arguably for nothing. Although many would argue our national identity and our Australian Values were born in the midst of the blood and fire of Gallipoli.
Fighting Mac wrote of those memorable days:
I don't know what the Australian papers say about these brave boys, but I want to tell you they accomplished a well-nigh impossible task…
My heart is full of one big sob for the loss of so many, hundreds of whom I knew so well…
Our brigadier and major are both gone, with so many other brave officers and men…
When I think of the anguish of the mothers I can only weep and pray for them. May God comfort them!
(From Anzac Padre.)
Fighting Mac personally buried hundreds of young Anzacs, often in the middle of a hail of bullets. During this period, he developed a life-long hatred for war. He wrote:
Many of the bravest and the best are gone…War is nothing short of insensitive folly. It is inconclusive in its results and devastating in its ultimate consequences.
Other soldiers described the duty and demeanour of this humble but courageous chaplain:
Among the duties of this Anzac chaplain – dubbed 'Anzac Mac' or 'Fighting Mac' by the men who had grown to love and respect him – was searching for the wounded and dead, as well as identifying bodies and giving them a decent burial and advising relatives by letter. Although officially forbidden from remaining in the front lines or from taking part in battles, Mac had no intention of standing idly by while, 'my boys fight'.
(From Fighting Mac.)
Stringer, in his book 'Fighting McKenzie', tells the story of the Battle of Lone Pine:
This was a day that has gone down in the annals of the young nation's history as one of our blackest. Some of Australia's finest young men were needlessly sacrificed. It was shocking decisions such as this that must have torn at the heart of Chaplain William McKenzie. The men pleaded with Mac not to put his life in danger, but to stay behind in the safety of the trenches. After all, as a non-combatant, he was not even supposed to be in the front lines and on numerous occasions he had been ordered to the rear. But Mac responded to a higher call, his boys needed him now. He replied, a quote that is now famous in the annals of Anzac:
"Boys I have lived with you, I've preached to you and I've prayed with you. Do you think I'm now afraid to die with you?"
Fighting Mac's great heart and love for his men just could not be contained any further. Snatching up a trenching shovel he climbed over the parapet and charged straight at the Turkish trenches. McKenzie was prepared to fight for the lives of his 'brave boys'. Obviously thinking that a shovel got around the regulations of international rules of war which stated that chaplains could not be armed.
The mateship, self-sacrifice and bravery, in the face of impossible odds, shown in the battlefields of World War I, exemplifies the values that have made Australia great.
Fighting McKenzie went on to serve with distinction in France. When he returned home the Melbourne Age wrote: "No soldier of the Australian Army could ever wish for a finer welcome home" 'Fighting McKenzie – Anzac Chaplain Tribute to a Hero' by Stringer.
Stringer goes on to say:
Australia gave her favourite son – Fighting Mac a tremendous welcome home, despite the fact they had been warned that the largest building would simply not be able to contain the crowds that would throng to meet their hero. And they were right. All over the nation huge crowds gathered. Mac was the most popular man in the country, save for Prime Minister Billy Hughes. From the city to the 'bush' thousands of people welcomed Mac home, In Melbourne's Exhibition Building some 7,000 people packed the building out. Hundreds of others were bitterly disappointed to be turned away at the door. Some admirers had waited from 2pm in the afternoon to be sure of getting a seat. Among the crowd were 1,500 returned soldiers, blind and maimed veterans amongst them. And what a tumultuous welcome they gave to their 'old padre' as his bodyguard of Diggers bore him into the building on their shoulders.
These overwhelming scenes were repeated across the nation in state capitals and bush centres and continued for almost two decades.
One might ask why such an outpouring of appreciation?
Perhaps it is summed up in the words from the bible describing Jesus' sacrifice that are repeated at every Anzac Dawn Service across Australia on 25 April every year:
Greater love has no one than this: to lay down one's life for one's friend.
Mateship, self-sacrifice and bravery are the values Australian's hold dear. These deeply spiritual values underpin the Anzac spirit exemplified by 'Fighting Mac'.
Lest we forget.
Warwick Marsh is the founder of the Dads4Kids Fatherhood Foundation and has worked as a musician and creative communicator/TV producer. He is editor in chief of the weekly Dads4Kids email newsletter and in 2001 received a Centenary Medal from the Governor-General for service in musical leadership for young people and the Aboriginal community and his international missions and aid work.
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Welcome to our family run bakery & cafe in Hampstead personal essay for graduate school Garden Suburb. We have been craft baking on the premises since 1952 where we specialise in hand made biscuits, miniature pastries and sandwiches made to order. Enjoy a coffee and cake at our cafewith seating inside and out. We look forward to custom essay services review seeing you soon!


I have a pretty low tolerance to pain, but had the treatments with no issue. The technician treating me used a cooling gel where I was going to have the laser – my underarms and upper lip. It was applied about 5 minutes before the treatment. It really felt more like the snapping of a rubber band on my skin. There were a few little stinging sensations, but definitely not a highly unpleasant experience. And this is coming from the girl who runs from the doctor when she has to get her blood drawn!
Cycles of hair growth play a major role in your hair removal treatment regimen. Excessive hair growth can be caused by a variety of things, heredity, stress, medication, and hormonal changes. For women puberty, pregnancy and menopause play important parts in determining hair growth.
Many researchers say that there can be as many as 2500 hair follicles per square inch but less than 100 hairs will be showing at any given time. For these reasons, during treatment, it is extremely difficult for anyone to predict, not even your doctor, the exact length of time before there is no more growth in the treatment area.
There are 3 stages of hair growth – Anagen, Catagen and Telogen. The "perfect" time for hair to be permanently destroyed is when it is in the Anagen or growing stage. It can take 6 to 12 weeks for a hair to grow to the surface of the skin. These cycles can vary somewhat from individual to individual, and in addition the individual patterns are different too.
In Victoria, NSW and South Australia there are no licensing, regulatory or certification requirements to perform any Laser or IPL treatments.
Queensland has Radiation Safety Act 1999 regulating licensing of operator and premises to operate laser for cosmetic treatments.
However we stress that unskilled technicians performing laser hair removal can result in the horror stories you may have heard from others.
So training is a prerequisites in our view to operate all hair removal devices.


Experienced instructor will guide you and explain the basics of kayaking on a river. Also, he will make sure you are safe. All the equipment will be provided. You will be able to try more kayak types, e.g. sea kayak/ tourist/ slalom/ speed or double kayak.
Moreover, after you gain some skills you will be able to become a member of the paddling club and join kayaking trips.
You can wear any kind of sports clothes. Thermal underwear is recommended, or wet suit if you are afraid of being cold. In case of colder weather a water proof anorak is helpful. Do not forget a towel and some dry pants to change after the lesson. We also have showers.
The time and date can be set individually for price 15€/ person.
Group kayaking lessons take part on Mondays and Wednesdays for price 5€/lesson. For availability check our online form.
- You need to call us to arrange the time of the lesson.
- It is necessary to bring the voucher in printed form with you.
- You must be 18 years old, or come with your legal representative.
- You need to respect your instructor and the other club members.
Last year kayaking school was attended by a few dozens of people. Some of them came just to give it a try and some became club members and can kayak on their own anytime.
We are pleased to have both types of clients and are happy to show you that there are many sports options in nature even though you are in the city center.
Contact us for English version.


text:
I/O request packets (IRPs) are kernel mode structures that are used by Windows Driver Model (WDM) and Windows NT device drivers to communicate with each other and with the operating system. They are data structures that describe I/O requests, and can be equally well thought of as "I/O request descriptors" or similar. Rather than passing a large number of small arguments (such as buffer address, buffer size, I/O function type, etc.) to a driver, all of these parameters are passed via a single pointer to this persistent data structure. The IRP with all of its parameters can be put on a queue if the I/O request cannot be performed immediately. I/O completion is reported back to the I/O manager by passing its address to a routine for that purpose, IoCompleteRequest. The IRP may be repurposed as a special kernel APC object if such is required to report completion of the I/O to the requesting thread.

IRPs are typically created by the I/O Manager in response to I/O requests from user mode. However, IRPs are sometimes created by the plug-and-play manager, power manager, and other system components, and can also be created by drivers and then passed to other drivers.

The I/O request packet mechanism is also used by Digital Equipment Corporation's VMS operating system, and was used by Digital's RSX-11 family of operating systems before that.  An I/O request packet in RSX-11 is called a directive parameter block, as it is also used for system calls other than I/O calls.

See also
 Architecture of Windows NT

References

External links
 Whitepaper on Windows I/O model

 IRP (Windows Drivers)

Windows NT architecture
Device drivers
Data structures by computing platform
Windows NT kernel
OpenVMS

de:IRP

redpajama_set_name: RedPajamaWikipedia


I need to correct an error in embedding the link to our form. We used HTTPS instead of HTTP.
Unfortunately, the business office is closed until Monday....April 21; will correct the error then with a new e-mail to members.
Thanks for your honesty to state that you shared the secure URL of your form by mistake.
Then, once it is disabled you must get the updated code and embed it to your website or if you are using the form URL, you need to share the updated unsecure URL and to advise your users to stop using the secure one, otherwise you will reach your SSL limit again and we will not be able to reset the counter again. And you will be obligated to upgrade to a paid plan.


Enough said now, we will talk about what powers and abilities this character might possess. First things first, since he is known as two sword style Orochi, he'll be pretty good at using swords and will be a handful swordsman.
He's from Wano. Even if he's a poor swordsman, he's still going to be at least a decent one because it is an art there. Every soldier has to learn it, and since he's the Shogun, he has to be at least strong.
In mythology Yamata no Orochi had a Kusanagi sword. I think that he'll have a Kusanagi sword and some other powerful sword. But in this post, I'll not be just talking about his swords but his devil fruit.
So, let me just focus on his devil fruit powers. First and foremost since he is a mythical zoan type devil fruit user he is going to possess tremendous strength and also durability. We have seen how humongous he becomes in his transformed form so his size will be hard to deal with for his opponents.


We offer a variety of camps from Instructional, Development, College Camps and Evaluation Camps. Our camps run year round and include Detailed Instruction, Appropriate Drills, Game Situation Scenarios, Competition and Charting, Awards and On-The-Spot Video Analysis.
Our camps are great opportunities to fine tune your mechanics and learn drills to help you prepare upcoming season. Our evaluation camps are an excellent opportunity to showcase your abilities on a local and national level.
Off-season Training (Kicking & Agility Session): Partnership with Game Face Training in Brooklyn Park- 6 week program (90 minutes). Runs November to April 2019. Weekly Sign Ups Available. Indoor K/P/LS technique work (45 min) + Explosive agility session (45 min). Mondays (6:00-7:30 PM) at the Brooklyn Park Facility or Wednesdays (6:00-7:30 PM) at new Edina Facility. The specialists loved this program so far!! Registration link here to sign up. Please contact us with any questions.
June 16-18: 2 Day All Inclusive Camp (Kicking and Snapping) held at Bemidji State University. 30 spots available. All-inclusive camp includes lodging, food, training, film study, pool workouts and more. Specialists can expect to receive high level instruction/drill work recommendation from credible staff and will be challenged to grow and improve as athletes. Check in Sunday evening and Check out Tuesday Evening. For High School, College and Middle School Specialists.
June 23: Georgia NKR Showcase (Kicking & Snapping Camp) in Atlanta, GA held at Alexander HS. Runs 1:30-5:00 PM. Camp includes specialist evaluation using the NKR Platform, Competitions, Awards, as well as a instructional clinic. Specialists can expect to receive high level instruction/drill work recommendation from credible staff as well as exposure for college recruiting purposes. For K/P/LS from High School/JUCO and Junior High levels.
July 14-17: 4 Day Training Camp (Kicking and Snapping) held at St John's University. High School & College Divisions (40 spots/ division). All inclusive camp includes lodging, food, training, film study, pool workouts and more. Specialists can expect to receive high level instruction/drill work recommendation from credible staff (flown in from around the US) and will be challenged to grow and improve as athletes. Check in Sunday evening and Check out Tuesday Evening. For High School, College and Middle School Specialists.
July 27-28: National NKR Showcase (Kicking and Snapping) in Indianapolis. Location Park Tutor HS (IN). Day and a half invitational camp for select specialists based on NKR Camp performances. Camp includes specialist evaluation using the NKR Platform, Competitions, Awards, as well as a 90 minute instructional clinic to follow. Specialists can expect to receive high level instruction/drill work recommendation from credible staff as well as exposure for college recruiting purposes. Contact us for more information.
Oct 20: Fall Minnesota NKR Showcase Camp – Athlete Evaluation, Competitions and Awards.
For any questions about the camps, please contact us. I will be involved with more camps outside of the Minnesota area. Information on those camps will be in future newsletters. Please email CoachHusby@gmail.com to be included on future newsletters and updates.


text:
New Opportunities To Study On The Bass Coast
Jun 1, 2020 | Latest News
Member for Monash Russell Broadbent said local students could live at home and work locally while also studying a tertiary qualification at a new Regional University Centre to be established on the Bass Coast.
Mr Broadbent welcomed the Coalition Government's commitment to tertiary education in the region and said the centre would boost opportunities for local students to gain skills and qualifications.
"The Bass Coast University Centre will be established in Wonthaggi and will service towns in shires from Cowes to Foster to Grantville. It will attract new students looking to enter current and emerging industries to support growth and development, and increase employment opportunities in our region," Mr Broadbent said.
"Regional University Centres provide study spaces, academic support, video conferencing and other support for students studying via distance at partner universities.
"This centre opens up more opportunities for people in our region to study than ever before, without having to leave our local community and their support networks."
Minister for Education Dan Tehan said the Bass Coast Centre was one of nine new centres being established across regional Australia under the Coalition Government's $53.2 million Regional University Centres program.
"Our Government made a commitment at the last election to establish more Regional University Centres as part of our plan to better support education in regional Australia," Mr Tehan said.
"We are keeping our promise to regional Australia by delivering nine new centres. We believe every Australian, no matter where they live, should be able to attend university.
"Our Government is putting regional and rural students at the centre of our focus.
"Since 2016, we have invested more than $600 million to improve support for regional and remote higher education."
More information about the Regional University Centres is at https://www.dese.gov.au/regional-university-centres.

redpajama_set_name: RedPajamaCommonCrawl


text:
Islet Studies
Successful Islet Transplantation
Continued Insulin Reserve Provides Long-Term Glycemic Control
Edmond A. Ryan1,
Jonathan R.T. Lakey23,
Breay W. Paty1,
Sharleen Imes4,
Gregory S. Korbutt3,
Norman M. Kneteman2,
David Bigam2,
Ray V. Rajotte3 and
A.M. James Shapiro2
1Department of Medicine, Clinical Islet Transplant Program, University of Alberta and Capital Health Authority, Edmonton, Alberta, Canada
2Department of Surgery, Clinical Islet Transplant Program, University of Alberta and Capital Health Authority, Edmonton, Alberta, Canada
3Surgical Medical Research Institute, Clinical Islet Transplant Program, University of Alberta and Capital Health Authority, Edmonton, Alberta, Canada
4Capital Health Authority, Edmonton, Alberta, Canada
Diabetes 2002 Jul; 51(7): 2148-2157. https://doi.org/10.2337/diabetes.51.7.2148
Clinical islet transplantation is gaining acceptance as a potential therapy, particularly for subjects who have labile diabetes or problems with hypoglycemic awareness. The risks of the procedure and long-term outcomes are still not fully known. We have performed 54 islet transplantation procedures on 30 subjects and have detailed follow-up in 17 consecutive Edmonton protocol-treated subjects who attained insulin independence after transplantation of adequate numbers of islets. Subjects were assessed pretransplant and followed prospectively posttransplant for immediate and long-term complications related to the procedure or immunosuppressive therapy. The 17 patients all became insulin independent after a minimum of 9,000 islets/kg were transplanted. Of 15 consecutive patients with at least 1 year of follow-up after the initial transplant, 12 (80%) were insulin independent at 1 year. In 14 subjects who have maintained demonstrable C-peptide secretion, glucose control has been stable and glycemic lability and problems with hypoglycemic reactions have been corrected. After 2 of the 54 procedures, some thrombosis was detected in the portal vein circulation. Five subjects had bleeding related to the percutaneous portal vein access procedures: three required transfusion alone, and in one subject, who had a partial thrombosis of the portal vein, an expanding intrahepatic and subscapular hemorrhage occurred while on anticoagulation, requiring transfusion and surgery. Elevated liver function test results were found in 46% of subjects but resolved in all. Complications related to the therapy have been hypercholesterolemia requiring statin therapy in 65%; a rise in creatinine in two patients, both of whom had preexisting renal disease; a rise in protein in four, all of whom had preexisting proteinuria; and antihypertensive therapy increased or started in 53%. Three of the 17 patients have required retinal laser photocoagulation. There have been no cases of posttransplant lymphoproliferative disorder or cytomegalovirus infection, and no deaths. The acute insulin response to arginine correlated better with transplanted islet mass than acute insulin response to glucose (AIRg) and area under the curve for insulin (AUCi), but the AIRg and AUCi were more closely related to glycemic control. The AUCi directly posttransplant was lower in those who eventually became C-peptide deficient. Our results, with a maximum follow-up of 34 months, indicate that prolonged insulin independence can be achieved after islet transplantation. There are some risks associated acutely with the procedure, and hypercholesterolemia and hypertension are treatable concerns on longer-term follow-up. All patients with persisting C-peptide secretion have had a resolution of both glycemic lability and problems with hypoglycemic reactions. Apart from the rise in serum creatinine in two subjects, no serious consequences of immunosuppressive therapy have been encountered. Islet transplantation is a reasonable option in those with severe problems with glycemic lability or hypoglycemia.
Interest in islet transplantation has increased enormously, because of the improved success rates with newer immunosuppressive regimens and islet preparation techniques (1,2). After our early results, many other centers are now initiating islet transplant programs (3,4). A favorable outcome depends primarily on having excellence in harvesting human islets, appropriate immunosuppression regimens, and medical expertise in selecting patients and in follow-up. Although successful islet transplant programs are relatively new, the concept of transplanting islets rather than the whole pancreas is attractive because of its technical ease and the ability to transplant early in the course of the disease. The early promise of islet transplantation is now a reality, but the process still carries potential risks.
In deciding whether it is worthwhile to undergo the risk of immunosuppression for labile diabetes or concerns with hypoglycemia, it is important to be aware of the problems and outcomes in the long term. The simplest measure of success is insulin independence, which must be judged in the context of glycemic control. However, other parameters have to be assessed, including the risks associated with both the procedure and immunosuppression, the improvement in glycemic lability, the eradication of problems with hypoglycemia, the effect of transplantation on long-term diabetes complications, and finally, the economic costs involved. In addition, early measures of success of the transplant other than the absolute measure of insulin independence would be helpful to assess function and outcomes. Measures of insulin release after the secretagogues glucose or arginine have been suggested but not formally studied in the setting of successful allotransplantation.
As of 1 January 2002, we performed 54 procedures as part of our islet transplant program, and these serve to delineate issues related to the procedure. Seventeen subjects have completed the Edmonton protocol and are the basis of this report of longer-term outcomes. Our results demonstrate the ability to stabilize labile diabetes and greatly improve problems with hypoglycemia. The better measure of insulin reserve appears to be the insulin response after intravenous glucose.
Thirty consecutive patients had islet transplantation, for a total of 54 procedures. Seventeen of these had islet transplantation using the Edmonton protocol, with provision of adequate numbers of islets for insulin independence. These 17 subjects have had a total of 38 procedures as part of their original transplant protocol. Three others have had their first transplant procedure and are in the process of completing the Edmonton protocol. Eight further subjects have had an islet transplant with another protocol using infliximab (nine procedures). Two more subjects had a transplantation under the Immune Tolerance Network protocol (two procedures), and 2 of the original 17 Edmonton protocol subjects had a supplemental infusion of islets.
The major indications were labile diabetes or decreased awareness of hypoglycemia giving rise to frequent or severe hypoglycemic reactions or progressive complications of diabetes. Further to our previous report (4), the latter is now a rare indication for an islet transplantation in our current subjects. Problems with hypoglycemia were characterized with a month's monitoring of glucose values and documentation of all occurrences of capillary glucose values <3.0 mmol/l with minimal or no symptoms of hypoglycemia or primarily neuroglycopenic symptoms. Typically, evidence of severe hypoglycemia (requiring outside help to treat the hypoglycemia) was required. Labile diabetes was characterized using mean amplitude of glycemic excursion (MAGE), (5) and evidence for disruption of daily lifestyle was also sought. Approval for either indication required confirmation that the problems had not been rectified by a period of intensive insulin therapy and intensive glucose monitoring. Of the 30 patients, 90% had problems with hypoglycemia awareness, 50% had labile diabetes, and 2 patients had progressive complications. All patients were fully briefed on the risks and complications associated with the procedure and immunosuppressive therapy, and all gave written informed consent. The protocols were approved by the Research Ethics Board of the University of Alberta.
The 30 patients, 14 men and 16 women with type 1 diabetes (absent C-peptide), had a mean age of 41.3 ± 1.6 years and a duration of diabetes of 25.5 ± 2.1 years. In the 17 subjects who completed the Edmonton protocol, 10 men and 7 women (mean age 39.7 ± 2.0 years and duration of diabetes 27.2 ± 2.8 years), 8 had evidence of treated proliferative retinopathy (1 was blind), and 3 others had nonproliferative retinopathy. Three subjects had elevated serum creatinine, five had both microalbuminuria and macroproteinuria, and two each had microalbuminuria or macroproteinuria. One subject had known coronary artery disease that had been previously treated by angioplasty and was stable. Two subjects had severe painful peripheral neuropathy, four gave a history suggesting possible autonomic neuropathy (impotence), and one patient had Charcot arthropathy. Pretransplant, all patients underwent a complete blood count (CBC), liver function tests (LFTs), and tests for electrolytes, calcium, magnesium, thyroid function, lipid profile, and renal function. Both Addison's disease and celiac disease as causes of labile diabetes or recurrent hypoglycemia were excluded; prostate-specific antigen levels were determined in men >40 years old, and women >40 underwent mammograms. An ultrasound of the abdomen was performed, as were chest X-ray, dental exam, and electrocardiogram. Further cardiac tests were performed if it was believed they were required. Screening was done for cytomegalovirus (CMV) IgG, Epstein-Barr nuclear antigen IgG, varicella-zoster IgG, hepatitis, syphilis, toxoplasmosis, and HIV. Lymphocytotoxic antibody screens were performed. All patients were screened for C-peptide status with determination of glucose and C-peptide levels before and 90 min after ingestion of a standard mixed meal.
Transplant procedures.
Islets were prepared as previously described (3,6–8). Briefly, human cadaveric pancreata were removed from brain-dead multiorgan donors following in situ vascular flushing with cold University of Wisconsin solution and transported to Edmonton. On arrival at the laboratory, the pancreatic duct was cannulated and liberase enzyme (Boehringer Mannheim, Indianapolis, IN) (8) was perfused. The pancreas was enzymatically and mechanically dissociated before the islets were separated on a refrigerated Cobe 2991 centrifuge (Cobe BCT, Lakewood, CO). A group of pancreata (n = 14) were preserved for a period of 2–3 h with a two-layer (University of Wisconsin/perfluorochemical) cold storage method, as the retrieval results for situations of longer cold ischemic time appear to improve islet recovery with this modification (T. Tsujimura, Y. Kuroda, T. Kin, J.G. Avila, R.V.R., G.S.K., E.A.R., A.M.J.S., J.R.T.L., unpublished observations). In addition, in some cases, isolated islets were cultured at 22°C for up to a maximum of 12 h before transplantation (n = 14) to facilitate timing of islet infusion. This did not appear to adversely affect viability, as measured in vitro after transplantation (3). Islet numbers were quantified in duplicate using an islet standard diameter of 150 μm (9). Once the islets were obtained, the patient was admitted and (for the Edmonton protocol) had the following tests: CBC, chest X-ray, LFTs, and coagulation screen. The patient was then brought to the Radiology Department, and portal vein cannulation was performed. Typically, a size 4F catheter is now used to minimize the risk of bleeding, and with this a Gelfoam plug is not required as previously reported (4). Once the portal vein was cannulated, the islets were slowly injected. To facilitate the slow pace, for the four most recent procedures, a gravity feed system has been used: the islets in culture medium were placed in an intravenous fluid bag and were allowed to infuse under gravity pressure, which may decrease the shear forces on the islets. Portal pressure was monitored after each infusion, and once the transplant was completed, the patient returned to the ward. The glucose was monitored hourly initially, and insulin therapy was withheld until glucose was >8.0 mmol/l premeal or ≥10.0 mmol/l 2-h postmeal.
Patients were usually discharged the following day once an ultrasound had confirmed the absence of any portal vein thrombosis and the CBC and LFT results were acceptable. Immunosuppressive therapy consisted of dacluzimab every 14 days for 10 weeks (1 mg/kg), sirolimus with a loading dose of 0.2 mg/kg followed by 0.1 mg/kg with target trough levels of 12–15 ng/ml, and tacrolimus at a dose of 2–4 mg twice a day with a target trough level of 3–5 ng/ml. Inhaled pentamidine was used for pneumocystis carinii prophylaxis originally, but sulfamethoxazole/trimethoprim has been used in its place for the most recent 13 patients because of its more broad coverage. Ganciclovir 1,000 mg three times a day for 3 months was given for CMV prophylaxis. CBC, drug levels, and basic parameters (LFTs, electrolytes, calcium, and magnesium) were measured three times a week for the first 2 weeks, twice a week for the next 2 weeks, and then weekly.
Metabolic monitoring.
Before transplantation, all patients had C-peptide and glucose measurements before and after mixed-meal stimulation tests (Ensure HP; Abbott Laboratories). After transplant, fasting C-peptide and glucose levels were measured daily for the first week and then weekly. If insulin was used, the dose was recorded as the amount used on the day before the clinic visit. The Edmonton protocol subjects had Ensure tests performed 2 weeks after the first transplant and then at 2 weeks off insulin therapy, 3 and 6 months off insulin, and every 6 months afterward. These subjects also had intravenous glucose tolerance tests (IVGTTs) and intravenous arginine stimulation tests between the first and second transplants, 1, 3, and 6 months after becoming insulin independent after the second transplant, and every 6 months thereafter. An oral glucose tolerance test (OGTT) was performed at 6 and 12 months and then at yearly intervals posttransplant in insulin-independent subjects. HbA1c and lipid profiles were checked monthly. In seven subjects, arginine and IVGTTs were performed pretransplant.
The meal tolerance test was performed in the fasting state with blood drawn for glucose and C-peptide at baseline and then at 90 min after drinking 360 ml Ensure (391 kcal with 8.5 g fat, 44 g carbohydrate, and 17 g protein). The morning of the test, subjects did not take insulin until the test was completed, and typically the test was postponed if the glucose was >15 mmol/l before starting. The OGTT was performed using 75 g of oral glucose, with blood samples drawn at baseline and 30, 60, 90, and 120 min.
IVGTTs were performed in the fasting state using 50% dextrose, 300 mg/kg body wt, given over 1 min after two baseline samples (–10 and 0 min) for glucose, insulin, and C-peptide were drawn. Sampling was then at 3, 4, 5, 7, 10, 15, 20, 25, and 30 min, with time 0 being the start of the infusion. On a separate day, 5 g arginine HCl was infused intravenously over 0.5 min into the patient in the fasting state, and insulin levels were checked at the following time periods: −10, 0, 2, 3, 4, 5, 7, and 10 min.
The IVGTT allowed calculation of the acute insulin response to glucose (AIRg) based on the mean of the insulin level at 3, 4, and 5 min after the infusion less the mean basal insulin level. Glucose disposal (KG) was calculated as the slope of the natural log of the glucose values from 10 to 30 min. The areas under the curve for insulin and C-peptide (AUCi and AUCC-p) were calculated as the area under the curve above baseline over 30 min postinfusion. Acute insulin response to arginine (AIRarg) was calculated as the mean of the three highest values for 2, 3, 4, and 5 min postinfusion less the mean basal value. Homeostasis model assessment (HOMA) was calculated based on the formula of Levy et al. (10) for the assessment of insulin sensitivity.
Glucose was measured by the hexokinase method using the Hitachi 917 system (Roche Diagnostics, Indianapolis, IN). As of December 2000, serum insulin was measured by Elecsys radioimmunoassay using a commercial kit (Roche Diagnostics) with local laboratory intra-assay and interassay coefficients of variation <8.2% and a lower limit of detectability of 0.2 μU/ml; all samples were measured in duplicate. Serum C-peptide was measured using a commercial assay (Diagnostic Systems Laboratories, Webster, TX). The lower limit of sensitivity of this assay was 0.1 nmol/l and the intra-assay and interassay coefficients of variation were <12.3%. An ischemic index was calculated by dividing the number of islets transplanted × 10–3 by the total cold ischemia time (time from cross clamp until time of islet infusion into the patient) as previously described (4). The ischemic index for each infusate was summed for a total for each patient.
All statistical and regression analyses were performed using Sigma-Stat from Jandel Scientific (San Rafael, CA), and descriptive statistics are given as means ± SE or medians (25–75% CI). Significance was taken at a P value of <0.05, and groups were compared with Student's t test and Mann-Whitney U rank sum test or Wilcoxon signed rank test when normality tests failed. ANOVA was used for multiple comparisons, with the Tukey test for assessing significance.
Control subjects.
Ten volunteers (six women, four men; age 32 ± 4 years, BMI 23.7 ± 0.8 kg/m2) were studied as control subjects for metabolic tests. All had confirmed normal OGTTs, with a fasting glucose of 4.2 ± 0.2 mmol/l; 2-h postload glucose was 4.4 ± 0.4 mmol/l. The subjects underwent mixed-meal tolerance testing for determination of glucose and C-peptide and both arginine and IVGTTs.
Of 54 islet transplant procedures, all were successful in achieving portal vein access and being able to use the islets for transplantation. The median hospital stay was 1 day (CI, 1–2). Two patients had transient bradycardia during the procedure, believed to be vasovagal attacks. Five patients had a bleed after the transplant, four of whom required blood transfusions. In one of these subjects, a thrombus occurred in the right portal vein (the main and left portal veins were patent), and anticoagulation was commenced. Three days later, an expanding intrahepatic and subcapsular bleed occurred, requiring transfusion and surgery to evacuate the hematoma with segmental hepatic resection. One other thrombus occurred as reported previously (4). In 12 of 54 procedures, moderate abdominal pain occurred, which was transient. In two patients, puncture of the gallbladder occurred, but in both cases it settled spontaneously and was noted at the time of the portal vein cannulation. LFT results rose to more than twice normal levels in 46% of cases; this peak typically occurred at 6 days posttransplant (CI, 4–9). In all these patients, LFTs returned to normal within a median time of 22 days (CI, 17–41). In only eight instances did alkaline phosphatase rise, and in all patients the peak aspartate aminotransferase was 189 ± 23 U/l (range, 62–563) (normal, <40 U/l) and the peak alanine aminotransferase was 208 ± 26 U/l (range, 59–614) (normal, <50 U/l).
Glycemic outcomes with the Edmonton protocol.
Seventeen patients have completed the islet transplant procedure using the Edmonton protocol. The median follow-up time for these 17 patients was 20.4 months (CI, 15–29), with a range of 3.2–34.2 months from the first transplant. HbA1c pretransplant was 8.21 ± 0.36, and the most recent value was 6.08 ± 0.77 (P < 0.001) (normal <6.1%). At 1 year after the initial transplant, 12 of 15 subjects were off insulin. As of 1 January 2002, of the 17 subjects, 11 remained off insulin and in these 11, HbA1c pretransplant was 8.48 ± 0.49% and the most recent value was 5.8 ± 0.13 (P < 0.001) at a median follow-up of 20.4 months (CI, 14.2–30.5) (Fig. 1A). Of these 11 subjects, 2 are on oral hypoglycemic agents but have good glycemic control. The oral hypoglycemic agents were started because the HbA1c rose above 6.5% in one subject and the postprandial glucose levels were consistently >10.0 mmol/l in the other subject. Glucose and C-peptide levels before and after the mixed-meal stimulation are shown in Figs. 1B and C for the pretransplant and most recent posttransplant tests. Although the C-peptide response was clearly improved and the stimulated C-peptide values were equivalent to those of control subjects, the glucose levels post-Ensure are higher in the posttransplant group than the control group but much better than pretransplant. All the subjects off insulin have stable glucose values and do not have hypoglycemic reactions.
Of the 6 patients who are now >2 years posttransplant, 4 remain off insulin, and of the 15 patients who are >1 year posttransplant, 9 are still off insulin. The more stringent criteria of the OGTT revealed that only two subjects currently meet the criteria for normal glucose tolerance. Of the 17 patients, 11 have diabetes by American Diabetes Association criteria, and in all but 3 of these there is detectable C-peptide secretion. The MAGE value pretransplant for the subjects judged to have increased lability was 10.6 (CI, 9.0–12.5), and the most recent value was 3.3 (CI, 2.6–5.7 mmol/l), indicative of more stable glucose control (P = 0.003). Fasting C-peptide was maintained over prolonged follow-up (Fig. 2). Of the six patients who are back on insulin, three lost C-peptide secretion at 7.5, 16, and 17 months posttransplant. Two of the three have become positive for glutamic acid decarboxylase (GAD) and islet cell antigen (ICA) antibodies and are believed to have had a recurrence of their autoimmune disease. The other subject who lost C-peptide remained negative for ICA and GAD antibodies, and one of the subjects on insulin with continuing C-peptide secretion (to 31 months) also had a rise in ICA and GAD antibodies. In the six patients requiring insulin, the median interval from the first transplant to restarting insulin was 10.1 months (CI, 2.5–14.1; range, 2–22.8 months). The current daily insulin dose in the three C-peptide-positive subjects on insulin is 0.33 ± 0.1 units/kg, which is significantly less than their pretransplant use of insulin (0.58 ± 0.08 units/kg; P = 0.015).
Immunosuppression regimen.
As previously reported, two of the three patients with preexisting elevation of serum creatinine had a further rise of serum creatinine. In both of these subjects, the creatinine level has remained stable over the last year after replacing tacrolimus with mycophenolate mofetil: baseline serum creatinine of 160, peak of 371, and most recent 234 μmol/l for the first patient; and baseline of 158, peak of 269, and most recent of 251 μmol/l for the second patient. Four others had an increase in urine protein and, again in the three subjects with follow-up for more than a year, the urine protein has remained stable. Only 2 of 17 subjects did not develop mouth ulcers, most of which were small and superficial and resolved within a few weeks. Two patients have had episodes of recurrent nausea and vomiting requiring intravenous hydration. Acne occurred in two subjects and arthralgias in one, and one patient has developed rheumatoid arthritis. Ten patients have had problems with diarrhea posttransplant, but the bowel problems have generally subsided with time. Eight patients developed anemia to a hemoglobin level of <100 g/l. Two of these patients had a rise in serum creatinine, two were subjects who had bleeding posttransplant, one had an ileal ulcer, one had transient colitis, and in two the finding was unexplained. The mean hemoglobin level for the group of 17 fell from 140 ± 4 g/l pretransplant to the most recent level of 123 ± 4 g/l posttransplant (P < 0.001). The white blood cell (WBC) count also fell from a pretransplant level of 6.2 ± 0.3 × 109/l to the most recent posttransplant level of 4.9 ± 0.3 × 109/l (P = 0.002). In four subjects, the WBC fell below 2.5 × 109/l (for at least two consecutive readings), and in two subjects the WBC fell below 2.0 × 109/l; granulocyte colony-stimulating factor was used in two patients briefly. This problem may have been related to high levels of sirolimus. The platelet count did not change significantly after transplantation. All patients currently have negative panel-reactive antibodies. Most patients lost weight: pretransplant 70.3 ± 2.3 kg versus posttransplant 65.4 ± 2.3 kg (P < 0.001).
Diabetes complications.
Three patients have had progression of their retinopathy so as to require laser photocoagulation. The mean serum creatinine for the 17 subjects rose slightly from 89 ± 8 pretransplant to 104 ± 14 μmol/l posttransplant (P = 0.047) and, excluding the two patients who had serious deterioration in renal function, there was no difference pre- and posttransplant (79 ± 5 vs. 85 ± 16 μmol/l, respectively; P = 0.117). Urine protein was unchanged in 15 of 17 subjects (excluding the two with a significant rise in serum creatinine), 0.2 (CI, 0.1–0.3) pretransplant versus the most recent posttransplant value 0.2 g/day (CI, 0.1–0.4) (P = 0.492), and creatinine clearance was unchanged pre- and posttransplant (1.68 ± 0.08 vs. 1.62 ± 0.13 ml · s–1 · 1.73 M2, respectively; P = 0.195). Four patients were hypertensive pretransplant, and 10 had a rise of blood pressure posttransplant, such that a total of 9 either started or increased antihypertensive therapy. No dramatic changes have been seen in neuropathy. Anecdotally, two patients with severe neuropathic pain, both off insulin with a duration of insulin independence of 30 and 20 months, have had no change in their pain. Cholesterol rose in 15 of 17 subjects, and in 4 it has dropped again on diet therapy. In the 11 subjects who are on statin therapy, the median cholesterol is 4.8 mmol/l (CI, 4.4–5.2), not significantly different from baseline in these subjects, 4.7 mmol/l (CI, 4.5–5.1), but the maximum cholesterol in these subjects was 6.1 ± 0.2 mmol/l. Triglyceride levels did not change, and the total-to-HDL cholesterol ratio for the entire group pretransplant was 3.2 ± 0.2 and reached a maximum level of 4.6 ± 0.3 (P < 0.001), but once treated the group ratio was 3.3 ± 0.1. One patient with preexisting coronary artery disease has been stable but has required further angioplasty. No cases of posttransplant lymphoproliferative disease have occurred, and in none of the 12 CMV mismatches (i.e., donor positive, recipient negative for CMV) has there been any occurrence of CMV. There have been no deaths.
Transplant details and metabolic outcomes.
The median interval between the first and second transplant was 29 days (CI, 21–54). All of the 17 subjects required at least two transplant procedures, and 4 required three procedures. In two instances, two pancreata were used for a single infusion (both pancreases became available simultaneously). The mean number of islet equivalents (IE) for the first and second transplants were 374,283 ± 20,247 and 391,647 ± 32,921, respectively; the total delivered islet mass was 850,035 ± 37,911 IE per patient (including the four patients who had three islet infusions). The mean numbers of IE/kg for the first and second transplants were 5,442 ± 327 and 5,678 ± 487, respectively, for a total of 12,330 ± 581 IE/kg provided. For the 17 patients who became insulin independent with the Edmonton protocol, the minimum number of islets required for insulin independence appears to be 9,000 IE/kg (Fig. 3). The subject with >12,000 IE/kg who was not insulin independent likely lost islets from a thrombosis of a peripheral branch of the portal vein. Two patients who resumed insulin therapy have had a supplemental infusion of islets but remain on exogenous insulin (one of these supplemental infusions resulted in the partial portal thrombus and hepatic bleed on subsequent anticoagulation).
As can be seen in Figs. 4A and B, measures of insulin secretion after intravenous glucose were reduced but clearly maintained in the subjects who remained insulin independent to 24 months. In a subanalysis of the four followed for 24 months, there were no significant changes in these parameters. Only one subject has been studied at 30 months, and his islet function is stable (insulin independent; HbA1c 5.7%). In addition, AUCC-p, KG, and insulin sensitivity HOMA did not change significantly over the follow-up period. In particular, the five patients with persisting C-peptide secretion who have had to resume either oral hypoglycemic agents or insulin therapy did not have a lower HOMA value than the remaining nine with persistent C-peptide secretion. The AIRg appears proportionately better after the second transplant than after the first transplant (Table 1), but this may reflect the limits of the test. The AIRarg was also significantly less than that of control subjects even after the final transplant (Table 1).
In control subjects, the AIRg and AIRarg did not correlate significantly with each other (r = 0.613, P = 0.059), whereas the AUCi did correlate significantly with AIRg (r = 0.9, P < 0.001). In the transplanted patients, this association of AIRg and AUCi held (r = 0.901, P < 0.001), but the correlation between AIRg and AIRarg was not nearly as strong (r = 0.294, P = 0.288). All the measures of insulin reserve correlated with the islet mass transplanted (Fig. 5 A and B; Table 2). The AIRarg showed a stronger correlation, but we have smaller numbers in this group and the level of significance is similar with all measures of function. Interestingly, the correlation with islet mass was stronger for the studies at 3 months than those at 1 month (data not shown), and the correlation was stronger when cold ischemia time was considered (Table 2). The relationship of these measures of insulin secretion and glycemic control were also determined. Insulin responses to intravenous glucose were more strongly correlated than insulin response after arginine, with both fasting plasma glucose and 2-h glucose after oral glucose load (Figs. 6A and B; Table 3). The 90-min glucose post-Ensure was related to the AIRg (n = 60, r = −0.593, P < 0.001) and AIRarg (n = 21, r = −0.697, P < 0.001), as were AUCi, AUCC-p, and KG. The 90-min glucose post-Ensure was significantly related to the 2-h glucose post-OGTT (r = 0.718, P < 0.001) in the posttransplant subjects. Finally, on long-term follow-up, the AUCi within 3 months of transplantation in the three subjects who lost C-peptide production was significantly lower than those who remained off insulin or oral hypoglycemic agents (94 ± 17 vs. 299 ± 38 μU · ml-1 · min-1; P < 0.05).
Our results show that as a therapy for subjects with unstable, labile diabetes or severe problems with hypoglycemia, islet transplantation can achieve consistent glucose values and alleviate these problems. Even in the six subjects who resumed insulin therapy, the three who have clearly present C-peptide have stable glucose levels and are using about one-half the pretransplant dose of insulin. Thus, for the majority of patients with major problems of hypoglycemia or lability, the islet transplant procedure can provide an excellent solution.
The risks involved primarily relate to the procedure itself and the drugs used for immunosuppression. The procedure was associated with a 10% chance of bleeding and a 4% chance of some thrombus within the portal venous circulation. In only one case was bleeding a major concern, the patient who had hemorrhage while on anticoagulation for a partial portal vein thrombosis. Moderate abdominal pain occurred in ∼20% of the subjects and settled readily. With a median hospital stay of 1 day and only one serious complication after 54 procedures, the overall safety profile of the percutaneous approach is acceptable. Other approaches such as using computed tomography guidance for percutaneous access (11), approaches by the transjugular route, or laparotomy could be considered as viable alternatives but would likely take longer, and the latter may be associated with further delay in recovery or potential long-term risk of adhesion formation. The rise in LFT results has become more frequent compared with our original findings without any obvious cause. Reassuringly, all the elevations in liver enzymes have resolved with time.
The only serious immunosuppression-related complication in the 17 patients to date has been a rise in the creatinine in 2 subjects with known preexisting renal impairment. This level of renal dysfunction is stable with the discontinuation of the potentially nephrotoxic tacrolimus (12). The previous rise in urine protein (4) has now stabilized on longer-term follow up. These findings prompted changes in the protocol so that tacrolimus levels in the lower range of the target level of 3–5 ng/ml are accepted and hypertension is more aggressively treated. If blood pressure is consistently >135/85 mmHg, antihypertensive therapy is initiated and a target level of <125/75 mmHg on therapy is sought. With these targets, we have had to use or increase antihypertensive therapy in 53% of subjects. Of the 17 patients, 3 have required laser photocoagulation. This is of concern, and it is likely that the acute stabilization of glucose control is contributing (13,14). These results demonstrate the need for confirmation of stable eye disease pretransplant and monitoring for retinopathy posttransplant. It is too early to comment on neuropathy, but no dramatic changes have been noted. A concern is the degree to which hypercholesterolemia is being encountered. The rise in cholesterol is associated with a rise in the HDL so that the total to HDL cholesterol ratio is not grossly elevated, but we believe that this hypercholesterolemia warrants aggressive therapy given the history of unstable diabetes in the subjects. All have responded well to statin therapy when required, but the implications of this for the vasculature are unknown and merit close observation. Interestingly, hypertriglyceridemia has not been a problem, although it is common in other transplant immunosuppressive regimens (15); the absence of glucocorticoids with the regimen used in our patients may be the difference. Significant anemia was seen in eight patients and although explainable in most cases (renal or gastrointestinal disease), in other cases it most likely reflects a side effect of the medications. The WBC has also fallen, and in two subjects granulocyte colony-stimulating factor was used temporarily, but no serious infections have occurred. No posttransplant lymphoproliferative disorder has been encountered, and no CMV infection occurred despite a significant number of mismatches. It may be that in the islet preparation there are few contaminating leukocytes, making CMV infection less likely.
Most patients lose weight over time after the islet transplant procedure. No specific diet plan is prescribed other than eating healthily; in particular, the timing of meals is not specified. Although the frequent occurrence of mouth ulcers may be contributing to weight loss, these are usually transient and resolve as sirolimus levels stabilize. The occurrence of diarrhea may also be contributing, but even this is not as much of a problem as previously. Finally, once hypoglycemia is no longer a problem, the subjects are likely not eating as much to treat low glucose values.
For the patient with labile diabetes or recurrent hypoglyemia, the results continue to be excellent. Even for those who are now using insulin again, glucose values are more stable than pretransplant, and in only three subjects has complete C-peptide secretion been lost. The more stringent criteria of the OGTT confirmed problems with islet mass and/or function. Although only two patients meet the criteria for normal glucose tolerance with OGTT, the remainder with continuing C-peptide secretion have stable glucose control and do not have problems with hypoglycemia. In general, patients still feel that they are much better off with stable posttransplant diabetes than with the labile type 1 diabetes they had pretransplant. Two of the three who have lost C-peptide secretion appear to have had a recurrence of autoimmunity, as others have found (16). The other three subjects on insulin have persisting fasting C-peptide levels not different from those when they were insulin independent, yet their HbA1c has risen. Why these individuals required insulin therapy is not clear. The acute insulin response to glucose was low from the time of transplant in these subjects. Whether the need for insulin simply reflects borderline islet mass that is failing over time or some insulin resistance induced by the tacrolimus or is a direct effect of the immunosuppressive drugs on islet function is unknown (17–19). We have considered supplemental islet infusions and will proceed cautiously with them in the absence of a recurrence of autoimmunity. In the presence of a raised titer of GAD or ICA antibodies, it would appear prudent to accept that the current immunosuppressive regimen may be inadequate and alternative regimens would be required for these subjects. Finally, in terms of glucose control, it is of interest that the C-peptide response to the mixed meal challenge was normal, albeit with a higher glucose level, yet the response to intravenous glucose was blunted. Perhaps the incretin response is more marked in this setting to account for the better C-peptide response to the oral challenge. The higher glucose level than the control subjects with equivalent C-peptides may be indicative of insulin resistance, other subtle metabolic derangements (20), or the venous drainage of the islets (whether portal or systemic), an issue yet to be resolved.
It continues to appear that an absolute minimum of 9,000 IE/kg is required for insulin independence in the absence of steroids (Fig. 3). The lack of previous long-term success with islet transplantation (21,22) was likely related to the presence of glucocorticoids combined with inadequate prophylaxis of rejection and autoimmune events. However, in the current study, each subject had an average of 850,000 islets transplanted; the nondiabetic pancreas is believed to have 1.0–1.7 × 106 islets (23,24). Thus the poor acute insulin response to the IVGTT we documented might suggest either loss of islets or poor β-cell function. Assessing β-cell mass has been difficult in this setting and yet is of importance. Many measures of insulin reserve are available. Although insulin independence is the most important end point, it has to be tempered with coexisting good glycemic control. Islet function can be severely impaired with the subject still insulin independent; thus the need for more detailed measures. Suggested tests of insulin secretion have included AIRg, AIRarg, AUCi, insulin response to glucagon, and glucose-potentiated response to arginine (25). We believe that any tests should be considered in the light of four issues: are they equivalent, do they correlate to islet mass, do they relate to glycemic control, and can they predict future function of the graft.
Both glucose and arginine have been used as acute stimuli of insulin secretion. A bolus of glucose stimulates insulin release by increasing intracellular ATP, leading to closure of islet potassium channels, influx of calcium, and insulin secretion. Arginine, a cationic amino acid, can directly lead to depolarization of the β-cell, calcium influx, and insulin release. The response to arginine is increased when hyperglycemia is present (26). Our results show that whereas AIRg and AUCi were closely related, there was no significant relationship of AIRg and AIRarg in control subjects or study subjects. Thus whereas both stimulate insulin release, they are not measuring the same mechanisms. The differential response to these secretagogues is also evident in early type 1 and 2 diabetes, where AIRarg is typically preserved after AIRg is lost (27–29). All the parameters used gave a measure of islet mass. The correlation coefficient was higher for AIRarg and islet mass than for AIRg or AUCi. Detailed assessments in streptozotocin-treated baboons, which had in vivo measures of insulin reserve that were then correlated with in vitro anatomical determinations of islet mass or direct measures of pancreatic insulin content, have indicated that AIRg correlates more closely with pancreatic insulin content than AIRarg (30). In that study, AIRg was linearly correlated (r = 0.92) with pancreatic insulin content, and the regression line passed through zero. Interestingly, islet mass was still detectable when insulin reserve in vivo was completely depleted. The correlation of AIRg with β-cell mass, although linear, had a y intercept of 0.2 g/pancreas, indicating that at a negligible AIRg there was no insulin reserve but there was persisting islet mass (30). AIRarg and glucose-potentiated arginine-stimulated insulin release did not correlate as well as AIRg with either insulin reserve or islet mass. Tobin et al. (31), using a rodent islet transplant model of known islet mass, likewise found that AIRg was the better correlate with islet mass. Our results appear to be following a slightly different pattern. With the first transplant procedure, we have provided a reasonable islet mass, adequate to reduce exogenous insulin requirements and stabilize glycemic control but with a poor AIRg (Table 1). When the second transplant is provided, AIRg appears to improve disproportionately, although it still remains reduced compared with that of control subjects. AIRarg appears independent of this and thus may provide the better measure of islet mass posttransplant. In addition, if nondiabetic subjects have closer to 1.7 × 106 rather than 1.0 × 106 islets (23,24), then the results for AIRarg as a percentage of control (Table 1) are consistent with this proposition.
Our results indicate that the insulin response to glucose correlates better with the measures of glycemia we used (fasting plasma glucose and glucose level at 2 h during the OGTT) than AIRarg and provides a better composite measure of islet mass and function. Finally, when we examined the dynamic tests in light of the final outcome of C-peptide production, the responses to intravenous glucose were lower in those whose islets eventually failed, but there were too few AIRarg studies available to assess this parameter. It is clear that an improved measure of islet mass and/or function is needed for evaluating these patients. It needs to be determined whether proinsulin determinations will permit detection of islets that are beginning to fail (32). The glucose-potentiated arginine stimulation test may help, but the possibility of imaging islets is more exciting as a measure of mass (33). In the meantime, 90-min post-Ensure glucose is a simple and helpful test for following these patients in the long term. Many of our patients have problems with the palatability of the Ensure, and some other standard meal test would be of benefit. Of the more invasive tests, AIRg and AUCi derived from an IVGTT appear to give the most information and correlate better with function and long-term outcome; AIRarg may be a better measure of islet mass.
In conclusion, our results show that continued insulin independence for up to 2 3/4 years is possible after islet transplantation. The glucose values are stable in 14 of 17 transplanted subjects, and at 1 year, 80% of patients were insulin independent, as were 4 of 6 subjects >2 years after their initial transplant, a major improvement over previous results (21,22). There are acute risks of the procedure and risks associated with the immunosuppressive drugs, demonstrating the need for further improvement. The insulin reserve is not normal but adequate to correct the problems with glycemia. Thus for many subjects who have very labile diabetes and severe problems with hypoglycemia, the risks are worth the outcome; careful patient selection remains essential to maximize the risk-benefit ratio for any individual patient as islet transplantation becomes more widespread.
A: HbA1c at 3-month intervals after islet transplantation in subjects who remained insulin independent (n = 11). Each line represents an individual subject. B: Plasma glucose levels derived from standard meal tolerance tests in control subjects (n = 10) and patients before and after islet transplantation who have remained insulin independent (n = 11). Values are means ± SE. C: Plasma C-peptide levels derived from standard meal tolerance tests in control subjects (n = 10) and patients before and after islet transplantation who have remained insulin independent (n = 11). Values are means ± SE. Levels pretransplant were below detectability of the assay.
Fasting plasma C-peptide levels during the first 4 weeks (top panel) and at 3-month intervals for the full duration of follow-up (lower panel) in the 11 patients who remained insulin independent. Shown also are the values pretransplant (pre-Tx) and after the first transplant (mid). Values are means ± SE.
Exogenous insulin use (units/kg) in relation to the number of islets transplanted (IE/kg). Values for pretransplant (•), after first transplant (□), after second transplant (⧫), and after the third procedure (○) are shown. All patients became insulin independent once adequate islet numbers were provided.
AIRg (A) and AUCi (B) over time in insulin-independent subjects (n = 11) before and after islet transplantation as derived from the IVGTT. The number of subjects studied is shown across the top of the figure. Mean values ± SE are provided for each time point. Values for all time periods up to 24 months are significantly different from those of control subjects.
A: Relationship of the number of islets transplanted and AIRarg as derived from intravenous arginine infusion test at midtransplant (n = 6) and 3 months (n = 3) after transplant. B: Relationship of AUCi and the number of islets transplanted as derived from IVGTT at midtransplant (n = 13) and 3 months (n = 13) after transplant.
A: Relationship of AIRg as derived from IVGTT and fasting plasma glucose in subjects after islet transplant who were not taking exogenous insulin. B: Relationship of AIRg as derived from IVGTT and 2-h plasma glucose during the OGTT in subjects after islet transplant who were not taking exogenous insulin.
Measures of insulin secretion after the first and final transplant
Relationship of both IE transplanted and the cold ischemic index with measures of insulin secretion and glucose disposal
Relationship of glycemia (fasting plasma glucose and the 2-h glucose during the OGTT) with measures of insulin secretion and glucose disposal
This work has been supported by funds from Juvenile Diabetes Research Foundation International, the Alberta Foundation for Diabetes Research, a generous donation from the Roberts family, a grant from the Canadian Institute for Health Research, the Alberta Health Services Innovation Fund, and institutional support by the University of Alberta Hospitals, University of Alberta Capital Health Authority, and the Muttart Diabetes Research and Training Center. A.M.J.S. is a Clinical Investigator of the Alberta Heritage Foundation for Medical Research, and J.R.T.L. and G.S.K. are recipients of scholarships from the Canadian Diabetes Association and the Alberta Heritage Foundation for Medical Research. G.S.K. received a Career Development Award from the Juvenile Diabetes Research Foundation International. N.M.K. is a senior scholar of the Alberta Heritage Foundation for Medical Research.
We thank the staff of the Clinical Investigation Unit, the nurse coordinators: Ingrid Larsen, Tracy Davyduke, Sheri Newitt, Lana Toth, and Cindy Yarmuch. We are grateful for the technical help of Deborah McGee-Wilson, Tatsuya Kin, Doug O'Gorman, Richard Wilson, Jose Avila, and Toshi Tsujimura for their expertise in the Human Islet Isolation Laboratory; to our colleagues in the Division of Vascular and Interventional Radiology for their expert assistance with the portal vein cannulation; to our colleagues in the organ procurement programs in Alberta and across Canada for identifying cadaveric donors; to the Human Organ Procurement and Exchange Program of Northern Alberta; to Jean Der and staff in the laboratory of the University of Alberta Hospitals for help with assays; to Louise Bohachyk for secretarial assistance; to Jonathan Levy, Radcliffe Infirmary, Oxford, U.K., for providing the HOMA disk program; and to George Eisenbarth, Barbara Davis Diabetes Center, Denver, CO, for the ICA and GAD determinations. We acknowledge support from Roche Canada, Wyeth-Ayerst Canada, and Fujisawa Canada for the kind gifts of daclizumab, sirolimus, and tacrolimus, respectively.
Address correspondence and reprint requests to Edmond A. Ryan, Clinical Islet Transplant Program, 2000 College Plaza, 8215 112th St., Edmonton, AB, Canada T6G 2C8. E-mail: edmond.ryan{at}ualberta.ca.
Received for publication 11 February 2002 and accepted in revised form 4 April 2002.
N.M.K. served as a consultant for Wyeth on structuring clinical trials with Sirolimus in liver transplantation.
AIRarg, acute insulin response to arginine; AIRg, acute insulin response to glucose; AUC, area under the curve; AUCC-p, area under the curve for C-peptide; AUCi, area under the curve for insulin; CBC, complete blood count; CMV, cytomegalovirus; GAD, glutamic acid decarboxylase; HOMA, homeostasis model assessment; ICA, islet cell antigen; IE, islet equivalents; IVGTT, intravenous glucose tolerance test; KG, glucose disposal; LFT, liver function test; MAGE, mean amplitude of glycemic excursion; OGTT, oral glucose tolerance test; PTLD, posttransplant lymphoproliferative disorder; WBC, white blood cell count.
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de Mattos AM, Olyaei AJ, Bennett WM: Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kid Dis 35:333–346, 2000
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Kahan BD, Kramer WG: Median effect analysis of efficacy versus adverse effects of immunosuppressants. Clin Pharmacol Ther 70:74–81, 2001
Bosi E, Braghi S, Maffi P, Scirpoli M, Bertuzzi F, Pozza G, Secchi A, Bonifacio E: Autoantibody response to islet transplantation in type 1 diabetes. Diabetes 50:2464–2471, 2001
Dmitrewski J, Krentz AJ, Mayer AD, Buckels JA, Barnes AD, Smith J, Nattrass M: Metabolic and hormonal effects of tacrolimus (FK506) or cyclosporin immunosuppression following renal transplantation. Diab Obes Metab 3:287–292, 2001
Duijnhoven EM, Boots JM, Christiaans MH, Wolffenbuttel BH, Van Hooff JP: Influence of tacrolimus on glucose metabolism before and after renal transplantation: a prospective study. J Am Soc Nephrol 12:583–588, 2001
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Tobin BW, Lewis JT, Chen DZX, Finegood DT: Insulin secretory function in relation to transplanted islet mass in STZ-induced diabetic rats. Diabetes 42:98–105, 1993
Davalli AM, Maffi P, Socci C, Sanvito F, Preshci M, Bertuzzi F, Falqui L, Di Carlo V, Pozza G, Secchi A: Insights from a successful case of intrahepatic islet transplantation into a type 1 diabetic patient. J Clin Endocrinol Metab 85:3847–3852, 2000
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July 2002, 51(7)
You are going to email the following Successful Islet Transplantation
Edmond A. Ryan, Jonathan R.T. Lakey, Breay W. Paty, Sharleen Imes, Gregory S. Korbutt, Norman M. Kneteman, David Bigam, Ray V. Rajotte, A.M. James Shapiro
Diabetes Jul 2002, 51 (7) 2148-2157; DOI: 10.2337/diabetes.51.7.2148
Atorvastatin Targets the Islet Mevalonate Pathway to Dysregulate mTOR Signaling and Reduce β-Cell Functional Mass
Metabolomics Identifies a Biomarker Revealing In Vivo Loss of Functional β-Cell Mass Before Diabetes Onset
Murine Perinatal β-Cell Proliferation and the Differentiation of Human Stem Cell–Derived Insulin-Expressing Cells Require NEUROD1
Show more Islet Studies


For those looking for more than just jazz, Andrew and his band step up the cool factor. From Gershwin and Ellington to the Beatles and Led Zeppelin, no other small group represents such a breadth of musical styles. Praised for his taste, touch and tone, Andrew consistently receives high marks from Boston's most demanding corporate and private clients. They are available as a duo, trio or quartet.


installation does not proceed with aura.
'aura -As intel-mkl' definitely shows the package as it should.
aura >>= No valid packages specified.
I have tried this multiple times. Manually downloading works however.
Upgrading works as expected with pacaur now.
@djimenez which lines in particular? You can always make custom changes in your PKGBUILD to change the installation procedure.
This latest update was a patch I recieved which cleaned up a lot of messy code in the PKGBUILD, so I don't know which parts have been affected in detail.
I have installed this package earlier today and have noticed that it does not install the debugger. Some lines regarding this seem to have been commented out of the pkgbuild file.
Can the debugger be added to the installer?
I updated the .SRCINFO via mksrcinfo, does the issue persist?


text:
Dieser Artikel zeigt die Ergebnisse der Qualifikationsrunden für die NASDAQ-100 Open 2004 des Damentennis. Insgesamt nahmen 48 Spielerinnen im Einzel und 8 Paarungen im Doppel an der Qualifikation teil, die von 22. bis 24. März 2004 stattfand.

Einzel

Setzliste

Ergebnisse

Doppel

Setzliste

Ergebnisse

Weblinks

WTA Tour 2004
Tennisturnier in Key Biscayne (Florida)


From tubes and wakeboards to surfboards and kneeboards, we have it all!
Here at Blue Springs Marine, we have everything you need for some summertime fun. We are a proud carrier of O'Brien Watersport's because their products are guaranteed to provide a fun time for everyone.
For over 50 years, much like us, O'Brien has been focusing on the ultimate experience of family fun on the water. O'Brien Watersports works hard to design, test, manufacture, and improve each and every product they make. They provide the newest technology and the latest manufacturing techniques to build the most advanced watersports products. Together, we take our commitment to maximizing your enjoyment very seriously. All while creating great products at surprisingly affordable prices, they strive to offer the quality, performance, and value for which the O'Brien name has been famous for. So why wait? Come and see us today, and make your summer dreams a reality with our O'Brien products.
"We strive to offer the quality, performance, and value for which the O'Brien name has been famous for more than 50 years."


Most people assume that all there is to seeing to it that their affairs are in order is to create a will, appoint a trustee, and make arrangements. However, estate planning is not always so easy and it is highly probable that some situations will bring about complications with your estate and for your estate trustee upon your death. When estate distribution is bound to be difficult, it is always best to appoint a trust attorney to oversee the situation and help the trustee through everything. Check out these complicated scenarios when hiring an attorney to oversee your designated estate trustee would be a good idea.
If you are a business owner, it is best to hire a trust attorney.
Being a business owner means that your assets will be completely different from the average person, but this also means there can be more debts to be dealt with and more complex issues that can come up for your trustee when you pass away. Any time you own a business, it is best to appoint a trustworthy trustee, but also speak with a trust attorney to oversee delegation of assets and actions by the trustee.
If you have several heirs, it is best to hire a trust attorney.
If you have several children, stepchildren, or even significant others past and current, it is best to include a trust attorney in your estate planning processes and to oversee the trustee once you are gone. In general terms, the more living heirs you have, the more complicated your will and trust can be because there is a higher likelihood of someone contesting the plans you have in place. Make sure you plan early, lay out clear plans with your trustee, and include an attorney in all stages to avoid confusion and problems later on.
If you owe a lot of debts, it is best to hire a trust attorney.
Debts will not disappear because you leave this life; they will be left to contend with by the appointed trustee. In most cases, debts will have to paid before distribution of the estate and your assets, which can definitely make the process a lot more complicated. It is a good idea to have a clear-cut plan of action in place for your debts with a trust attorney, like Wright Law Offices, PLLC, who can ensure these monies are paid in logical terms and your trustee does not accidentally get caught having to pay your bills.


On the heels of launching a series of posts about the way that a consumer-mindset hinders our missional convictions (and the way that that mindset is challenged by some wonderful people of witness--like Zach Hunter), I came across this most interesting--and possibly, to some disturbing--piece.
Time Magazine is running an article based on some recently released letters where Mother Teresa reveals that she had a 50-year "dark night" of the soul. It is fascinating reading that makes some nervous. As for me, I deeply appreciate it the beauty of a life lived in obedience to Christ's commands, even in the face of an experiential crisis.
While it seems incongruous to so many of us who believe that Christian faith guarantees a "spiritual intimacy" with God, Mother Teresa's candor reveals a most challenging re-thinking of what faith is, offers and accomplishes, especially in our consumer-focused world.
The excerpts from her letters are brutally blunt in their longing and agony. They are almost assaulting to those of us who have grown accustomed to nothing but "victorious" Christian voices. But they ring of an honesty and earthy realism that is found no less than in the Scriptures themselves. She joins a chorus of others like C.S. Lewis, St. John of the Cross, Sister Teresa of Avila and even the Lord himself whose life and faith include the absence of God.
Mother Teresa reveals an often ignored reality of the Christian life: There are no guarantees of "spiritual experiences", only the trust that clings to Christ's promises, God's character and the hope of mercies that are new every morning amidst a long dark night.
A 15-year old who is "Being the Change"
Zach Hunter is a 15-year-old abolitionist. At our High School and Junior High Summer camp, we featured his life and his book as a model for a new generation of revolutionaries. Those of us in the 25-45 year old set are inspired and heartened by this guy.
I even used his story in a sermon I gave last weekend on James 5: 1-6.
Please watch the video about him and let me know what you think.
And then I'll tell you some about how our teenagers responded to the challenge of his life and the challenge that their response means for church leaders like me.


text:
Christmas trees in demand earlier than ever as holiday season begins
By Richard Giacovas
Christmas trees already in high demand
With 'Christmas Creep' getting worse and worse each year, with the coronavirus pandemic it seems like people can't wait to start the Christmas season this year.
NEW YORK - It would normally be far from crunch time when it comes to Christmas trees.
But it's 2020 and it appears that people can't wait this year for the smell of fresh pine to fill their living rooms.
Like millions of other Americans this year, Marcie Mule and her wife Jeanine Dooley just couldn't wait anymore.
"I feel very bad for Thanksgiving but it's like, we're going to decorate the tree all day tomorrow because why not?" said Mule.
Pete DiMeglia has already gone through 150 trees so far. And as the manager of Danny's Christmas Trees and Wreaths in Eastchester, he's still waiting for more trucks to come all the way from Canada.
"I think most of these trees to be gone by the weekend. Nice weather and people are in the Christmas spirit" says DiMeglia
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text:
Cirencester old Grammarians
1940's Association
Grammarian Obituaries
Quarterly Lunches
The Grand Reunions
REUNION COMMITTEE
Chairman: Vacant
Vice Chairman: Vacant
Hon. Secretary: Peter Rowe
Treasurer: Mrs Brenda Lissimore (Wormald)
Committee: Mrs Mavis Mills (Stewart), Mrs Patsy Gronland (Outhwaite), Pauline Parker (Sampson), Jenny Hale (Cullip),
Tony Hale, Tony Harris, Mrs Maureen Rose (Packer), Ralph Wilkins, Edwin Cuss
President: Dr. Brian Gegg,
Vice President: Peter Rowe.
Chairman: This office rotates amongst committee members.
Hoint Hon. Secretaries: Mrs Ann Green (Da Silva) and Mrs Pauline Parker (Sampson)
Treasurer: Pauline Parker
Magazine Editor: Peter Rowe
Miss Janet Edwards, Mrs Isabel Pitts (Beale) Malcolm Whitaker and Ralph Wilkins
OLD GRAMMARIANS' PUBLICATIONS
THE HISTORY OF CIRENCESTER GRAMMAR SCHOOL
LOOKING BACK AT CIRENCESTER GRAMMAR SCHOOL
for the period 1880-1966.
A series of photographs compiled by Edwin Cuss (1996)
Both publications are now out of print with just a few appearing from time to time in secondhand bookshops and other sources such as E Bay.
The proceeds from the sales of the two books were made the subject of a special fund from which donations totalling over £4,000 were made to schools in the former Grammar School catchment area.
A RECORD OF THOSE FORMER PUPILS WHO SERVED
THEIR COUNTRY DURING WORLD WAR II
By Peter Rowe LL.B, BA, A 1940s Association publication
Compiled and published during 1993
This is a typescript record of all former Grammar School pupils who served in the Armed Forces during the Second World War with pride of place being given to those who lost their lives. Based on this information a memorial to the fallen was commissioned which hangs along with its Great War companion in the Bingham Hall.
A copy is available, for reference purposes only, at the Bingham Library. Copies were also provided for The Corinium Museum and Gloucestershire Record Office.
THE NEW CIRENCESTRIAN – THE 1940s MAGAZINE
Published in December each year and distributed free to 1940s members of the Cirencester Old Grammarians (1940s) Association.
THE OLD GRAMMARIANS' NEWSLETTER
This is published twice yearly by the Reunion Committee and contains news of former Grammarians to enable them to keep in touch. It includes letters from Old Grammarians worldwide and nostalgic articles on days gone by. It is likely that 2016, following the Grand Reunion, will see the final addition.
The Newsletter, price £ 4 per annum (including UK postage), is obtainable from Brenda Lissimore at 14 Somerford Road, Cirencester, GL7 1TN. Cheques for the Newsletter should be made payable to "CGS Newsletter".
A COUNTRY LAD'S JOURNEY THROUGH LIFE
This is an autobiographical work by John Keen (Class of 1939). It is a highly entertaining read and profusely illustrated. Not only does the book, in its 373 pages, trace the history of the Keen family in detail, at the same time it reflects the life and times through which John and his family lived. Give a year or two either way, that reflects our life and times too, especially if we began life in rural surroundings.
Enquiries in respect of both the Reunion Committee and the 1940s Association may be referred to any of the respective committee officers or members. Email enquiries may be sent directly to members but any new enquiries should be referred in the first instance to:
peter.rowe137@gmail.com


Amin Maredia, CEO of Phoenix-based Sprouts Farmers Market, will leave the company at the end of this year, the company said in a statement.
Amin Maredia, CEO of Phoenix-based Sprouts Farmers Market, will leave the company at the end of the year, the company said in a statement.
Maredia, who also sits on the board of directors, will "transition'' out of the company on Dec. 30.
Maredia will remain for a period of time in an advisory role to assist with the transition, the company said in a statement Thursday.
"It has been an enormous privilege to have been part of the Sprouts team during this incredible period in the company's history over the past eight years," Maredia said in a statement. "As I transition, it is comforting knowing that Sprouts is well-positioned with a strong management team for robust growth and sustained success."
Maredia has been CEO since August 2015; before that, he was its chief financial officer.
Sprouts soon will begin searching for a new CEO, the statement said.
"On behalf of the board of directors, I would like to express our gratitude to Amin for his many years of service to Sprouts," board Chairman Joseph Fortunato said in a statement. "Over the past three years, Amin has overseen our tremendous growth from coast to coast and put us on a firm footing for continued success. We wish Amin all the best in his future endeavors."
Maredia was listed among Arizona's highest paid CEOs at publicly traded companies as published by The Arizona Republic earlier this year.
His summary compensation was $4,519,931 in 2017; his adjusted compensation was $2,205,582.
Jim Nielsen, the company's president and chief operating officer, and Brad Lukow, the company's chief financial officer, will serve as the company's co-interim CEOs until the company names a permanent successor, the statement said.
Nielsen has served as the company's president and chief operating officer since August 2015 after he became the company's chief operating officer in April 2011. Before that, Nielsen served as president of Henry's Farmers Markets from 2007 through April 2011, the company said.
Lukow has served as the company's chief financial officer since March 2016 and was previously the executive vice president and chief financial officer of Shoppers Drug Mart, Canada's leading drugstore retailer, from 2009 to 2014, the company said.
Sprouts is headquartered in Phoenix and has more than 300 stores in 19 states nationwide. The company's website lists 38 stores in Arizona.
Amkor Technology Inc.'s Stephen Kelley: Summary compensation: $7,859,696. Adjusted compensation: $6,176,929. TTM profit: $285 million. TTM revenue: $4.3 billion. 2017 stock: (4.7 percent). Capitalization: $2.1 billion. Amkor Technology Inc.
Avnet Inc.'s Richard Hamada (ex-CEO): Summary compensation: $4,356,815. Adjusted compensation: $8,610,170. TTM profit: $134 million. TTM revenue: $18.6 billion. 2017 stock: (15.3 percent). Capitalization: $5.2 billion. Avnet Inc.
Axon Enterprise Inc.'s Patrick Smith: Summary compensation: $3,765,675. Adjusted compensation: $4,459,252. TTM profit: $14 million. TTM revenue: $366 million. 2017 stock: 9.3 percent. Capitalization: $3.9 billion. Axon Enterprise Inc.
First Solar Inc.'s Mark Widmar: Summary compensation: $10,699,783. Adjusted compensation: $3,923,469. TTM profit: ($92 million). TTM revenue: $2.6 billion. 2017 stock: 110.4 percent. Capitalization: $5.7 billion. First Solar Inc.
Insight Enterprises Inc.'s Kenneth Lamneck: Summary compensation: $4,498,318. Adjusted compensation: $6,302,471. TTM profit: $110 million. TTM revenue: $7 billion. 2017 stock: (5.3 percent). Capitalization: $1.8 billion. Insight Enterprises Inc.
Knight-Swift Transportation Holdings' David Jackson (CEO): Summary compensation: $2,496,099. Adjusted compensation: $1,420,328. TTM profit: $540 million. TTM revenue: $3.4 billion. 2017 stock: 33 percent. Capitalization: $6.8 billion. Knight Transportation Inc.
Knight-Swift Transportation Holdings' Kevin Knight (executive chairman): Summary compensation: $7,530,854. Adjusted compensation: $7,615,076. TTM profit: $540 million. TTM revenue: $3.4 billion. 2017 stock: 33 percent. Capitalization: $6.8 billion. Knight Transportation Inc.
Magellan Health Inc.'s Barry Smith: Summary compensation: $7,434,946. Adjusted compensation: $3,200,838. TTM profit: $104 million. TTM revenue: $6.3 billion. 2017 stock: 28.3 percent. Capitalization: $2.4 billion. Magellan Health Inc.
Sprouts Farmers Market Inc.'s Amin Maredia: Summary compensation: $4,519,931. Adjusted compensation: $2,205,582. TTM profit: $179 million. TTM revenue: $4.8 billion. 2017 stock: 28.7 percent. Capitalization: $3 billion. Rick Gayle Studio Inc.
Vereit Inc.'s Glenn Rufrano: Summary compensation: $8,203,992. Adjusted compensation: $4,909,826. TTM profit: $49 million. TTM revenue: $1.3 billion. 2017 stock: (1.4 percent). Capitalization: $7.4 billion. Vereit Inc.
Versum Materials Inc.'s Guillermo Novo: Summary compensation: $8,152,446. Adjusted compensation: $2,765,165. TTM profit: $178 million. TTM revenue: $1.3 billion. 2017 stock: 35.4 percent. Capitalization: $4.1 billion. Versum Materials Inc.