EASD Clinical Summer1 2007

ClinicalAn Official

Journal of theAmericanDiabetes

Association

Practical Information for Primary Care

Middle East Edition Volume 6 Number 3 Summer 2007

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FEATURES

84 Bariatric Surgery for Patients With Diabetes Aaron W. Eckhauser, MD; William O. Rich-

ards, MD, FACS; and Michael J. Fowler, MD

91 Diabetes Management Issues for Patients With Chronic Kidney Disease Kerri L. Cavanaugh, MD

DEPARTMENTS

82 Editorial: Diabetes, Weight Loss, and Sisyphus Tom Elasy, MD, MPH, Editor-in-ChieF

99 Landmark Studies: Intraoperative Intensive Insulin Therapy Did Not Improve Outcomes Among Patients Undergoing Cardiac Surgery Reviewed by Michael Pignone, MD, MPH

100 Practical Pointers: Nutrition 911: The First Responders’ Guide to Food and Diabetes Dianne L. Davis, RD, LDN, CDE, and Re-

becca P. Gregory, MS, RD, LDN, CDE

103 Patient Information: Eating With Type 2 Diabetes

104 Diabetes Foundation: Diabetes Treatment, Part 1: Diet and Exercise Michael J. Fowler, MD

109 Case Studies: Challenges of Managing Diabetes in Com-

mercial Truck Drivers Jeremy B. Soule, MD, and Leonard E. Egede, MD, MS Management of Type 2 Diabetes After Bariatric Surgery Julia P. Dunn, MD, and Shubhada M. Jagasia, MD A 52-Year-Old Woman With Hypertension and Diabetes Who Presents With Chest Pain George D. Harris, MD, MS

LOCALARTICLES

118 Recommendations for Management of Hy-perglycemia in Type 2 Diabetes in the Arab Countries Based on the consensus statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

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“Reprinted with permission from Clinical Diabetes. Copyright © 2007 by American Diabetes Association, Inc.”

From the Editor’s Desk

ClinicalDiabetes

A PublicAtion of the AmericAn DiAbetes AssociAtion®, inc. tm

miDDle eAst eDition, Volume 6, number 3, 2007

I n this issue of our Journal you will find a very important new manuscript about Recommen-dations for Management of Hyperglycemia

in Type 2 Diabetes in the Arab Countries Based on the consensus statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

The (ADA) and the (EASD) have published a consensus statement on the management of hyperglycemia in type 2 diabetes (1); the rec-ommendations and algorithm were based on clinical trials that have examined different mo-dalities of therapy of type 2 diabetes and on the authors’ clinical experience and judgment.

The algorithm did highlight the primary goal of achieving and maintaining glucose lev-els as close to the nondiabetic range as possible. The most recent glycemic goal recommended by the ADA is «in general» a hemoglobin A1C level of less than 7%, or «as close to normal (<6%) as possible without significant hypogly-cemia». The most recent glycemic goal set by the European Union – International Diabetes Federation is an A1C level of 6.5%. The upper limit of the nondiabetic range is 6.1% (mean A1C of 5%+2 SD) with the DCCT-standardized assay, which has been promulgated through the National Glycohemoglobin Standardization Program (NGSP) and adopted by the vast ma-jority of commercially available assays .

There was a real need to create new recom-mendations based on the above to suit more the conditions in the Arab countries

To create an algorithm more applicable in the Arab world, a group was convened in March 2007 to review the ADA/EASD recommenda-tions and modify them taking into account is-sues specific to the developing world in gener-al and Arab countries in particular, most partic-ularly the burden of cost on patients with diabe-tes. Most patients in the Arab world are not in-sured and have to pay for medications, glucose monitoring supplies, laboratory tests and visits with health care providers out of pocket. Free medical care is often provided through govern-ment supported hospitals and primary care cen-ters which usually do not provide higher cost drugs while metformin and sulphonylureas (SU) are generally readily available. Limited availability of medical specialists and diabe-tes education programs further compound these problems for patients and primary care provid-ers. These are among the factors considered while developing an algorithm for the manage-ment of hyperglycemia of type 2 diabetes the Arab world.

Unfortunately there are barriers to effective management of hyperglycemia in type 2 diabe-tes, particularly in much of the Arab world.

antihyperglycemic therapies with the pos-sible exception of TZD should be titrated fre-quently (at intervals of days to at most weeks) based on glucose levels achieved and tolerabil-ity. Most patients can achieve A1C levels less than 7% in a matter of a few months. Subopti-mal healthcare systems impede achievement of glycemic goals.

Other barriers to effective management in-clude insufficient communication with patients due to limited physician consultation time. This often contributes to inappropriate prescription of medications which patients cannot afford or will not tolerate and contributes to poor adher-ence. A multidisciplinary team approach to di-abetes care - involving diabetologists, primary care providers, diabetes specialist nurses, phar-macists, dieticians and health educators, among others, with the patient at the centre of the team - has been demonstrated to improve both glyce-mic control and patient quality of life.

I hope you will find these recommendations of some help in your practice .

Mahmoud Ashraf Ibrahim , MD

Editor , Middle East Edition

Volume 6, Number 3, 2007 • CLINICAL DIABETES (MIDDLE EAST EDITION)118

Recommendations for Management of Hyperglycemia in Type 2 Diabetes in the Arab Countries

Based on the consensus statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

From the 1 Dasman Center for Research and Treatment of Diabetes, Kuwait; 2Depart-ment of Internal Medicine & Diabetes, Faculty of Medicine, Mansura University, Mansura, Egypt; 3National Institute of Nutrition, Tunis, Tunisia; 4Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Caro-lina; 5Department of Medicine, University of California and VA San Diego Healthcare, San Diego, California; 6Department of Internal Medicine & Endocrinology, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 7Department of Internal Medicine & Diabetes, Faculty of Medicine, Cairo Univer-sity, Cairo, Egypt; 8Department of Medicine, Glan Clwyd Hospital, Rhyl, Denbighshire, U.K.; 9Egyptian Diabetes Center, Cairo, Egypt; 10Ministry of Health, Palestinian National Authority, Shifa Hospital, Gaza, Palestine; 11Dubai Hospital, Dubai, United Arab Emirates; 12Al-Nour Hospital, Mekkah, Saudi Arabia.

Address correspondence and reprint requests to Mahmoud Ashraf Ibrahim, MD, 19 Nasouh St., Zeitoun, Cairo 11321, Egypt. E-mail: [email protected]

Abbreviations: SU, sulphonylureas; TZD, thiazolidinediones; DCCT, Diabetes Control and Complications Trial; A1C, glycosylated haemoglobin A1c; GI, gastrointestinal.

Diabetes mellitus, especially type 2, is a serious disease and a cause for growing public health concern in both developed and developing countries. In many nations, it is now a leading cause of death, disability and rising health care cost. These facts have been recently underscored in a United Nations landmark resolution on diabetes recognizing the global threat of the diabetes epidemic (1).

Diabetes in the Arab world is character-

ized by high prevalence associated with strong ethnic influence, rapid socioeconomic transformation and lifestyle change, specifically the consumption of diets high in saturated fat and processed carbohydrate in concert with decreasing physical activity. Four of the Arab countries are among the top 10 countries with respect to diabetes prevalence (2). In Saudi Arabia the prevalence of diabetes rose from 2.2% in 1977 to 12.3% in 1997. Egypt is expected to be number 9 worldwide in the number of diabetic individuals in the year 2025. There is also a high prevalence of obesity among Arab individuals, ranging between 30 and 40%. The prevalence of obesity among those with type 2 diabetes was found to be 60% (3).

In the setting of type 1 diabetes, achieving glycemic levels as close to the nondiabetic range as possible has proved to minimize diabetes specific complications, retinopathy, nephropathy and neuropathy (4,5); in type 2 diabetes, more intensive treatment regimens have been shown to prevent, minimize or at least postpone complications(6-8). Despite the fact that many reviews on the manage-ment of type 2 diabetes have been published in recent years (9-12), diabetes health care providers are left without a well established evidence based strategy for management of type 2 diabetes.

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have published a consensus statement on the management of hyperglycemia in type 2 diabetes (13); the recommendations and algorithm were based on clinical trials that have examined differ-ent modalities of therapy of type 2 diabetes and on the authors’ clinical experience and judgment.

The algorithm did highlight the primary

goal of achieving and maintaining glucose levels as close to the nondiabetic range as possible. The most recent glycemic goal recommended by the ADA is «in general» a hemoglobin A1C level of less than 7% (14) , or «as close to normal (<6%) as possible without significant hypoglycemia». The most recent glycemic goal set by the European Union – International Diabetes Federation is an A1C level of 6.5%. The upper limit of the nondiabetic range is 6.1% (mean A1C of 5%+2 SD) with the DCCT-standardized assay, which has been promulgated through the National Glycohemoglobin Standardization Program (NGSP) and adopted by the vast majority of commercially available assays (15).

To create an algorithm more applicable in the Arab world, a group was convened in March 2007 to review the ADA/EASD recommendations and modify them taking into account issues specific to the develop-ing world in general and Arab countries in particular, most particularly the burden of cost on patients with diabetes. Most patients in the Arab world are not insured and have to pay for medications, glucose monitoring supplies, laboratory tests and visits with health care providers out of pocket. Free medical care is often provided through government supported hospitals and primary care centers which usually do not provide higher cost drugs while metformin and sulphonylureas (SU) are generally readily available. Limited availability of medical specialists and diabetes education programs further compound these problems for patients and primary care providers. These are among the factors considered while developing an algorithm for the management of hyperglycemia of type 2 diabetes the Arab world.

The ADA/EASD consensus opinion was

MONIRA AL-AROUJ, MD1, MEGAHED ABU AL-MAGD, MD2, RADHIA BOUGUERRA, MD3, JOHN B. BUSE, MD,

PHD4, STEVEN V. EDELMAN5, MOHAMED FAHMY6, SHERIF HAFEZ, MD, FACP7, MOHAMED HASSANEIN, FRCP8,

MAHMOUD ASHRAF IBRAHIM, MD9, SUHAIL KISHAWI, MD10, ABDULRAZZAQ AL-MADANI, MD11, ABDALLA BEN

NAKHI, MD1, KHALED TAYEB, MD12

L O C A L A R T I C L E SL O C A L A R T I C L E S

Volume 6, Number 3, 2007 • CLINICAL DIABETES (MIDDLE EAST EDITION) 119

that a hemoglobin A1C level of 7% or higher should serve as a call to action to begin or to modify therapy. Our group does support this approach as we did not find a practical dif-ference between proposed targets of less than 7% versus 6.5% or specific evidence that the lower target was more appropriate from an evidence base. Fundamentally, achieving either target is extremely challenging in the current health care environment in the Arab world. Since A1C assays are not routinely available in some areas and for many patients in Arab countries, we considered whether repeated fasting and/or postprandial plasma glucose measurements can be substituted.

The revolutionary advance in the number of blood glucose-lowering medications has led to some confusion for both practitioners and patients regarding the most appropriate way to treat diabetes. We agree that the choice of specific antihyperglycemic agents should be based primarily on their A1C lowering capacity, demonstrated safety and efficacy in long-term studies, tolerability and expense (16, 17). Specific effects of individual therapies on cardiovascular disease risk factors, such as hypertension or dys-lipidemia, were also considered important. There are no definitive comparative outcomes data at this time to recommend one class of glucose-lowering agents, or one combination of medications, over others with respect to their ability to reduce microvascular or macrovascular complications.

Modified Algorithm

See figure 1 and table 1.

Step 1 (life-style intervention and metformin):

Lifestyle changes to limit carbohydrate intake, decrease weight and increase activity is inexpensive and provides broad benefits (18). Unfortunately, it often fails in the first year, in part related to inadequate interven-tion or follow-up by practitioners as well as poor buy-in and adherence on the part of patients. Metformin is generally inexpen-sive and not associated with weight gain or hypoglycemia and has demonstrated benefits in numerous long-term studies making it the logical first-line pharmacotherapy in diabetes. It can be associated with gastrointestinal side effects and multiple contraindications (renal, hepatic or cardiac failure). However, it is rarely associated with lactic acidosis. Therefore, we concur

with the ADA/EASD group that metformin generally should be initiated concurrently with lifestyle intervention at diagnosis.

Average A1C reduction by metformin as monotherapy, ~1.5%, (19) will often be inad-equate. Thus our group recommends more attention by practitioners working collabora-tively with patients towards effective lifestyle change. Worldwide as well as in Arab countries, ineffective diet/exercise initiatives are common. These interventions should be implemented by health care professionals with appropriate training and experience not only in diabetes, physical activity and nutri-tion but also in behavior modification prin-ciples, specifically registered dietitians and diabetes educators. The lack of widespread diabetes education and lifestyle intervention programs in the Arab world is compounded by a lack of awareness of their potential of these programs to substantially impact not only glycemic control, but also weight, blood pressure, lipids and drug costs.

Awareness and sensitivity to ethnic and cultural issues is critical to success. Special attention must be directed to the type of food consumed in the Arab countries, generally a diet high in carbohydrates (20,21). Special occasions like fasting at Ramadan among Muslims (22) and avoidance of animal prod-ucts during multiple times of the year among Orthodox Christians should be considered in treatment strategies.

The presenting glycemic status in newly diagnosed people with diabetes should also be considered. If the fasting glucose is greater than 250 mg/dl or random glucose over 300 mg/dl, it may be reasonable to consider using sulfonylurea instead of metformin, or a combination of both, or the initiation of insulin therapy at diagnosis.

Among Arab countries there is a high prevalence of hepatitis C and impaired liver function. Egypt has the highest prevalence of hepatitis C in the world, 18.1%. Other Arab countries report lower but still substantial hepatitis C prevalence rates: Jordan 2.1%, Kuwait 3.3% Libyan Arab Jamahiria 7.9%, Mauritania 1.1%, Morocco 1.1%, Oman 0.9%, Qatar 2.9%, Sudan 3.2%, United Arab Emirates 0.8% (23). This potential underlying problem complicates drug therapy as the liver is a critical organ in drug metabolism (some sulfonylureas), in lactate

clearance (metformin) and in the response to hypoglycemia (sulfonylurea and insulin). There is a contraindication to the use of acarbose and thiazolidinediones in the setting of marked hepatocellular disease, though it may be less of an issue with rosiglitazone and pioglitazone than a previous TZD withdrawn from the market due to liver toxicity.

Step 2 (additional medications):

Insulin, which has no dose limit, is inex-pensive, and improves the lipid profile, par-ticularly triglycerides. However, it requires injections, capillary glucose monitoring and may be associated with hypoglycemia and weight gain.

Sulfonylureas (SU) are inexpensive but may give rise to weight gain and hypo-glycemia. However, severe hypoglycemia is relatively uncommon with sulfonylurea therapy and the weight gain generally modest. Chlorpropamide and glibenclamide are more likely to cause hypoglycemia than glimepiride, gliclazide MR and glipizide. Average A1C with SU monotherapy is ~1.5% (24).

The thiazolidinediones (TZD) improve the lipid profile but are expensive and may cause fluid retention and weight gain. They are contraindicated in patients with diabetes and coexisting class III/IV heart failure as defined by the New York heart Association (NYHA) (25) as well as in the setting of liver disease, characterized by greater than 3-fold elevations in transaminases. Attention should be paid to the higher rate of fractures of humerus, hand and foot in women reported with use of TZD (26). They are associated with average A1C reduction as monotherapy of 0.5% to 1.4% (27). Insulin plus a TZD are particularly effective means of lowering glycemia (28); this combination used for years in the U.S. was recently approved in the European Union (29); A recent meta-analysis suggests that Rosiglitazone may be associated with excess myocardial infarction; this is being tested formally in the RECORD study(30).

Step 3 (further adjustment):

Treatment of type 2 diabetes should be individualized and take account of individu-als lifestyle, patients wishes and technical



abilities. Local expertise of healthcare providers should be also considered. These issues can be barriers to insulin therapy. However, achieving treatment targets is important to avoid complications and insu-lin is arguably the most effective glucose lowering agent available. Tight glycaemic control, particularly with insulin, may be associated with severe hypoglycemia. Patients initiating insulin therapy should be advised about the benefits of regular blood glucose monitoring, as well as the signs and symptoms and the prevention and treatment of hypoglycemia. Analogue insulin though generally substantially more expensive than human insulin is associated with a modestly lower incidence of hypoglycaemia in clinical trials.

Basal Insulin:

The addition of basal insulin should be taken at diagnosis or immediately after treatment with metformin and lifestyle intervention if hyperglycemia is profound or at any time if oral antihyperglycemic agents are not able to achieve treatment targets. Reasonable options for adding bedtime basal insulin to oral agents include NPH human insulin or one of the long acting insulin analogues (glargine and detemir). NPH human insulin is a relatively low cost option and is as effective as long-acting analogs in A1C reduction.

Intensified Insulin:

The combination of basal insulin with meal-associated rapid acting insulin should be used in patients who are unable to achieve glycemic control on basal insulin with or without oral antihyperglycemic therapies. The type of insulin used should reflect the patient glycemic profile (postprandial and fasting) as well as the individual lifestyle. Patients can continue to take insulin with metformin with or without glitazones but should stop taking secretagogues when rapid acting insulin is added to the regimen.

So called basal-bolus therapy provides the most physiological glycemic control and optimal flexibility for people with diabetes to adjust therapy to match lifestyle choices such as changes in physical activity or the timing or carbohydrate content of meals. Alternatively, premixed insulin (NPH

plus regular human insulin or rapid acting analog insulin) can be used in one or more daily doses, generally before supper, before breakfast and supper or prior to each meal. This approach is generally effective in patients with very consistent lifestyles and in those who are less capable of managing a basal-bolus titration regime.

Other drugs:

The glinides (nateglinide and repaglinide) are short half-life agents which bind to the sulfonylurea receptor. They are expensive and require three times daily dosing. Repaglinide is more effective at lowering A1C, ~1.5%, than is nateglinide which is the secretagogue with the lowest risk of severe hypoglycemia(31,32).

Alpha-glucosidase inhibitors are weight neutral but have frequent gastrointestinal adverse effects, generally require three times daily dosing, and are expensive. They are less effective in lowering glycemia than metformin, SU or TZD, reducing A1C by 0.5-0.8 % (33).

The glucagon-like peptide 1 agonist exenatide is associated with modest weight loss in addition to glucose lowering but has the disadvantages of high cost, twice daily injections for administration and frequent gastrointestinal adverse effects at initiation of therapy; ~40% of patients experience intermittent nausea, vomiting or diarrhea which is generally mild to moderate in intensity. Exenatide is not indicated for use in monotherapy or combination with insulin, but is associated with average A1C reduction of 0.5% to 1% (34,35).

DDP-4 inhibitors interfere with the degradation of GLP-1 by blocking the action of the DPP-4 enzyme and therefore raise GLP-1 levels 2- to 3-fold. Vildagliptin and sitagliptin are administered orally and are generally well tolerated but are just being released for clinical use as of this writing, so clinical experience with these agents is minimal. They are expensive and moderately effective, lowering A1C 0.5 to 0.8% (36).

Pramlintide, an amylin analogue, is only indicated for use in combination with rapid acting insulin, is modestly effective in reducing A1C (~0.6%) as well as weight, but requires injections before each meal and is

expensive. Furthermore, clinical experience is limited (37).

Summary

We would like to emphasize that step-wise interventions will help to achieve glyce-mic goals. Unfortunately there are barriers to effective management of hyperglycemia in type 2 diabetes, particularly in much of the Arab world (38)

We would like to emphasize that antihyperglycemic therapies with the possible exception of TZD should be titrated frequently (at intervals of days to at most weeks) based on glucose levels achieved and tolerability. Most patients can achieve A1C levels less than 7% in a matter of a few months. Suboptimal healthcare systems impede achievement of glycemic goals.

Other barriers to effective management include insufficient communication with patients due to limited physician consultation time. This often contributes to inappropriate prescription of medications which patients cannot afford or will not tolerate and contrib-utes to poor adherence. A multidisciplinary team approach to diabetes care - involving diabetologists, primary care providers, diabetes specialist nurses, pharmacists, dieti-cians and health educators, among others, with the patient at the centre of the team - has been demonstrated to improve both glycemic control and patient quality of life (39).

Equally or arguably more critical to optimizing patient outcomes is adequate treatment of comorbid conditions (e.g. dyslipidemia, hypertension, hypercoagulabil-ity) and early complications (e.g. retinopathy, microalbuminuria and the insensate foot). A team approach with appropriate attention to patient education, motivation and adherence is critical to success, even if the team is just a patient and a primary care provider working together in a context of mutual respect with shared goals, understanding of their indi-vidual roles and open communication (40).

We strongly feel that these basic principles should guide every practitioner working with every patient with type 2 diabetes to ensure optimal care in their individual circumstance with an overall aim of reducing the proportion of patients who do not achieve control of diabetes with its asso-



ciated comorbidities and complications from current levels of more than 60% (41,42). Putting into consideration the local concerns mentioned above, our group supports the ADA/EASD consensus algorithm. Our aim is to highlight specific barriers in the Arab world and to adapt these recommendations to be more consistent with local circumstances in our countries.

Acknowledgments:

The Egyptian Diabetes Center, with a support from Les Laboratoires Servier, made this work possible. We are grateful to Dr. Richard Kahn, Chief Scientific & Medical Officer of the ADA for his continuous & sincere support.

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L O C A L A R T I C L E S


Expected decrease in A1C

(%)Advantages Disadvantages

Step 1 : Initial Therapy

Lifestyle : Diet & Exercise 1–2 Low costMany benefits

Poor complianceFails in most cases

Metformin 1.5 Weight neutralInexpensive

GI side effects Contraindications(renal, hepatic, heart failure) Lactic acidosis (very rare)

2 : Additional TherapyStep

Insulin 1.5–2.5

No dose limit EffectiveInexpensive(except analogues)Improves lipids

Daily injectionsFrequent glucose monitoringHypoglycemiaWeight gain

Sulfonylureas 1.5 Effective , Inexpensive

Weight gainHypoglycemia*

TZDs 0.5–1.4Improved lipid profileLower monotherapy failure

Fluid retentionWeight gainFractures in womenExpensive

Other Therapy

Alpha-glucosidase inhibitors 0.5–0.8 Weight neutralFrequent GI side effectsDosing before each mealExpensive

Exenatide 0.5–1.0 Weight loss

Daily injectionsFrequent GI side effectsExpensiveLittle experience

Glinides 1–1.5 Short duration Dosing before each mealExpensive

Pramlintide 0.5–0.7 Weight loss

Dosing before each mealFrequent GI side effectsExpensiveLittle experience

DPP-IV Inhibitors 0.6–0.8 Well toleratedWeight neutral

ExpensiveLittle experience

Table 1—Summary of Antidiabetic Interventions as Monotherapy, Adapted From Nathan Etal. (13).


*Severe hypoglycemia is relatively infrequent with sulfonylurea therapy. Chlorpropamide, glyburide,

glibenclamide are more likely to cause hypoglycemia than glipizide, glimepiride and gliclazide MR .


Figure 1. Algorithm For Management Of Type 2 Diabetes

Newly Diagnosed Type 2 Diabetes

Lifestyle + Metformin*

Lifestyle, Metformin+

SU

Lifestyle, MetforminSU+

Basal Insulin

Lifestyle, Metformin +

TZD

Lifestyle, MetforminTZD

+SU

Lifestyle, MetforminTZDSU+

Basal Insulin


Basal Insulin


Intensive Insulin

LifestyleMetformin

TZDIntensive Insulin

Rei

nfor

ce L

ifes

tyle

mea

sure

s at

Eac

h St

ep

* If fasting glucose > 250 mg/dl, instead of using metformin as initial therapy, it would be reasonable to use sulfonylurea,

sulfonylurea plus metformin or insulin as initial therapy.


Figure 1 - Algorithm for the management of type 2 diabetes. The middle path of the algorithm is highlighted as the preferred course by consensus. Therapy should be advanced along one of the pathways provided based on patient, provider and health care system preferences every 1-3 months until the A1C is under 7%. If A1C testing is not readily available, premeal glucose levels between 70 and 130 mg/dl and postprandial levels less than 180 mg/dl should provide a similar level of control.

Documents

EASD Clinical Summer1 2007