Jaslok Hospital and Research Centre,
Today, we are in a position where we can manage most of the acute complications associated with diabetes quite adequately. Unfortunately, the same cannot be said about the long term complications. The commonest cause of death in a person with diabetes over the age of thirty is still from cardiovascular disease especially coronary artery disease. Peripheral vascular disease in association with diabetic neuropathy is a major cause of foot problems in India. In fact, lower limb amputations due to diabetes associated complications ranks only second to accidents. 5% of all diabetics may go on to become legally blind and after cataracts, diabetes eye disease is the leading cause for this blindness. The kidneys may be commonly involved in diabetes and some studies have shown that one out of every three to four patients undergoing dialysis or a renal transplant has diabetes.
Whilst it is true that with the help of modern day medical facilities, one can treat many of these complications, this is not without a tremendous socio-economic consequence and even then one cannot be sure of success. Personally, I feel that trying extremely hard to manage the severe long term problems is a little like trying to buy the best possible lock for the house after everything there has been stolen. I feel that the best management for these long term complications would be to try and prevent them in the first place or at least try and diagnose the presence of these complications in the early stages.
This brings us to very important questions. Firstly, can the long term problems associated with diabetes be prevented? Secondly, how are these complications to be diagnosed at an early stage? The latter question brings up another question. Even if we do diagnose the complications at an early stage, is there anything we can do to either reverse these complications or at least retard the development of these complications so that they do not reach a severe stage and remain at a level at which they do still allow a patient to live a basically "normal" life?
There are a few authorities who feel that there is nothing that one can do to avoid the long term complications. They feel that these complications are a "part and parcel" of the diabetes syndrome and that the very genes that predispose one to diabetes also makes one prone to the complications. In other words, there is nothing that the patient or his doctor can do to avoid the complications and that this is basically in the "stars" of the patient, The genes of the patient not only predispose the patient to the complications but also determine the severity of these complications.
This is not a view that is universally shared. Most authorities feel that it is in our "hands" to do something about these complications. It is widely accepted that the presence and the severity of the complications is determined by the degree of control of the blood glucose levels. The higher the levels of the blood glucose, the greater are the chances of the diabetic getting the complications. The severity of the hyperglycemia and the duration to which the body is exposed to high blood glucose levels will also determine the extent of these complications. In other words it is in our "hands" to prevent the complications or at least retard their progression so that they tend to remain at a mild level. In view of these directly opposite views, what is the real situation?
Without going into any more controversial aspects, I feel that there is enough evidence before us to feel that the chronic complications have both, a genetic as well as an environmental component. Whilst genes may predispose a diabetic to these complications, there must be the presence of additional "environmental" factors which together determine the onset, progression and severity of the long term complications. In the rare person, the genetic propensity to get these complications to a severe degree is so strong that even the slight presence of environmental factors may cause the patient to get these severe complications. Conversely, there are those rare patients who have such a mild genetic trend to get these problems, that even a large amount or the environmental factors may allow them to escape from these complications. People at these two extremes are a miniscule portion of the diabetic populations and as far as the vast majority of the patients are concerned, their genes confer on them a certain amount of susceptibility but they require the presence of environmental factors to get the complications especially to any significant extent.
Since, we are not in a position to alter the genetic background of the patient, it becomes essential that we understand these environmental factors so that controlling them can help in preventing or alleviating the long term complications. Thus, one can say that the answer lies both in our "stars" and in our "hands"!
Incidently, I am often asked whether that miniscule portion of diabetics who seem to be immune to the chronic complications can be delineated. The reason being that such patients can be left quite well alone without insisting on an optimal control. Unfortunately, at the present times we do not have in our means the capacity to pick out these patients. In any case, the number of such patients is so small that one would come across a very few of these patients even in a fully diabetes practice. We should be more concerned with the vast majority of patients in whom the management and optimal control of the environmental factors is of utmost importance.
Before we consider these environmental factors, let us see whether it is possible to reverse the complications once they have set in. Here again there seems to be some sort of a controversy but the general consensus is that it may be possible to revert the complications if they are diagnosed at the early stages and corrective measures taken. In later stages, once the long term complications have set in to a severe extent, it may not be plausible to completely revert the complications. I am not convinced that this is true for all the complications. I have seen a number of patients who come with "burning" feet and who get a significant relief with adequate nutrition and optimal control. Even if all the other complications may not revert back completely to normal, it is true that we can definitely arrest the progression or at least slow down the rate of progression of the complications and thereby better the quality of life of the patient as well as prolong the life.
I have always referred to the non-genetic factors as "environmental". This is with a definite purpose in mind. We are often under the mistaken notion that diabetes control is the same as control of the blood glucose levels. This is a fallacy. Although blood glucose control is one of the most important aspects of diabetic control, there are other significant risk factors to which a person with diabetes is prone and which definitely contribute to the long term complications. Thus, excellent diabetes management not only means that the blood glucose levels would be optimally controlled, but also other risk factors will have to be adequately and optimally managed.
What are these "environmental" risk factors?
First, let us consider the management of the blood glucose levels. These should be "optimal", but what level constitutes an optimal control? Ideally, the blood glucose levels should approximate normal throughout the 24 hours. Such a tight control may not be feasible with the currently available means in our hands without exposing the patient to some risk. Therefore, one has to opt for optimal control. Although the values that constiute optimal control would vary according to the individual and the circumstances, one can generalise and say that the fasting blood glucose levels should be below 120gm%, the 2 hour postmeal level should be below 160mg%, with the blood glucose levels remaining below this value throughout the 24 hours. The glycosylated hemoglobin level should be within the acceptable range. I would like to make it clear that these values are just generalisations that may not hold good for every individual patient. As an example, I would feel that these values would be too high for a pregnant diabetic or those who may be on the verge of losing their eyesight due to macular edema. Conversely, in a 80 year old man without any other major problem, these values may be thought of as being a little too rigorous. Thus, whilst these values would need to be adjusted for every patient, they would still hold good for the vast majority.
I do not intend to discuss in detail in this section how these optimal values are to be achieved. But I will only touch upon those aspects of the management which may have a direct bearing on the long term complications. In trying to achieve optimal control, it is very important that the patient is not exposed to repeated and/or severe episodes of hypoglycemia. It is now well established that such episodes of hypoglycemia may bring about a start of, or a rapid progression of, the very long term complications that we are trying to avoid.
Another aspect about the management of the blood glucose levels is that one should avoid bringing down the levels of the blood glucose too rapidly unless there is a definite reason for this. Often, efforts are made to bring the blood glucose down very rapidly by using heavy doses of medications and putting the patient on severely restricted diets. This can precipitate problems. It is known that such therapeutic manoevres can lead to problems like burning neuropathies!
In order to achieve "tight" control, a few doctors are offering what I would term as a completely indiscriminate use of the so-called insulin "pumps". 1 have extensively used these insulin pumps as a research method and agree with the general consensus that in their present forms they are associated with too many complications including death, for them to be allowed to be used routinely on our patients. In so far as the long term complications only are concerned, they are associated with an unacceptable level of hypoglycemic reactions and interestingly, in a initial study carried out abroad, the prevalence of retinopathy increased when patients are put on the pump inspite of what was felt to be a better control!
One of the other major risk factor that we see often in a diabetic is the increase in the levels of the triglycerides and the LDL-cholesterol associated with a decrease in the HDL-cholesterol levels. The latest recommendations state that in adults with diabetes, the optimal LDL-C level is less than 100 mg/dL and the optimal HDL-C level is more than 45 mg/dL; triglyceride levels of less than 200 mg/dL are desirable. You will realize that these recommendations are much more stringent than those evolved in the past. A few years back, levels of LDL-C greater than 160mg% were considered as being in the "high risk" category. Levels between 130 and 159mg% were in the "borderline risk" category whilst levels of LDL-C below the 139mg% value are felt to be safe. Levels of HDL-C below 35mg% were are considered to be in the "high risk" category for the development of atherosclerosis. It has been shown that even changes of as small a magnitude as 5-10mg% in the HDL-C levels will bring about significant change in the relative risk involved.
It was also felt in the past that fasting triglyceride levels below 250mg% were safe and should not merit active therapy unless the associated levels of LDL-C were more than 160mg% Levels, between 250mg% and 500mg% were considered "borderline" high whilst those above 500% are considered as being in the "high risk" category. I do not accept these values and feel that the serum triglycerides should be kept below the 200mg% mark at the very least. In fact, for a diabetic patient, active efforts must be made to lower the TG values as much as is possible and I feel that the aim of treatment should be to lower the TG levels to around 150mg%, especially in view of the recent evidence that TG itself is an independent risk factor for macrovascular disease.
Hypertension is much more common in a person with diabetes, often being a part of the so-called "metabolic syndrome". It is an extremely important risk factor in the pathogenesis the long term complication especially, nephropathy, retinopathy and cardiovascular disease. All patients who have high blood pressure should have this normalised. At one time it was felt that maintaining the blood pressure at 140/90 would be adequate, but now we know that in a person with diabetes, one should aim for a blood pressure reading of 120/80. This is very crucial as we tend to get so involved at looking at the blood glucose levels that we often ignore what we feel is just a slightly raised blood pressure levels.
I usually ask patients who have hypertension to keep a meter at home so that they can closely monitor the blood pressure levels themselves.
The role of controlling the hypertension should never be minimised. Even those doctors who feel that long term diabetic complications can reach a level of "no return", in the sense that the complication will relentlessly progress irrespective of the blood glucose control, believe that controlling the blood pressure will still be of immense help in retarding the progression. Diabetic nephropathy is a case in point. It is essential that the blood pressure be controlled irrespective of the stage of the renal involvement. This can help in retarding the progression of the nephropathy.
Even if the patient does not have high blood pressure at the initial examination, this should be evaluated at every opportunity. Often, the slight rise in the blood pressure may be the first indication of involvement of the kidneys. More commonly, a sudden appearance of high blood pressure in a patient who is usually normotensive may be a clue to the presence of subclinical hypoglycemia and allow us to take adequate preventive measures to avoid precipitating a complete and severe attack of hypoglycemia. I feel that the blood pressure should be recorded in the lying down, sitting and the standing positions. The presence of postural hypotension may be the first clue to the involvement of the autonomic nerves in diabetes.
At the same time, it should be clear that the management of hypertension in a diabetic is not very simple. Without going into details about the drugs that should be used to manage the hypertension, I will only say that the drugs have to be chosen very carefully as many of the drugs have side effects which affect blood glucose control or even the long term complications themselves! It may not be easy to control the hypertension in a diabetic, but it is definitely possible and the benefits that the patient gets from this control far outweigh the trouble that doctors have to take to control the raised blood pressure.
The management of hypertension is a patient with diabetes is discussed in a separate chapter.
The weight of the diabetic should be optimal. I have discussed this aspect in detail in the section dealing with diet therapy and will only mention here that the best parameter to judge the optimal body weight is to use the Body Mass Index, and the Waist-Hip ratio.
The sex, age, and the duration of diabetes are other risk factors over which we do not have much control. The environmental factors that I have discussed till now are those what I would term as "general" factors having an impact on many of the long term complications. There are risk factors which are relatively specific for some of the chronic complications and I will discuss these in the next section where I will also describe how the long term complications are diagnosed at an early stage.
We are very fortunate that we are in a position to directly look at the retinal blood vessels. Consequently, there can really be no excuse for not being able to diagnose retinal changes at the very early stages. When diabetic retinopathy sets in, one of the earliest changes seen is the presence of microaneurysms. These represent areas of weakness in the smallest of the blood vessels and can be seen quite distinctly as small red dots through the ophthalmoscope. If the aim is to diagnose diabetic retinopathy at an early stage, then it is at this point that the diagnosis should be made. When retinopathy progresses, other changes can be seen but as we are concentrating on the early changes, these will not be alluded to here.
The macula is an area of the retina very near the optic disc. It seems to be devoid of blood vessels but is one of the most important areas of the retina as it is responsible for "central" vision. One can well understand the role of central vision if one reflects that if the macula is affected and one tries to see or read anything, the very central part on which the eyes would focus would appear either distorted or as a black spot! When the vessels surrounding the macula are affected by diabetic microangiopathy the condition is known as diabetic maculopathy or diabetic macular edema. I consider this as an acute emergency and immediate corrective steps need to be taken to rectify the problem.
As I have mentioned before, there is really is no valid reason why one should not be able to diagnose diabetic retinopathy at the initial stages as we are in a position to look directly at the retinal vessels. All newly diagnosed patients should undergo a thorough check for the presence of retinopathy. If there is no evidence of retinopathy, then careful attention should be paid to the risk factors that we have discussed above so that one could try and avert the onset of retinal changes. I usually insist that all patients even though they show no changes of diabetic retinopathy, must have a complete evaluation of their retina at yearly intervals. It is obvious that if there is already the presence of retinal changes, one would need to keep a more frequent check on the retinal status even though the appropriate corrective measures are taken and the risk factors corrected.
Often when I ask patients whether they have their eyes examined, they say that their eyes have been examined recently. What they usually mean is that they have had their vision checked to see if they need "glasses" or if there is a change in the "number". Such an examination in no way examines the retina and therefore, it is essential that the patient be told what a retinal examination means. They must also be told that it is possible that the doctor who examines the eyes may put some drops in them and that the vision would be blurred for a few hours. Therefore, it would be better for them to be accompanied by someone and it is obvious that they should not be driving a car!
I have discussed how the macula is so important and that any problems affecting this area should be considered as an emergency. When the retina is examined, the macular area would also be looked at. But the next examination may be a year away and what happens if there is any problem in the meantime. Often the initial signs and symptoms may be very subtle and in my opinion, most of the patients who have macular problems come to us at a relatively late stage when the chance of normalising the vision may be that much harder. I usually give patients an Amslers Chart which they can use to test for macular vision. This chart is given alongside. I ask the patients to test central vision daily or at least twice a week and to seek immediate attention if there seems to be any problem. I have found that this is an extremely useful chart and allows the patient to be diagnosed at the every early stages of macular involvement.
1. Look at the square (grid).
2. Wear your reading glasses (if you use one) and cover one eye.
3. Focus on the center dot for one full minute.
4. While looking directly at the center, be sure that all the lines are straight and clear, and all the small squares are the same size.
5. Repeat the test in the other eye.
6. If any lines or squares appear distorted, wavy, blurred, discolored, or otherwise abnormal, call your eye doctor right away.
7. In healthy eyes the lines are straight.
The Amsler's chart is very useful for early detection of macular problems and thus is very important as this may be an early sign of macular problems and lead to a loss of central vision! But one must know its limitations.The Amsler grid will NOT detect proliferative diabetic retinopathy, most preproliferative changes and other types of damage that may threaten vision, nor is it useful for detecting any of the early changes. Remember: a normal Amsler grid test does not rule out the presence of retinopathy that can threaten your vision.It cannot replace routine eye exams. Only regular eye exams can do this.
As we are discussing vision changes, it should also be realised that many patients complain of some blurring of their vision in the initial two to three weeks of their therapy. This does not imply that the, patient is getting retinal changes but is mostly a consequence of the lowering of the blood glucose levels and this usually corrects itself in a couple of weeks. Finally, blurring of vision may be a manifestation of hypoglycemia and this should always be ruled out.
Meticulous management of the risk factors and an early diagnosis would go a long way towards averting diabetic retinopathy or retarding the progression of the retinal changes even if one is not able, to revert the changes that have occurred.
Unlike the retina, where we are in a position to look directly at the blood vessels, one has to rely on laboratory tests to detect the early signs of diabetic nephropathy. This is the detection of albuminuria. Even normally, a person excretes about 5 micrograms of albumin per minute in his urine. With incipient diabetic nephropathy, the amount of albumin that the patient excretes in the urine increases and this should alert us to the possibility of diabetic kidney disease.
Incipient nephropathy is the stage of microalbuminuria;
Microalbuminuria is defined as albumin excretion rate:
Albumin excretion can be estimated through the following methods:
|24 hour collection||Timed collection||Spot collection|
|mg / 24 hours||ug / min||ug/mg Creatinine|
Although dipsticks are available to detect microalbumin levels, they are costly. It may be worthwhile to do a spot or timed collection of urine and then see the albumin to creatinine ratio to judge the level of renal involvement.
In the absence of methods to routinely look for the presence of microalbuminuria, the use of dipsticks to look for albumin in the urine must suffice to warn of the presence of diabetic nephropathy, and it is esential that this test routinely and frequently be carried out in all diabetic patients.
Unfortunately, our routine method of detecting the presence of albumin in the urine is not very sensitive and by the time albumin can be detected even by the use of the "dipstick", the amount of albumin excreted is around 150 micrograms per minute. Before this level is reached, the albumin excreted by the patient is not detectable by the routine methods and is termed "microalbuminuria". As our aim is to catch the presence of disease at the very early stages, it would be better for the diabetic to be diagnosed at the microalbuminuric stage.
It should be clear that there are numerous causes for the presence of albumin in the urine and diabetic nephropathy is only one of these. Therefore, if albumin is found in the urine of a diabetic, it should not be taken to mean that the patient has nephropathy. I usually ask my patients to repeat the test after a few days and only if this positive, then I investigate to rule out the other more common causes of albuminuria. The most frequent cause of albuminuria is any infection in the urinary tract although any generalised infection in the body can cause albuminuria. Hypertension, cardiac failure and indeed drugs used in the management of these two conditions are also known to lead to albuminuria. Even in a diabetic, one should always keep in mind that the renal involvement may be due to a non-diabetic cause. Even otherwise, a very poorly controlled diabetic may show an increased excretion of albumin in the urine without signifying diabetic nephropathy. This usually corrects itself after adequate control. Many people show a positive test after exercise and importantly, although this is not well known, drinking a large amount of water may increase the albumin excretion. Many a patient when he has to go for a test where he will need to give a urine sample, drinks a large amount of water so as to be able to give the sample without any problem, without realising that this act in itself may increase the amount of albumin in the urine. It should be mentioned that this is usually seen if something like two or three big glasses of water are rapidly drunk. It should also be remembered that many young people normally excrete albumin in the upright position. In other words there are numerous causes of an increase in the urinary albumin excretion and all these have to be ruled out before one accepts the possibility that the albuminuria could be due to diabetic nephropathy.
Incipient diabetic nephropathy (diabetic microalbuminuria) should only be diagnosed when seen to be present on repeat testing and when other causes of raised urinary albumin have been excluded. I feel that checking for microalbumin levels and especially repeat testing is usually not feasible in most cases. I usually start the patient on a small dose of an ACE inhibitor or an Angiotensin Receptor Blocker (ARB) or a combination of both irrespective of whether the patient has hypertension or not. There is overwhelming evidence to suggest that the use of these agents can reverse the early or incipient diabetic nephropathy or at the very least slow down significantly the progression.
Along with these measures there are certain other aspects that need close attention. These are factors that worsen the prognosis in diabetic nephropathy unless they are avoided or treated in time. By themselves the factors may appear trivial but they may add up over the years and avoiding them may make the crucial difference between the patient who remains at a stage where there is just albuminuria as compared to reaching a stage of full blown renal failure where life can be maintained only with dialysis or renal transplant. The first important factor is infection of the urinary tract. This is detrimental to the diabetic kidney and the best solution to this is early detection and adequate management. Although such infections may be suspected from symptoms like burning micturation, dysuria, passing small but frequent urine, mild infections of the urinary tract may go unnoticed and may only be detected when the complete urine examination is done. Urinary tract infections are more common in diabetics. Besides the fact that poorly controlled diabetics, in general, have a tendency to infections, long- standing diabetics, have some degree of autonomic neuropathy which leads to bladder atony, incomplete emptying and stagnation of some urine. This coupled with the presence of glucose in the urine of poorly controlled diabetics favors the growth of bacteria and infection. The stagnation of the urine also makes it that much more difficult to eradicate any infection.
I usually ask my patients, especially women who are more prone to chronic urinary tract infections, to have a complete urine examination done every three months or so irrespective of whether these have any signs and symptoms of urinary infection or not. If there is any evidence of infection, then I ask for a culture and sensitivity and treat the infection until the urine is sterile. In patients who are prone to recurrent urinary infections, the antibiotic to which the organism is sensitive may be continued in a small nighttime dose for a prolonged period. This often helps in avoiding frequent infections. The patient may also need to be taught methods which will help in a more complete emptying of the bladder. Occassionally drugs may be of some aid and in very severe case surgery may be required especially in male patients who may have some degree of an enlarged prostate that makes complete emptying of the bladder difficult.
Two other aspects which also may seem quite trivial in themselves but may have important implications in patients with incipient nephropathy are "water deprivation" arid drugs and medicines which may have an adverse effect on the kidneys. It is absolutely essential that there should be adequate hydration. It is well known that dehydration can adversely affect the kidney. That is the reason why all diabetics should always be asked to drink an adequate amount of water so that normal quantities of urine are passed. I ask my patients to drink a glass of water at bedtime and to have some liquids on waking up. A problem that arises in our country is the fasts that people keep, especially those types of fasts where even water is not allowed. This in my opinion is harmful to some extent to a diabetic kidney, but one can only firmly advise in this matter as questions of religion are involved.
But one area where doctors can definitely do something is regarding the advise we give the patient when they have to go for their blood tests. Often the patients are asked to go fasting and are told to have nothing from 10pm the previous night. By the time the patient finishes giving the blood it often happens that more than 12 hours have elapsed without any liquid intake. I have never understood the reason for not allowing the patient to have even water. I have come across no evidence that having a glass of water in the morning would in any significant manner affect the test results! Unfortunately, this standing instructions to go completely fasting have become the "order of the day" and is accepted without question. The problem even gets worse when the patient has to go for an X-ray examination on a fasting stomach. By the time these tests are over, more than 12-14 hours may have elapsed without water. Whenever my patient is called for an X-ray in the fasting stage, I usually make it a point to inquire whether even a glass of water would affect the quality of the X-rays. If this is so, then I insist that my patient be taken up first in preference to other non-diabetics. I also instruct the patient to have more than the normal amount of water the previous night. I am not implying that one occassion that the patient stays without water for about 12 hours will cause a renal shutdown, but when there is no need to be without water and when one knows that dehydration can harm the diabetic kidney, is it not better to take all precautions to avoid even mild dehydration? If one thinks of the number of times that we ask patients to go fasting for something or the orther, and one can well imagine the these small "insults" to the kidneys may well add up! And it is so simple to avoid these insults.
The third aspect is the use of drugs that have the potential to be toxic to the kidneys. Some drugs should be avoided completely in patients with nephropathy whilst the dose of some other drugs needs to be carefully adjusted depending on the state of the renal function. It would be worthwhile to avoid the use of these drugs in cases with diabetic nephropathy especially if safer alternatives are available. Here again one may feel that occassionally taking a drug with a potential for renal toxicity may not have a significant effect on the final outcome of the renal disease, but these "minor" matters do add up and if one can avoid taking even these-minor risks, I really cannot find a valid reason for not doing so.
It of course goes without saying that optimal control of the glucose levels and the hypertension, if present to as close to 120/80, Is of utmost importance.
Involvement of the nerves in diabetes seems to be the commonest long term diabetic complication. It has been estimated that after several years of diabetes, most of the patients would have some involvement of the nerves although this may vary in severity between patients. I think that diabetic neuropathy is so common that I have discussed the clinical manifestations of diabetic neuropathy in a separate chapter.
In view of the fact that some degree of nerve affection is so common, a question is often asked whether it is possible to avoid neuropathy. This is obviously a very difficult question to answer, except to point out that a smooth and gradual control of the blood glucose levels to an optimal level, along with adequate attention to nutrition would help in retarding the onset and/or progression of the diabetic neuropathy. This is a very important point as it is often noticed that when the blood glucose levels are brought down very rapidly, and this is associated with a severely curtailed diet and frequent and/or severe episodes of hypoglycemia, one sees the start of or the rapid progression in the severity of the neuropathy.
It is absolutely essential to look for even the slightest evidence of neuropathy especially if this is accompanied by some degree of hypoesthesia or anaesthesia. Although this may only seem a minor irritant in itself, it prediposes the patient to foot problems. The prevention of foot problems is of utmost importance.
One simple method which should be routinely used is the use of the Monofilament test as shown above.
Sensation threshold screening using a 10 gram monofilament(also known as Semmes-Weinstein monofilament)
|1. Use the 10g monofilament to test sensation.|
|2. The sites to be tested are indicated on the foot diagram below.|
|3. Apply the filament perpendicular to the skin's surface ( see Diagram A).|
|4. The approach, skin contact and departure of the monofilament should be approximately 1.5 seconds duration.|
|5. Apply sufficient force to allow the filament to bend ( see Diagram B)|
|6. Do not allow the filament to slide across the skin or make repetitive contact at the test site.|
|7. Randomise the order and timing of successive tests.|
|8. Do not apply to an ulcer site, callous , scar or necrotic tissue.|
|The circles represent the places on the foot to test with the monofilament|
|Consider your feet to be "at risk" if you cannot feel the 10gm monofilament at any of the sites marked.|