Among the early symptoms of Alzheimer disease is the degradation of the orientating senses in space as it was discovered by an american study that was published in The Archives of Neurology.

This study, made by the researchers of the Kansas University, is demonstrating that the degradation of other mental capabilities can be early symptoms of the Alzheimer disease. One of this is the orientation in space that involves, for example, the interpretation of a map or the capacity to solve the cube of Rubick.

We all know that the lost of memory is the first symptom of the Alzheimer disease but this is one of the last symptoms that appears.

This study is also demonstrating that the loss of memory appears 1 year before the diagnostication of the disease. The degradation of the visual and space orientation skills appears 3-4 years before the diagnostication of this malady.

Other symptoms are very common and we are not aware of them, symptoms like disorders of language, substituting unusual words.

The disorders of mood, when we rapidly pass from a calm mood to anger, apparently without reason, is one of the most common early symptoms of the Alzheimer disease.

From this symptom is only a step to the next one, the personality disorders. The ones that are affected by Alzheimer may become suspicious, even with the best friends and with the family members, they can fear of something without reason or they can depend of a family member.

The continue drowsiness, the refusals to perform the daily activities, are part of the early symptoms.

The ones that are affected by Alzheimer will have difficulties of solving the daily tasks, as paying the bills, handling the money; judgment disorders that will make them to take wrong decisions.

Is recommended to schedule a consultation at the doctor when these symptoms appear in a range of 2 weeks or when symptoms like attention disorder, confusion and the loss of memory can determine injuries of the affected person.

No one has discovered yet all the causes of this disease and because of this there is no treatment for it. The doctors are making researches to develop a vaccine against Alzheimer, although there are minimal chances to find one in the close future.

There are only medications that are preventing the appearance of other disorders on the patients affected by Alzheimer

Alzheimer disease tends to evolve slowly. If symptoms like confusion or other changes in mental abilities are installed suddenly, within days or hours, the problem may be delirium tremens, a condition that requires emergency treatment.

The recommended specialist doctors that can offer you a consult are the psychiatrist, the family doctor, the neurologist and the geriatrics.

No one has discovered yet all the causes of this disease and because of this there is no treatment for it. The doctors are making researches to develop a vaccine against Alzheimer, although there are minimal chances to find one in the close future.

There are only medications that are preventing the appearance of other disorders on the patients affected by Alzheimer

Cholestatic liver disease or  primary biliary cirrhosis is an autoimmune liver disease  which leads to a process of progressive destruction of the bile canaliculi (small bile ducts) within the liver.  As a consequence of the destruction of these  ducts,  cholestasis occurs (bile builds up in the liver ) and in time the hepatic tissue is being damaged. This process will lead to hepatic fibrosis and cirrhosis. This disease affects to 1 in 3-4,000 people and it affects women more frequently than men, the sex ratio being around  9:1 (women to men).

The signs and symptoms of cholestatic liver disease are mainly common to all the chronic liver diseases.

Fatigue occurs in about 65% of the patients with cholestatic liver disease and in many cases is the first reported symptom. It exacerbates after meals and it may be associated with sleep abnormalities such as excessive daytime somnolence probably due to the disturbance of the  hypothalamic-pituitary-adrenal axis. Depression and obsessive-compulsive behavior may also be associated to this symptom.

Pruritus (itching) may occur in any liver disease but it occurs more commonly in primary biliary cirrhosis and in sclerosing cholangitis. In
some patients with  cholestatic liver disease the generalized itching may limit normal activities, lead to sleep deprivation, and it may a major impact on the overall quality of life. The pruritus, especially if severe may lead to skin excoriations which may become superinfected. The pathogenesis of pruritus is not well known but it seems to be related to the increased central opioidergic tone.

The patients with cholestatic liver disease will also have a higher risk of acquiring an infection. There have been performed many studies showing that incidence of bacterial infections in these patients is very high, and the incidence of nosocomial bacterial infection (infection acquired while being admitted into a hospital) is much higher than in the general population. It appears that these patientstend to develop many infections determined by gram-negative bacilli especially in the patients who have decreased gastric motility. This change (the decreased gastric motility) will lead to changes in the intestinal flora which will increase the risk of gram-negative bacteremia, through the disruption of the intestinal permeability barrier. Another cause which may predispose to bacterial translocation is gut wall edema, hypoalbuminemia and ascites fluid.

Cachexia and malnutrition are seen in many  patients with primary biliary cirrhosis. There are many factors contributing to the development of this sign: malabsorption of nutrients due to the intestinal edema, diarrhea the decreased bile flow, and the reduced hepatic deposits of  hydrosoluble vitamins. Anorexia results from fatigue and nausea, and the early satiety due to ascites , the decreased gastric emptying, and the psychological discomfort determined by the frequent hospitalizations will lead to a poor food intake. Moreover, the patients with primary biliary cirrhosis have an impaired intermediary metabolism as a result of increased  levels of proinflammatory cytokines and the altered balance of the hormones maintaining the metabolic homeostasis.

Other clinical manifestations of cholestatic liver disease are right upper quadrant discomfort (pain or tenderness -10%), hepatomegaly (increased size of the liver-25%), splenomegaly (spleen larger than normal -9%), hyperpigmentation (25%), xanthomas (cholesterol deposits seen in the palmar creases or above the eyes- 10%), and jaundice (10%).

Parkinson's disease is a motor system disorder, which is the result of the destruction of dopamine-producing neurons. The four major symptoms of Parkinson disease consist in tremor, ( trembling in arms, hands, legs, jaw) stiffness of the arms, legs and trunk (rigidity); bradykinesia, (the slowness of movement); and postural instability (impaired balance and lack of coordination). As the disease progresses and the symptoms become more obvious, patients will have trouble walking, talking, or completing simple tasks. Parkinson disease usually occurs people over 50 but there have been reported cases of early onset Parkinson disease.
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Early symptoms of Parkinson disease are subtle and develop gradually, going unnoticed even for years and the speed with whic the disease progresses varies from one patient to another.  As the disease progresses, the tremor, which affects Most of the Parkinson Disease patients,  may begin to interfere with their daily routine.  The tremor is characteristic: a rest tremor ( with a maximal intensity when the limb is resting and it disappears with voluntary movement and sleep); which it consists in a pronation - supination movement that is described as "pill-rolling" or "coin counting". Tremor affects in a greater extent the distal part of the limb and at the onset of the disease is usually unilateral.

Rigidity, determined by the muscular hypertonia (increased muscle tone) and articular stiffness, combined with the tremos produces a the typycal "cogwheel rigidity" a ratchety type of rigidity which occurs when the limb is passively moved. Joint pain may occur, frequently representing the first sign of the disease.

Bradykinesia (the slowness of movement) and akinesia (the absence of movement) will also occur as the disease aggravates. Bradykinesia is the most specific clinical aspect of Parkinson disease and it impairs not only the execution of a voluntary movement but also it affects the planning and the initiation of movement The performance simultaneous or sequential movements is also affected.The amplitude of the movements decreases too. Motor blocks, or gait freezing are a specific manifestation of akinesia . It represents a sudden episode of inability to move the feet and legs lasting  less than 10 seconds. Its intensity and duration may increase cluttered spaces usually when the patient approaches a destination.

The speech and the swallowing are also impaired, Parkinson Disease leading to : soft speech (hypophonia), monotonic speech (hoarse, soft speech), Drooling (determined by a weak swallow)most likely caused by a weak, infrequent swallow. The difficulties to swallow (dysphagia); which occurs in Parkinson Disease is probably determined either by an inability in initiating the swallowing reflex or by an impaired laryngeal or oesophageal movement (prolonged swallowing movements).

The neuropsychiatric features are either determined by the disease (dementia, loss of short term memory, difficulties in: differential allocation of attention,  set shifting, prioritizing and impulse control) or are a consequence of the impact hat the disease has on the patient's life and the life of his/her family (depression).

Most people with kidney disease are asymptomatic (have no symptoms) or may present with nonspecific complaints such asanorexia, fatigue and malaise. Because of this, many patients present to a specialist only when advanced kidney disease has developed. More specific symptoms of kidney disease include hypertension, nocturia, polyuria, hematuria (blood in urine), edema, or dark-colored urine. A medical history of diabetes and hypertension has an important diagnostic value. A history of recurrent urinary tract infections or kidney stones or a family history of kidney disease is also very important and should be mentioned when seeking medical advice.

High blood pressure or hypertension is very important because there is a vicious cycle between hypertension and kidney disease. Hypertension leads to arterial and capilar damage and blood vessels, and when this affects the arteries and capilaries inside the kidney, the kidney ability to remove properly the excess sodium and water from the body. As sodium and water accumulate, the blood pressure is raised even further,leading to an increased damage to the kidneys and so on.

Edema, or the swelling of the body parts, is also an important sign of kidney disease. The edema in kidney disease presents as a facial swelling and a puffy aspect of the skin around the eyes upon awakening, or swelling of the feet and ankles. Edema is a common symptom of other conditions as well, this being the reason why kidney problems may be overlooked. When the kidneys are distressed, they are unable to eliminate the excess of water and the toxins efficiently. As the amount of water in the body increases edema occurs, as the water infiltrates the subcutaneous tissue (the tissue under the skin).


Fatigue may be another early symptom of kidney disease. This symptoms occurs because the production of erythropoetin, a hormone which stimulates the production of red blood cells. The red blood cells transport the oxygen throughout the body. If the kidneys are impaired, the production of erythropoetin decreases and the number of erythrocytes (red blood cells) declines causing a condition named anemia, leading to hypoxia and a loss of energy.

Another  early sign of kidney disease is represented by the changes in the volume of urine eliminated daily (the urinary output). These changes include the need to urinate more frequently or less often or waking up during sleep. A low output of urine when still feeling the need to urinate accompanied by change in urine color, should determine one to go to a specialist immediately.

Phosphorus, which is normally eliminated in the urine, accumulates in the  body of  the patients with kidney failure. The build up of phosphorus chemical compounds may cause the skin to itch. Bad breath or bad taste in the mouth may also be determined by kidney disease because of the urea and waste products (resulted from the proteic metabolism) which may accumulate in the saliva.

Hirsutism, acne, chronic anovulation with consequent menstrual disorders are symptoms speciffically associated with disorders affecting androgen hormones production and metabolism in adolescent girls. In both the prepubertal boys and girls the androgen excess leads to premature pubarche ( the early development of pubic and axillary hair, acne, and/or adult-type apocrine odor which occurs before the age of eight years in girls and nine in boys.

Hyperandrogenemia is generally determined by the excessive androgen secretion by the adrenal gland's cortex, by the ovaries (in girls), or testes (in boys). Other clinical manifestations of hyperandrogenemia are represented by menstrual disorders, the enlargement of the clitoris, breast atrophy, masculine body habitus, voice changes and male-pattern baldness. The magnitude of the signs and symptoms of androgen excess are not always correlated with the serum androgen concentrations.

The symptoms of polycystic ovary disease usually begin around menarche . Premature pubarche, the result of early secretion of adrenal steroids, may be heralding the following disturbances. Almost 80% of the girls with polycystic ovary disease first notice the hirsutism.

Hirsutism representss the presence of excessive  hair growth which appears in a male pattern in women.It usually presents as the appearance of coarse terminal hairs in areas known as androgen-dependent in a female. The parents and the patients often consider hirsutism as a strictly cosmetic problem and may postpone seeing a physician.



The women with polycystic ovary disease often have a LH hypersecretion which commonly leads to chronic anovulation which most often manifests as oligomenorrhea (less than nine menses with a reduced menstrual flow per year) or amenorrhea. An increased risk of endometrial hyperplasia may occur due to these menstrual abnormalities.  There should be made a difference between primary amenorrhea and secondary amenorrhea. Primary amenorrhea represents the absence of menarche (the first period) by the age of 16 in the presence of normally developed breast and pubic hair.

The absence of menses for three  months (consecutively) after a period or regular (relatively regular) menses represents secondary amenorrhea. The anovulatory cycles may have as a consequence dysfunctional uterine bleeding and lead to a decreased fertility and later in life miscarriage or ectopic pregnancy can occur due to the endometrial abnormalities

A great amount of women with polycystic ovary disease are overweight; even obese. Even though obesity is not considered to be the most relevant feature of the disease, the excess weight can lead to an exacerbation of the associated metabolic disturbances characterising the disease.

The teenage  and adult women with polycystic ovary disease have a higher risk to develop the metabolic syndrome. This syndrome consists of a wide range of disturbances including hypertension, insulin resistance, and dyslipidemia.  The insulin resistance will lead to an increased risk for impaired glucose tolerance and diabetes mellitus type 2.

Phenylketonuria (PKU disease) is an autosomal recessive genetic disorder which determines a deficiency in the enzyme named phenylalanine hydroxylase, necessary in the metabolism of phenylalanine. If phenylalanine hydroxylase is deficient, phenylalanine will accumulate and it will be converted into phenylpyruvate. The degree of enzyme deficiency, and as a consequence, the severity of the disease depends on the specific mutation and it varies among patients. At the moment, there is no cure for this disease, but some treatments are available.

The early diagnosis of the disease is very important and a genetic routine screening should be performed in every newborn , because at birth most newborns with the disease are clinically normal and do not display any . The clinical features of PKU disease will become obvious over several months as phenylalanine and phenylpyruvirate accumulates.

The typical sign of untreated PKU disease is severe mental retardation. Children also tend to be hyperactive and may develop a rash similar to infantile eczema. Albinism may occur due to the impaired synthesis of melanin (the pigment that gives the colour of the skin, eyes and hair) , but it may go unnoticed in the milder forms of the disease when the babies are considered to have blonde hair and blue eyes.

Other signs of nervous system function disturbances may be more subtle such as more active muscle tendon reflexes and an increased muscle toneor be more obvious such as seizures.

The untreated children may also have: microcephaly (smaller than normal head), proeminent zygomatic and maxilar bones, widely spaced teeth, poor development of tooth enamel, a delayed growth. With treatment and a good dietary control, the disease impact on the physical and mental development are minimized. Recent studies however indicate that the loss of dietary control during chilcdhood can have a great impact on cognitive development. These studies show that the people with PKU should maintain a strict dietary control throughout their lifetime. If development problems arise and dietary causes are suspected an intervention should be instituted as soon as possible

The excess of phenylacetic acid in perspiration leads to a specific odour of the babies diagnosed with the PKU disease. This smell has been described as musty or mousey.

The dermatological features of the disease are: an eczematoid skin rash, coarse skin and reduced pilosity. Other skin problems are represented by dry skin and severe itching.

The women with PKU disease who want to have a baby must to follow the PKU diet in order to avoid the high levels of phenilalanine which may affect the future physical and mental development of the fetus but they should also get enough nutrients to support the fetus.

Scurvy is a  serious disease determined by vitamin C defficiency , a substance of extreme importance in the synthesis of collagen. The impaired collagen syntetis results in the weakening of the small blood vessels (capillaries), which causes , bleeding of the gums, loosening of the teeth and tissue hemorrages with consequent anemia, fatigue and general debility. The disease has been mentioned in ancient documents (Hippocrates) , but the discovery of the link between the diet and the disease has not been made until the experiences of the 18 th century sailors have been studied. The simple observation that  the consumption of fresh fruit helped to prevent the disease was made by James Lind in his book, A Treatise of the Scurvy (1753)

Nowadays scurvy still occurs primarily in teenagers with anorexia or in the elderly, isolated individuals with alcoholism.

The main vitamin C deficiency sign is represented by the impaired production and maintenance of collagen, affecting all fibrous tissues: the matrix of cartilages, the matrix of the bones, the dentine and the vascular endothelium (the non-epithelial structures). As a result the capilaries will develop an increased permeability to the red blood cells, leading to hemorrhages. As the disease progresses, affecting the collagen from the bone matrix, the formation of new bone tissue is stopped but the bone absorption keeps going on and so the bones will become more fragile and friable at the growing ends. The impaired collagen formation will also affect the skin, leading to and increased time for wound healing and an increased risk of infection. In other situations, the collagen structures formed due to the process of wound healing will be absorbed and the wounds will reopen.

Other important symptoms of the disease are the gradual weakening, sunken eyes, tender gums, even loosening and loss of teeth , pain in the skeletal muscles,  and internal bleeding leading to anemia and its symptoms.

Psoriasiform hyperplasia is a characteristic dermatological clinical aspect of scurvy accompanied by the pallor of the lower half of the epidermis.Other dermatological manifestations of the disease are: a rash determined by tiny bleeding spots around the hair follicles, hyperkeratosis and the fact that the skin of the people with scurvy bruises easily.

In the more advanced stages of the disease more symptoms occur. The general edema and oligurai are determined by kidney damage.

Bone involvement is a typical sign for infantile scurvy. The bone becomes brittle with consequent microscopic fractures of the spicules between the shaft and calcified cartilage. Subperiosteal hemorrhage will also occur, because these microscopic fractures loosen the periosteum.

Petechial hemorrhage of the skin and mucous membranes may occur, but only in the severe cases, signs of severe internal bleeding (hematuria, hematochezia, and melena ) have been documented.

HBSC disease or sickle-cell disease, (also known as sickle-cell anaemia, siclemia, or drepanocytosis), is a life-long hemoglobinopathy characterized bya biochemical lesion consisting in the replacement of the glutamic acid from the sixth position of the beta chain of hemoglobin with valin, resulting a new type of hemoglobin, with new properties, and so, the red blood cells will have an abnormal, sickle shape. This form has as a consequence a decreased cell flexibility and a risk of various complications. The life expectancy in people with siclemia is shortened, and the studies performed have reported an average life expectancy of 42 years for men and 48 years for women. The disease is determined by a mutation in the hemoglobin gene.

The symptoms of HbSC disease (or sickle-cell disease) depend on whether the patient is homozygot for the mutated gene or not.

The heterozygotic form is usually asymptomatic , the carriers being accidentally discovered on the ocasion of medical investigations for other conditions. There should be known that in some situations such as diving or general anaesthesia thrombosis may occur, leading to infarction affecting virtually any organ.

The homozygotic form has the signs and symptoms determined by two causes: hemolysis and occlusion.

The hemolysis determines the chronic hemolytic anemia which is responsible of the aspect of the characteristic aspec of the children with HbSC disease: short body, long legs and arms, lumbar lordosis and cranial abnormalities. The jaundica is variable, depending on the degree of hemolysis. The spleen does not develop normally due to the reccurent infarctions and in adult life the atrophy and fibrosis will lead to a condition called autosplenectomy.

Almost 30% of the patients will also develop pigmentary gallstones. In these cases the cholecistectomy ia not indicated, unless the colic pain occurs.  The differential diagnosis in this case must be made between the pain produced by acute cholecystitis and the pain from cholelithiasis determined by siclemia.

Splenomegaly may occur if the HbSC disease is associated with other blood disorders.

The occlusion ofthe blood vessels may affect any organ or tissue, leading to infarction. The vaso-occlusive crisis is determined by the sickle-shaped red blood cells  obstructing the capillaries and restricting the blood flow to a tissue or organ, resulting in pain and ischemia leading to organ damage. The severity and duration of these crises vary considerably.

Another classic form of sickle crisis is the acute chest syndrome, a syndrome characterised by fever, dyspnea (shortness of breath) , chest pain and pulmonary infiltrate on a chest X ray. Given the fact  that pneumonia and sickling in the lung have all these symptoms the patient should be  treated for both conditions. This syndrome may be triggered by respiratory infections,  atelectasis, opiate administration, bone-marrow embolisation, or , possibly, by surgery.

Hashimoto's thyroiditis, Hashimoto's disease or chronic lymphocytic thyroiditis are medical terms reffering to a thyroid autoimmune disorder in which the body's own T-cells attack the folicular thyroid cells. Hashimoto's disease is the first documented autoimmune disease and it is considered to be the most common cause of hypothyroidism in the United States where almost 2 in 1000 people develop this disease. This disorder affects far more  women than men ( 20 :1), and its prevalence peaks between 45 and 65 years of age. In Europe a form of atrophic autoimmune thyroiditis is more frequent than Hashimoto's disease.


The underlying specific immune mechanisms of systemic destruction of the thyroidian cells has not been clearly determined. There has been documented the presence of various autoantibodies may be present against TSH receptors and thyroglobulin even though a small percentage of the people who develop the disease may not have these antibodies. Another small percentage of the general population may have these antibodies in their blood but without ever developing the disease. Many patients have a family history of thyroid disorder and the studies have shown that the incidence of the disease is increased in the people with chromosomial disorder, especially 21 trisomy (Down's syndrome), X trisomy , Klinefelter's syndrome, X monosomy (Turner Syndrome)



The disease has an insidious onset and it consists in a slow, constant destruction of the thyroid cells resulting in the gland's inability to produce sufficient thyroid hormone - hypothyroidism. During the course of the disease there may be periods when the thyroid function may spike, even leading to a temporary hyperthyroidism, followed invariably by returns to hypothyroidism. These variations and bouncing between hypothyroidism and hyperthyroidism is a characteristic feature of Hashimoto's disease. So, for example, periods specific to hyperthyroidism with symptoms such as anxiety, insomnia, diarrhea, weight loss may be followed by depression, fatigue, constipation and weight gain.

Many patients do not have any  symptoms and seek medical assistance just because of the specific sign of the disorder - the goiter.  The goiter (the gradual enlargement of the thyroid gland) is usually asymptomatic and painless, but in some cases the patients complain of a feeling of local pressure, voice changes (hoarseness) and dysphagia (pain or difficulty while swallowing).
In the early stages of the disease depression and anxiety may occur but an underlying depression may also be aggravated by Hashimoto's disease.



The disease leads to hypercolesterolemia (high colesterol levels) with consequent predisposition to heart disease but heart disease may be determined also by the impact of the low levels of thyroid hormones on the cardiac activity, leading to contraction and rhythm disorders.Other clinical features of the disease are dry brittle hair and nails, hair loss, osteoarticular pain, insomnia, fatigue and weight changes.

The severity of the disease may decrease during pregnancy and there have also been documented very few cases of thyroid disorders in pregnant women, due to the fact that the immune system is slightly depressed during pregnancy in order to protect the fetal development. However, during the postpartum period the disease may increase in severity in the post partum period. There should be known that hypothyroidism may affect fetal development, leading to an increased risk of miscarriage or malformations (such as cleft lip or cleft palate) or to an impaired psychomotor development and a lower IQ.

The disorders affecting the gallbladder and the biliary tract are extremely common. The main role of the gallbladder  and biliary tract is to transport the bile into the intestine, which is essential for the digestion and absorbtion of fat. The symptoms of gallbladder disease are determined not only by the disease but also by the impact of the disease on normal digestion.

The most common gallbladder disorder is represented by gallstones, and some studies studies performed in the USA and Europe, have shown that about 15% of adults have gallstones. Most people with gallstones do not have any symptom (about 60%), in up to 30% of the people biliary colic or chronic cholecystitis will occur, and almost 15%  will develop acute complications. The main cause of all the clinical features of gallstone disease is represented by the obstruction of the biliary tract, obstruction which may occur at any level of biliary tract ( the cystic duct, common hepatic duct, common bile duct or ampulla of Vater).

The symptoms occur due to the contraction of the gallbladder during a transient obstruction by gallstones, but a persistent obstruction  leads to an inflammation or an infection of the gallbladder leading to consequent acute colecystitis. Biliary colic represents the common symptom of gallbladder disease and it presents as an intermittent pain which occurs in the right-upper quadrant. The other symptoms may be  nonspecific and include: nausea and vomiting .

Chronic cholecystitis refers to the "nonacute" symptoms determined by the presence of gallstones over a longer period of time (days or even years). Biliary pain is represented  typically by a steady ache in the epigastric region or in hte right upper quadrant, with a sudden onset.  Nausea and vomiting may occur, as well as  nonspecific symptoms such as dyspepsia, fatty food intolerance, heartburn, bloating and flatulence.



Acute cholecystitis consists in the distention, inflammation, edema and secondary infection of the gallbladder, as a result of the obstruction of the biliary tract by gallstones, by cancer or  by sludge. The characteristic clinical feature of acute cholecystitis is the acute onset of pain in the right upper quadrant, lasting for several hours. The severity of the pain increases, and the pain tends to localize to the epigastrium or right hypochondrium radiating to the right lumbar, scapular areas.  Other common features are nausea, vomiting and mild fever and in some cases a mild jaundice may be observed.

Acute (suppurative) cholangitis is a life-threatening infection and inflammation of the biliary tract determined by choledocholithiasis. The classic clinical manifestation are Charcot's triad : abdominal pain,  fever and jaundice. This disorder is a medical/surgical emergency and if untreated it has a fast evolution towards sepsis, shock, and death.

Primary sclerosing cholangitis is an idiopathic condition  which consists in a chronic inflammatory fibrosis and consequent obliteration of the hepatic bile ducts. The clinical manifestations of primary sclerosing cholangitis are various and range from asymptomatic patients with abnormal levels of liver enzymes  to recurrent  fever,  abdominal pain, chills, and jaundice.