<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Marchiafava–Bignami disease and can you explain it in depth? [/INST] Marchiafava–Bignami disease is a progressive neurological disease of alcohol use disorder, characterized by corpus callosum demyelination and necrosis and subsequent atrophy. The disease was first described in 1903 by the Italian pathologists Amico Bignami and Ettore Marchiafava in an Italian Chianti drinker. In this autopsy, Marchiafava and Bignami noticed that the middle two-thirds of the corpus callosum were necrotic. It is very difficult to diagnose and there is no specific treatment. Until 2008 only around 300 cases had been reported. If caught early enough, most patients survive.

Symptoms and signs
Symptoms can include, but are not limited to lack of consciousness, aggression, seizures, depression, hemiparesis, ataxia, apraxia, coma, etc. There will also be lesions in the corpus callosum.

Causes
It is classically associated with chronic alcoholism especially with red wine consumption and sometimes associated nutritional deficiencies. Alcohol use disorder can also cause thiamine deficiency, which is also observed to cause MBD.

Mechanism
Individuals with MBD usually have a history of excessive alcohol consumption, but this is not always the case. The mechanism of the disease is not completely understood, but it is believed to be caused by a Vitamin B deficiency, malnutrition, or alcohol use disorder. The damage to the brain can extend into neighboring white matter and sometimes go out as far as subcortical regions.

Diagnosis
Marchiafava–Bignami disease is routinely diagnosed with the use of an MRI because the majority of clinical symptoms are non-specific. Before the use of such imaging equipment, it was unable to be diagnosed until autopsy. The patient usually has a history of alcohol use disorder or malnutrition and neurological symptoms are sometimes present and can help lead to a diagnosis. MBD can be told apart from other neural diseases due to the symmetry of the lesions in the corpus callosum as well as the fact that these lesions dont affect the upper and lower edges.There are two clinical subtypes of MBD
Type A- Stupor and coma predominate. Radiological imaging shows involvement of the entire corpus callosum. This type is also associated with symptoms of the upper motor neurons.Type B- This type has normal or only mildly impaired mental status and radiologic imaging shows partial lesions in the corpus callosum.

Treatment
Treatment is variable depending on individuals. Some treatments work extremely well with some patients and not at all with others. Some treatments include therapy with thiamine and vitamin B complex. Alcohol consumption should be stopped. Some patients survive, but with residual brain damage and dementia </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Pyostomatitis vegetans and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Syringocystadenoma papilliferum and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Meibomian gland dysfunction and can you explain it in depth? [/INST] Meibomian gland dysfunction (also known as MGD) is a chronic disease of the meibomian glands, which is commonly characterized by obstruction of the end of the duct that delivers the secretion produced by the glands (called meibum) to the eye surface,  which prevents the glandular secretion to reach the ocular surface. The dysfunction could be that the amount of secretion produced may be abnormal (either too little or too much meibum produced). Dysfunction could also be related to the quality of the meibum produced. MGD may result in evaporative dry eye, blepharitis, chalazion, unsealed lid during sleep, and meibomian gland atrophy.MGD causes the glands to be obstructed by thick, cloudy-to-yellow, more opaque and viscous-like, oily and waxy secretions, a change from the glands normal clear secretions. Besides leading to dry eyes, the obstructions can be degraded by bacterial lipases, resulting in the formation of free fatty acids, which irritate the eyes and sometimes cause punctate keratopathy. MGD has been described as "the most underrecognized, underappreciated and undertreated disease in ophthalmic care [...] so common as to be taken as ‘normal’ in many clinical practices".The dysfunction is more often seen in women, and is regarded as the main cause of dry eye syndrome. Factors that contribute to the dysfunction can include things such as a persons age and/or hormones, or severe infestation of Demodex brevis mites.
Treatment can include warm compresses to thin the secretions and eyelid scrubs with baby shampoo or eyelid cleanser, or emptying ("expression") of the gland by a professional. Lifitegrast and Restasis are topical medication commonly used to control the inflammation and improve the oil quality. In some cases topical steroids and topical (drops or ointment)/oral antibiotics (to reduce bacteria on the lid margin) are also prescribed to reduce inflammation.  Intense pulsed light (IPL) treatments have also been shown to reduce inflammation and improve gland function.  Meibomian gland probing is also used on patients who experience deep clogging of the glands.
The dysfunction may be caused by some prescription medications, notably isotretinoin. A blocked meibomian gland can cause a meibomian cyst known as a chalazion to form in the eyelid.
Untreated blepharitis or MGD makes the eyes look red and puffy as if the person have been drinking or have a substance abuse problem.

Classification
MGD can be classified based on gland secretion. MGD can be low delivery and high delivery </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Lymphangiomatosis and can you explain it in depth? [/INST] Lymphangiomatosis is a condition where a lymphangioma is not present in a single localised mass, but in a widespread or multifocal manner. It is a rare type of tumor which results from an abnormal development of the lymphatic system.It is thought to be the result of congenital errors of lymphatic development occurring prior to the 20th week of gestation. Lymphangiomatosis is a condition marked by the presence of cysts that result from an increase both in the size and number of thin-walled lymphatic channels that are abnormally interconnected and dilated. 75% of cases involve multiple organs. It typically presents by age 20 and, although it is technically benign, these deranged lymphatics tend to invade surrounding tissues and cause problems due to invasion and/or compression of adjacent structures. The condition is most common in the bones and lungs and shares some characteristics with Gorham’s disease. Up to 75% of patients with lymphangiomatosis have bone involvement, leading some to conclude that lymphangiomatosis and Gorham’s disease should be considered as a spectrum of disease rather than separate diseases. When it occurs in the lungs, lymphangiomatosis has serious consequences and is most aggressive in the youngest children. When the condition extends into the chest it commonly results in the accumulation of chyle in the linings of the heart and/or lungs.Chyle is composed of lymph fluid and fats that are absorbed from the small intestine by specialized lymphatic vessels called lacteals during digestion. The accumulations are described based on location: chylothorax is chyle in the chest; chylopericardium is chyle trapped inside the sack surrounding the heart; chyloascites is chyle trapped in the linings of the abdomen and abdominal organs. The presence of chyle in these places accounts for many of the symptoms and complications associated with both lymphangiomatosis and Gorham’s disease. The incidence of lymphangiomatosis is unknown and it is often misdiagnosed. It is separate and distinct from lymphangiectasis, lymphangioleiomyomatosis (LAM), pulmonary capillary hemangiomatosis, Kaposi’s sarcoma, and kaposiform hemangioendothelioma. Its unusual nature makes lymphangiomatosis (and Gorham’s disease) a diagnostic and therapeutic challenge. A multidisciplinary approach is generally necessary for optimal diagnosis and symptom management. The term literally means lymphatic system (lymph) vessel (angi) tumor or cyst (oma) condition (tosis).

Signs and symptoms
Lymphangiomatosis is a multi-system disorder. Symptoms depend on the organ system involved and, to varying degrees, the extent of the disease. Early in the course of the disease patients are usually asymptomatic, but over time the abnormally proliferating lymphatic channels that constitute lymphangiomatosis are capable of massive expansion and infiltration into surrounding tissues, bone, and organs. Because of its slow course and often vague symptoms, the condition is frequently under-recognized or misdiagnosed.Early signs of disease in the chest include wheezing, cough, and feeling short of breath, which is often misdiagnosed as asthma. The pain that accompanies bone involvement may be attributed to "growing pains" in younger children. With bone involvement the first indication for disease may be a pathological fracture. Symptoms may not raise concern, or even be noted, until the disease process has advanced to a point where it causes restrictive compression of vital structures. Further, the occurrence of chylous effusions seems to be unrelated to the pathologic "burden" of the disease, the extent of involvement in any particular tissue or organ, or the age of the patient. This offers one explanation as to why, unfortunately, the appearance of chylous effusions in the chest or abdomen may be the first evidence of the disease.Following are some of the commonly reported symptoms of lymphangiomatosis, divided into the regions/systems in which the disease occurs:

Heart and chest
Symptoms that arise from disease of the cardiothoracic region include a chronic cough, wheezing, dyspnea (shortness of breath)—especially serious when occurring at rest or when lying down—fever, chest pain, rapid heartbeat, dizziness, anxiety, and coughing up blood or chyle. As the deranged lymphatic vessels invade the organs and tissues in the chest they put stress on the heart and lungs, interfering with their ability to function normally. Additionally, these lymphatic vessels may leak, allowing fluid to accumulate in the chest, which puts further pressure on the vital organs, thus increasing their inability to function properly. Accumulations of fluid and chyle are named based on their contents and location: pulmonary edema (the presence of fluid and/or chyle in the lung), pleural effusions (fluid in the lung lining), pericardial effusions (fluid in the heart sack), chylothorax (chyle in the pleural cavity); and chylopericardium (chyle in the heart sack).

Abdominal
Lymphangiomatosis has been reported in every region of the abdomen, though the most reported sites involve the intestines and peritoneum; spleen, kidneys, and liver. Often there are no symptoms until late in the progression of the disease. When they do occur, symptoms include abdominal pain and/or distension; nausea, vomiting, diarrhea; decreased appetite and malnourishment. When the disease affects the kidneys the symptoms include flank pain, abdominal distension, blood in the urine, and, possibly, elevated blood pressure, which may result in it being confused with other cystic renal disease. When lymphangiomatosis occurs in the liver and/or spleen it may be confused with polycystic liver disease. Symptoms may include abdominal fullness and distension; anemia, disseminated intravascular coagulopathy (DIC), fluid accumulation in the abdomen(ascites), decreased appetite, weight loss, fatigue; late findings include liver failure.

Bones
Symptoms of lymphangiomatosis in the skeletal system are the same as those of Gorham’s disease. Frequently asymptomatic, skeletal lymphangiomatosis may be discovered incidentally or when a pathological fracture occurs. Patients may experience pain of varying severity in areas around the effected bone. When the disease occurs in the bones of the spine, neurological symptoms such as numbness and tingling may occur due to spinal nerve compression. Progression of disease in the spine may lead to paralysis. Lymphangiomatosis in conjunction with Chiari I malformation also has been reported.

Causes
The cause of lymphangiomatosis is not yet known. As stated earlier, it is generally considered to be the result of congenital errors of lymphatic development occurring prior to the 20th week of gestation.  However, the root causes of these conditions remains unknown and further research is necessary.

Diagnosis
Because it is rare and has a wide spectrum of clinical, histological, and imaging features, diagnosing lymphangiomatosis can be challenging. Plain x-rays reveal the presence of lytic lesions in bones, pathological fractures, interstitial infiltrates in the lungs, and chylous effusions that may be present even when there are no outward symptoms.The most common locations of lymphangiomatosis are the lungs and bones and one important diagnostic clue is the coexistence of lytic bone lesions and chylous effusion. An isolated presentation usually carries a better prognosis than does multi-organ involvement; the combination of pleural and peritoneal involvement with chylous effusions and lytic bone lesions carries the least favorable prognosis.When lung involvement is suspected, high resolution computed tomography (HRCT) scans may reveal a diffuse liquid-like infiltration in the mediastinal and hilar soft tissue, resulting from diffuse proliferation of lymphatic channels and accumulation of lymphatic fluid; diffuse peribronchovascular and interlobular septal thickening; ground-glass opacities; and pleural effusion. Pulmonary function testing reveals either restrictive pattern or a mixed obstructive/restrictive pattern.  While x-rays, HRCT scan, MRI, ultrasound, lymphangiography, bone scan, and bronchoscopy all can have a role in identifying lymphangiomatosis, biopsy remains the definitive diagnostic tool.Microscopic examination of biopsy specimens reveals an increase in both the size and number of thin walled lymphatic channels along with lymphatic spaces that are interconnecting and dilated, lined by a single attenuated layer of endothelial cells involving the dermis, subcutis, and possibly underlying fascia and skeletal muscle. Additionally, Tazelaar, et al., described a pattern of histological features of lung specimens from nine patients in whom no extrathoracic lesions were identified, which they termed "diffuse pulmonary lymphangiomatosis" (DPL).Recognition of the disease requires a high index of suspicion and an extensive workup. Because of its serious morbidity, lymphangiomatosis must always be considered in the differential diagnosis of lytic bone lesions accompanied by chylous effusions, in cases of primary chylopericardium, and as part of the differential diagnosis in pediatric patients presenting with signs of interstitial lung disease.

Treatment
There is no standard approach to the treatment of lymphangiomatosis and treatment often is aimed at reducing symptoms. Surgical intervention may be indicated when complications arise and a number of reports of response to surgical interventions, medications, and dietary approaches can be found in the medical literature.Unfortunately, there is no standardized treatment for lymphangiomatosis and no cure.
Treatment modalities that have been reported in the medical literature, by system, include:

Heart and chest
Thoracocentesis, pericardiocentesis, pleurodesis, ligation of thoracic duct, pleuroperitoneal shunt, radiation therapy, pleurectomy, pericardial window, pericardiectomy, thalidomide, interferon alpha 2b, Total Parenteral Nutrition (TPN), medium chain triglyceride (MCT) and high protein diet, chemotherapy, sclerotherapy, transplant;

Abdominal
interferon alpha 2b, sclerotherapy, resection, percutaneous drainage,  Denver shunt, Total Parenteral Nutrition (TPN), medium chain triglyceride (MCT) and high protein diet, transplant, splenectomy;

Bone
Interferon alpha 2b, bisphosphonates (i.e. pamidronate), surgical resection, radiation therapy, sclerotherapy, percutaneous bone cement, bone grafts, prosthesis, surgical stabilization.

Epidemiology
Lymphangiomatosis can occur at any age, but the incidence is highest in children and teenagers. Signs and symptoms are typically present before the age of 20 and the condition is often under-recognized in adults.It affects males and females of all races and exhibits no inheritance pattern. The medical literature contains case reports from every continent.Because it is so rare, and commonly misdiagnosed, it is not known exactly how many people are affected by this disease.

References
Further reading
Dellinger M. T., Garg N, Olsen B.R. (2014). "Viewpoints on vessels and vanishing bones in Gorham-Stout disease". Bone. 63C: 47–52. doi:10.1016/j.bone.2014.02.011. PMID 24583233.{{cite journal}}:  CS1 maint: multiple names: authors list (link)
Trenor C, Chaudry G (Aug 2014). "Complex lymphatic anomalies" </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Phthisis bulbi and can you explain it in depth? [/INST] Phthisis bulbi is a shrunken, non-functional eye. It may result from severe eye disease, inflammation or injury, or it may represent a complication of eye surgery. Treatment options include insertion of a prosthesis, which may be preceded by enucleation of the eye.

Symptoms
The affected eye is shrunken, and has little to no vision. The intraocular pressure in the affected eye is very low or nonexistent </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Paraneoplastic cerebellar degeneration and can you explain it in depth? [/INST] Paraneoplastic cerebellar degeneration (PCD) is a paraneoplastic syndrome associated with a broad variety of tumors including lung cancer, ovarian cancer, breast cancer, Hodgkin’s lymphoma and others. PCD is a rare condition that occurs in less than 1% of cancer patients.
As is the case with other paraneoplastic syndromes, PCD is believed to be due to an autoimmune reaction targeted against components of the central nervous system, mostly to Purkinje cells.It is thought to be triggered when tumor cells (in PCD, most commonly ovarian or breast cancer) ectopically express proteins normally expressed in the cerebellum </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Sigmoid colon volvulus and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Autoimmune retinopathy and can you explain it in depth? [/INST] Autoimmune retinopathy (AIR) is a rare disease in which the patients immune system attacks proteins in the retina, leading to loss of eyesight. The disease is poorly understood, but may be the result of cancer or cancer chemotherapy. The disease is an autoimmune condition characterized by vision loss, blind spots, and visual field abnormalities. It can be divided into cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR). The condition is associated with retinal degeneration caused by autoimmune antibodies recognizing retinal proteins as antigens and targeting them. AIRs prevalence is extremely rare, with CAR being more common than MAR. It is more commonly diagnosed in females (approximately 60% of diagnosed patients are females) in the age range of 50–60.

Types
Cancer-associated retinopathy
A division of AIR, cancer-associated retinopathy is a paraneoplastic syndrome, which is a disorder caused by an immune system response to an abnormality. Autoimmune antibodies target proteins in retinal photoreceptor cells. The proteins targeted as antigenic are recoverin, α‐enolase and transducin. This autoimmune response leads to photoreceptor cell death. It causes progressive vision loss that can lead to blindness. CAR is typically associated with the anti-recoverin antibody.

Melanoma-associated retinopathy
Retinal bipolar cells (cells in retina that transmit signals) react with the antibodies, leading to cell death. Although it is less prevalent than CAR, diagnosed cases of MAR continue to increase while CAR numbers decrease.

Signs and symptoms
Both CAR and MAR share the same symptoms. This is because they are both paraneoplastic syndromes.  AIR symptoms are numerous and shared by many other diseases.

Diagnosis
Diagnosis of AIR can be difficult due to the overlap of symptoms with other disorders. Examination of the fundus (inner surface of eye) can show no results or it can show narrowing of the blood vessels, abnormal colouration of the optic disc, and retinal atrophy. Fundus examination results are not indicative of autoimmune retinopathy but they are used to initiate the diagnostic process. An electroretinogram (eye test used to see abnormalities in the retina) is used to detect AIR. An abnormal electroretinogram (ERG) with respect to light and dark adaptations indicates AIR. The ERG also allows differentiation between cancer-associated retinopathy and melanoma-associated retinopathy. If the ERG shows cone responses, CAR can be prematurely diagnosed. If the ERG shows a significant decrease in b-wave amplitude, MAR can be prematurely diagnosed. To confirm, analysis for anti-retinal antibodies through Western blotting of serum collected from the patient is done.

Treatment
Due to the difficulty of diagnosis, managing this disease is a challenge. For this reason, there is no established treatment for AIR. Clinicians try to reduce and control the autoimmune system attack to prevent any irreversible retinal damage. Methods of treatment include intravenous immunoglobulin (IVIG), plasmapheresis, and corticosteroids.

Immunoglobulin
Immunoglobulin samples are obtained from a large pool of healthy, matched donors (10000 - 20000). The immunoglobulin mixture is then administered through IV at a rate of 0.4g/kg/day for 5 days. Antibodies in the IVIG mixture interact with binding sites of the disease-associated antibodies (such as anti-recoverin antibodies). This prevents binding to proteins targeted as antigenic and reduces disease activity. Responses to this treatment can vary and are impacted if the patient is diagnosed with any type of cancer. Patients who respond positively show improvement in the clarity of their vision and their visual field.

Plasmapheresis
Plasmapheresis involves separating blood into two parts - blood cells and plasma. The blood plasma components, such as the antibodies, are treated outside of the body </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Boomerang dysplasia and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Atherosclerosis and can you explain it in depth? [/INST] Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no symptoms, but if they develop, symptoms generally begin around middle age. When severe, it can result in coronary artery disease, stroke, peripheral artery disease, or kidney problems, depending on which arteries are affected.The exact cause is not known and is proposed to be multifactorial. Risk factors include abnormal cholesterol levels, elevated levels of inflammatory markers, high blood pressure, diabetes, smoking, obesity, family history, genetic, and an unhealthy diet. Plaque is made up of fat, cholesterol, calcium, and other substances found in the blood. The narrowing of arteries limits the flow of oxygen-rich blood to parts of the body. Diagnosis is based upon a physical exam, electrocardiogram, and exercise stress test, among others.Prevention is generally by eating a healthy diet, exercising, not smoking, and maintaining a normal weight. Treatment of established disease may include medications to lower cholesterol such as statins, blood pressure medication, or medications that decrease clotting, such as aspirin. A number of procedures may also be carried out such as percutaneous coronary intervention, coronary artery bypass graft, or carotid endarterectomy.Atherosclerosis generally starts when a person is young and worsens with age. Almost all people are affected to some degree by the age of 65. It is the number one cause of death and disability in the developed world. Though it was first described in 1575, there is evidence that the condition occurred in people more than 5,000 years ago.

Signs and symptoms
Atherosclerosis is asymptomatic for decades because the arteries enlarge at all plaque locations, thus there is no effect on blood flow. Even most plaque ruptures do not produce symptoms until enough narrowing or closure of an artery, due to clots, occurs. Signs and symptoms only occur after severe narrowing or closure impedes blood flow to different organs enough to induce symptoms. Most of the time, patients realize that they have the disease only when they experience other cardiovascular disorders such as stroke or heart attack. These symptoms, however, still vary depending on which artery or organ is affected.Abnormalities associated with atherosclerosis begin in childhood. Fibrous and gelatinous lesions have been observed in the coronary arteries of children aged 6–10. Fatty streaks have been observed in the coronary arteries of juveniles aged 11–15, though they appear at a much younger age within the aorta.Clinically, given enlargement of the arteries for decades, symptomatic atherosclerosis is typically associated with men in their 40s and women in their 50s to 60s. Sub-clinically, the disease begins to appear in childhood and rarely is already present at birth. Noticeable signs can begin developing at puberty. Though symptoms are rarely exhibited in children, early screening of children for cardiovascular diseases could be beneficial to both the child and his/her relatives. While coronary artery disease is more prevalent in men than women, atherosclerosis of the cerebral arteries and strokes equally affect both sexes.Marked narrowing in the coronary arteries, which are responsible for bringing oxygenated blood to the heart, can produce symptoms such as chest pain of angina and shortness of breath, sweating, nausea, dizziness or light-headedness, breathlessness or palpitations. Abnormal heart rhythms called arrhythmias—the heart beating either too slowly or too quickly—are another consequence of ischemia.Carotid arteries supply blood to the brain and neck. Marked narrowing of the carotid arteries can present with symptoms such as: a feeling of weakness; being unable to think straight; difficulty speaking; dizziness; difficulty in walking or standing up straight; blurred vision; numbness of the face, arms and legs; severe headache; and loss of consciousness. These symptoms are also related to stroke (death of brain cells). Stroke is caused by marked narrowing or closure of arteries going to the brain; lack of adequate blood supply leads to the death of the cells of the affected tissue.Peripheral arteries, which supply blood to the legs, arms and pelvis, also experience marked narrowing due to plaque rupture and clots. Symptoms of the narrowing are numbness within the arms or legs, as well as pain. Another significant location for plaque formation is the renal arteries, which supply blood to the kidneys. Plaque occurrence and accumulation lead to decreased kidney blood flow and chronic kidney disease, which, like in all other areas, is typically asymptomatic until late stages.According to United States data for 2004, in about 66% of men and 47% of women, the first symptom of atherosclerotic cardiovascular disease is a heart attack or sudden cardiac death (death within one hour of onset of the symptom).
Cardiac stress testing, traditionally the most commonly performed non-invasive testing method for blood flow limitations, in general, detects only lumen narrowing of ≈75% or greater, although some physicians claim that nuclear stress methods can detect as little as 50%.Case studies have included autopsies of U.S. soldiers killed in World War II and the Korean War. A much-cited report involved the autopsies of 300 U.S. soldiers killed in Korea. Although the average age of the men was 22.1 years, 77.3 percent had "gross evidence of coronary arteriosclerosis". Other studies done of soldiers in the Vietnam War showed similar results, although often worse than the ones from the earlier wars. Theories include high rates of tobacco use and (in the case of the Vietnam soldiers) the advent of processed foods after World War II.

Risk factors
The atherosclerotic process is not well understood. Atherosclerosis is associated with inflammatory processes in the endothelial cells of the vessel wall associated with retained low-density lipoprotein (LDL) particles. This retention may be a cause, an effect, or both, of the underlying inflammatory process.The presence of the plaque induces the muscle cells of the blood vessel to stretch, compensating for the additional bulk. The endothelial lining then thickens, increasing the separation between the plaque and lumen. The thickening somewhat offsets the narrowing caused by the growth of the plaque, but moreover, it causes the wall to stiffen and become less compliant to stretching with each heartbeat.

Modifiable
Western pattern diet
Abdominal obesity
Insulin resistance
Diabetes
Dyslipidemia
Hypertension
Trans fat
Tobacco smoking
Bacterial infections
HIV/AIDS

Nonmodifiable
South Asian descent
Advanced age
Genetic abnormalities
Family history
Coronary anatomy and branch pattern

Lesser or uncertain
Thrombophilia
Saturated fat
Excessive carbohydrates
Elevated triglycerides
Systemic inflammation
Hyperinsulinemia
Sleep deprivation
Air pollution
Sedentary lifestyle
Arsenic poisoning
Alcohol
Chronic stress
Hypothyroidism
Periodontal disease

Dietary
The relation between dietary fat and atherosclerosis is controversial. The USDA, in its food pyramid, promotes a diet of about 64% carbohydrates from total calories. The American Heart Association,  the American Diabetes Association and the National Cholesterol Education Program make similar recommendations. In contrast, Prof Walter Willett (Harvard School of Public Health, PI of the second Nurses Health Study) recommends much higher levels of fat, especially of monounsaturated and polyunsaturated fat. These dietary recommendations reach a consensus, though, against consumption of trans fats.The role of eating oxidized fats (rancid fats) in humans is not clear.
Rabbits fed rancid fats develop atherosclerosis faster. Rats fed DHA-containing oils experienced marked disruptions to their antioxidant systems, and accumulated significant amounts of phospholipid hydroperoxide in their blood, livers and kidneys.Rabbits fed atherogenic diets containing various oils were found to undergo the most oxidative susceptibility of LDL via polyunsaturated oils. In another study, rabbits fed heated soybean oil "grossly induced atherosclerosis and marked liver damage were histologically and clinically demonstrated." However, Fred Kummerow claims that it is not dietary cholesterol, but oxysterols, or oxidized cholesterols, from fried foods and smoking, that are the culprit.Rancid fats and oils taste very unpleasant in even small amounts, so people avoid eating them.
It is very difficult to measure or estimate the actual human consumption of these substances. Highly unsaturated omega-3 rich oils such as fish oil, when being sold in pill form, can hide the taste of oxidized or rancid fat that might be present. In the US, the health food industrys dietary supplements are self-regulated and outside of FDA regulations. To properly protect unsaturated fats from oxidation, it is best to keep them cool and in oxygen-free environments.

Pathophysiology
Atherogenesis is the developmental process of atheromatous plaques. It is characterized by a remodeling of arteries leading to subendothelial accumulation of fatty substances called plaques. The buildup of an atheromatous plaque is a slow process, developed over a period of several years through a complex series of cellular events occurring within the arterial wall and in response to a variety of local vascular circulating factors. One recent hypothesis suggests that, for unknown reasons, leukocytes, such as monocytes or basophils, begin to attack the endothelium of the artery lumen in cardiac muscle. The ensuing inflammation leads to the formation of atheromatous plaques in the arterial tunica intima, a region of the vessel wall located between the endothelium and the tunica media. The bulk of these lesions is made of excess fat, collagen, and elastin. At first, as the plaques grow, only wall thickening occurs without any narrowing. Stenosis is a late event, which may never occur and is often the result of repeated plaque rupture and healing responses, not just the atherosclerotic process by itself.

Cellular
Early atherogenesis is characterized by the adherence of blood circulating monocytes (a type of white blood cell) to the vascular bed lining, the endothelium, then by their migration to the sub-endothelial space, and further activation into monocyte-derived macrophages. The primary documented driver of this process is oxidized lipoprotein particles within the wall, beneath the endothelial cells, though upper normal or elevated concentrations of blood glucose also plays a major role and not all factors are fully understood. Fatty streaks may appear and disappear.Low-density lipoprotein (LDL) particles in blood plasma invade the endothelium and become oxidized, creating risk of cardiovascular disease. A complex set of biochemical reactions regulates the oxidation of LDL, involving enzymes (such as Lp-LpA2) and free radicals in the endothelium.Initial damage to the endothelium results in an inflammatory response. Monocytes enter the artery wall from the bloodstream, with platelets adhering to the area of insult. This may be promoted by redox signaling induction of factors such as VCAM-1, which recruit circulating monocytes, and M-CSF, which is selectively required for the differentiation of monocytes to macrophages. The monocytes differentiate into macrophages, which proliferate locally, ingest oxidized LDL, slowly turning into large "foam cells" – so-called because of their changed appearance resulting from the numerous internal cytoplasmic vesicles and resulting high lipid content. Under the microscope, the lesion now appears as a fatty streak. Foam cells eventually die and further propagate the inflammatory process.In addition to these cellular activities, there is also smooth muscle proliferation and migration from the tunica media into the intima in response to cytokines secreted by damaged endothelial cells. This causes the formation of a fibrous capsule covering the fatty streak. Intact endothelium can prevent this smooth muscle proliferation by releasing nitric oxide.

Calcification and lipids
Calcification forms among vascular smooth muscle cells of the surrounding muscular layer, specifically in the muscle cells adjacent to atheromas and on the surface of atheroma plaques and tissue. In time, as cells die, this leads to extracellular calcium deposits between the muscular wall and outer portion of the atheromatous plaques. With the atheromatous plaque interfering with the regulation of the calcium deposition, it accumulates and crystallizes.  A similar form of intramural calcification, presenting the picture of an early phase of arteriosclerosis, appears to be induced by many drugs that have an antiproliferative mechanism of action (Rainer Liedtke 2008).Cholesterol is delivered into the vessel wall by cholesterol-containing low-density lipoprotein (LDL) particles. To attract and stimulate macrophages, the cholesterol must be released from the LDL particles and oxidized, a key step in the ongoing inflammatory process. The process is worsened if it is insufficient high-density lipoprotein (HDL), the lipoprotein particle that removes cholesterol from tissues and carries it back to the liver.The foam cells and platelets encourage the migration and proliferation of smooth muscle cells, which in turn ingest lipids, become replaced by collagen, and transform into foam cells themselves. A protective fibrous cap normally forms between the fatty deposits and the artery lining (the intima).These capped fatty deposits (now called atheromas) produce enzymes that cause the artery to enlarge over time. As long as the artery enlarges sufficiently to compensate for the extra thickness of the atheroma, then no narrowing ("stenosis") of the opening ("lumen") occurs. The artery becomes expanded with an egg-shaped cross-section, still with a circular opening. If the enlargement is beyond proportion to the atheroma thickness, then an aneurysm is created.

Visible features
Although arteries are not typically studied microscopically, two plaque types can be distinguished:
The fibro-lipid (fibro-fatty) plaque is characterized by an accumulation of lipid-laden cells underneath the intima of the arteries, typically without narrowing the lumen due to compensatory expansion of the bounding muscular layer of the artery wall. Beneath the endothelium, there is a "fibrous cap" covering the atheromatous "core" of the plaque. The core consists of lipid-laden cells (macrophages and smooth muscle cells) with elevated tissue cholesterol and cholesterol ester content, fibrin, proteoglycans, collagen, elastin, and cellular debris.  In advanced plaques, the central core of the plaque usually contains extracellular cholesterol deposits (released from dead cells), which form areas of cholesterol crystals with empty, needle-like clefts. At the periphery of the plaque are younger "foamy" cells and capillaries. These plaques usually produce the most damage to the individual when they rupture. Cholesterol crystals may also play a role.
The fibrous plaque is also localized under the intima, within the wall of the artery resulting in thickening and expansion of the wall and, sometimes, spotty localized narrowing of the lumen with some atrophy of the muscular layer. The fibrous plaque contains collagen fibers (eosinophilic), precipitates of calcium (hematoxylinophilic), and rarely, lipid-laden cells.In effect, the muscular portion of the artery wall forms small aneurysms just large enough to hold the atheroma that are present. The muscular portion of artery walls usually remains strong, even after they have remodeled to compensate for the atheromatous plaques.However, atheromas within the vessel wall are soft and fragile with little elasticity. Arteries constantly expand and contract with each heartbeat, i.e., the pulse. In addition, the calcification deposits between the outer portion of the atheroma and the muscular wall, as they progress, lead to a loss of elasticity and stiffening of the artery as a whole.The calcification deposits, after they have become sufficiently advanced, are partially visible on coronary artery computed tomography or electron beam tomography (EBT) as rings of increased radiographic density, forming halos around the outer edges of the atheromatous plaques, within the artery wall. On CT, >130 units on the Hounsfield scale (some argue for 90 units) has been the radiographic density usually accepted as clearly representing tissue calcification within arteries. These deposits demonstrate unequivocal evidence of the disease, relatively advanced, even though the lumen of the artery is often still normal by angiography.

Rupture and stenosis
Although the disease process tends to be slowly progressive over decades, it usually remains asymptomatic until an atheroma ulcerates, which leads to immediate blood clotting at the site of the atheroma ulcer.  This triggers a cascade of events that leads to clot enlargement, which may quickly obstruct the flow of blood. A complete blockage leads to ischemia of the myocardial (heart) muscle and damage.  This process is the myocardial infarction or "heart attack".If the heart attack is not fatal, fibrous organization of the clot within the lumen ensues, covering the rupture but also producing stenosis or closure of the lumen, or over time and after repeated ruptures, resulting in a persistent, usually localized stenosis or blockage of the artery lumen. Stenoses can be slowly progressive, whereas plaque ulceration is a sudden event that occurs specifically in atheromas with thinner/weaker fibrous caps that have become "unstable".Repeated plaque ruptures, ones not resulting in total lumen closure, combined with the clot patch over the rupture and healing response to stabilize the clot is the process that produces most stenoses over time. The stenotic areas tend to become more stable despite increased flow velocities at these narrowings. Most major blood-flow-stopping events occur at large plaques, which, before their rupture, produced very little if any stenosis.From clinical trials, 20% is the average stenosis at plaques that subsequently rupture with resulting complete artery closure. Most severe clinical events do not occur at plaques that produce high-grade stenosis. From clinical trials, only 14% of heart attacks occur from artery closure at plaques producing a 75% or greater stenosis before the vessel closing.If the fibrous cap separating a soft atheroma from the bloodstream within the artery ruptures, tissue fragments are exposed and released. These tissue fragments are very clot-promoting, containing collagen and tissue factor; they activate platelets and activate the system of coagulation. The result is the formation of a thrombus (blood clot) overlying the atheroma, which obstructs blood flow acutely. With the obstruction of blood flow, downstream tissues are starved of oxygen and nutrients. If this is the myocardium (heart muscle) angina (cardiac chest pain) or myocardial infarction (heart attack) develops.

Accelerated growth of plaques
The distribution of atherosclerotic plaques in a part of arterial endothelium is inhomogeneous. The multiple and focal development of atherosclerotic changes is similar to that in the development of amyloid plaques in the brain and that of age spots on the skin. Misrepair-accumulation aging theory suggests that misrepair mechanisms play an important role in the focal development of atherosclerosis. Development of a plaque is a result of repair of injured endothelium. Because of the infusion of lipids into sub-endothelium, the repair has to end up with altered remodeling of local endothelium. This is the manifestation of a misrepair. Important is this altered remodeling makes the local endothelium have increased fragility to damage and have reduced repair efficiency. As a consequence, this part of endothelium has an increased risk factor of being injured and improperly repaired. Thus, the accumulation of misrepairs of endothelium is focalized and self-accelerating. In this way, the growing of a plaque is also self-accelerating. Within a part of the arterial wall, the oldest plaque is always the biggest, and is the most dangerous one to cause blockage of a local artery.

Components
The plaque is divided into three distinct components:

The atheroma ("lump of gruel", from Greek  ἀθήρα (athera) gruel), which is the nodular accumulation of a soft, flaky, yellowish material at the center of large plaques, composed of macrophages nearest the lumen of the artery
Underlying areas of cholesterol crystals
Calcification at the outer base of older or more advanced lesions. Atherosclerotic lesions, or atherosclerotic plaques, are separated into two broad categories: Stable and unstable (also called vulnerable). The pathobiology of atherosclerotic lesions is very complicated, but generally, stable atherosclerotic plaques, which tend to be asymptomatic, are rich in extracellular matrix and smooth muscle cells. On the other hand, unstable plaques are rich in macrophages and foam cells, and the extracellular matrix separating the lesion from the arterial lumen (also known as the fibrous cap) is usually weak and prone to rupture. Ruptures of the fibrous cap expose thrombogenic material, such as collagen, to the circulation and eventually induce thrombus formation in the lumen. Upon formation, intraluminal thrombi can occlude arteries outright (e.g., coronary occlusion), but more often they detach, move into the circulation, and eventually occlude smaller downstream branches causing thromboembolism.Apart from thromboembolism, chronically expanding atherosclerotic lesions can cause complete closure of the lumen. Chronically expanding lesions are often asymptomatic until lumen stenosis is so severe (usually over 80%) that blood supply to downstream tissue(s) is insufficient, resulting in ischemia. These complications of advanced atherosclerosis are chronic, slowly progressive, and cumulative. Most commonly, soft plaque suddenly ruptures (see vulnerable plaque), causing the formation of a thrombus that will rapidly slow or stop blood flow, leading to the death of the tissues fed by the artery in approximately five minutes. This event is called an infarction.

Diagnosis
Areas of severe narrowing, stenosis, detectable by angiography, and to a lesser extent "stress testing" have long been the focus of human diagnostic techniques for cardiovascular disease, in general. However, these methods focus on detecting only severe narrowing, not the underlying atherosclerosis disease. As demonstrated by human clinical studies, most severe events occur in locations with heavy plaque, yet little or no lumen narrowing present before debilitating events suddenly occur. Plaque rupture can lead to artery lumen occlusion within seconds to minutes, and potential permanent debility, and sometimes sudden death.Plaques that have ruptured are called complicated lesions. The extracellular matrix of the lesion breaks, usually at the shoulder of the fibrous cap that separates the lesion from the arterial lumen, where the exposed thrombogenic components of the plaque, mainly collagen, will trigger thrombus formation. The thrombus then travels downstream to other blood vessels, where the blood clot may partially or completely block blood flow. If the blood flow is completely blocked, cell deaths occur due to the lack of oxygen supply to nearby cells, resulting in necrosis. The narrowing or obstruction of blood flow can occur in any artery within the body. Obstruction of arteries supplying the heart muscle results in a heart attack, while the obstruction of arteries supplying the brain results in an ischaemic stroke.

Lumen stenosis that is greater than 75% was considered the hallmark of clinically significant disease in the past because recurring episodes of angina and abnormalities in stress tests are only detectable at that particular severity of stenosis.
However, clinical trials have shown that only about 14% of clinically debilitating events occur at sites with more than 75% stenosis. The majority of cardiovascular events that involve sudden rupture of the atheroma plaque do not display any evident narrowing of the lumen.
Thus, greater attention has been focused on "vulnerable plaque" from the late 1990s onwards.Besides the traditional diagnostic methods such as angiography and stress-testing, other detection techniques have been developed in the past decades for earlier detection of atherosclerotic disease. Some of the detection approaches include anatomical detection and physiologic measurement.Examples of anatomical detection methods include coronary calcium scoring by CT, carotid IMT (intimal media thickness) measurement by ultrasound, and intravascular ultrasound (IVUS).  Examples of physiologic measurement methods include lipoprotein subclass analysis, HbA1c, hs-CRP, and homocysteine. Both anatomic and physiologic methods allow early detection before symptoms show up, disease staging, and tracking of disease progression. Anatomic methods are more expensive and some of them are invasive in nature, such as IVUS. On the other hand, physiologic methods are often less expensive and safer. But they do not quantify the current state of the disease or directly track progression. In recent years, developments in nuclear imaging techniques such as PET and SPECT have provided ways of estimating the severity of atherosclerotic plaques.

Prevention
Up to 90% of cardiovascular disease may be preventable if established risk factors are avoided. Medical management of atherosclerosis first involves modification to risk factors–for example, via smoking cessation and diet restrictions.  Prevention then is generally by eating a healthy diet, exercising, not smoking, and maintaining a normal weight.

Diet
Changes in diet may help prevent the development of atherosclerosis. Tentative evidence suggests that a diet containing dairy products has no effect on or decreases the risk of cardiovascular disease.A diet high in fruits and vegetables decreases the risk of cardiovascular disease and death. Evidence suggests that the Mediterranean diet may improve cardiovascular results. There is also evidence that a Mediterranean diet may be better than a low-fat diet in bringing about long-term changes to cardiovascular risk factors (e.g., lower cholesterol level and blood pressure).

Exercise
A controlled exercise program combats atherosclerosis by improving circulation and functionality of the vessels. Exercise is also used to manage weight in patients who are obese, lower blood pressure, and decrease cholesterol. Often lifestyle modification is combined with medication therapy. For example, statins help to lower cholesterol. Antiplatelet medications like aspirin help to prevent clots, and a variety of antihypertensive medications are routinely used to control blood pressure.  If the combined efforts of risk factor modification and medication therapy are not sufficient to control symptoms or fight imminent threats of ischemic events, a physician may resort to interventional or surgical procedures to correct the obstruction.

Treatment
Treatment of established disease may include medications to lower cholesterol such as statins, blood pressure medication, or medications that decrease clotting, such as aspirin. A number of procedures may also be carried out such as percutaneous coronary intervention, coronary artery bypass graft, or carotid endarterectomy.Medical treatments often focus on alleviating symptoms. However measures which focus on decreasing underlying atherosclerosis—as opposed to simply treating symptoms—are more effective. Non-pharmaceutical means are usually the first method of treatment, such as stopping smoking and practicing regular exercise. If these methods do not work, medicines are usually the next step in treating cardiovascular diseases and, with improvements, have increasingly become the most effective method over the long term.The key to the more effective approaches is to combine multiple different treatment strategies. In addition, for those approaches, such as lipoprotein transport behaviors, which have been shown to produce the most success, adopting more aggressive combination treatment strategies taken on a daily basis and indefinitely has generally produced better results, both before and especially after people are symptomatic.

Statins
The group of medications referred to as statins are widely prescribed for treating atherosclerosis. They have shown benefit in reducing cardiovascular disease and mortality in those with high cholesterol with few side effects. Secondary prevention therapy, which includes high-intensity statins and aspirin, is recommended by multi-society guidelines for all patients with history of ASCVD (atherosclerotic cardiovascular disease) to prevent recurrence of coronary artery disease, ischemic stroke, or peripheral arterial disease. However, prescription of and adherence to these guideline-concordant therapies is lacking, particularly among young patients and women.Statins work by inhibiting HMG-CoA (hydroxymethylglutaryl-coenzyme A) reductase, a hepatic rate-limiting enzyme in cholesterols biochemical production pathway. By inhibiting this rate-limiting enzyme, the body is unable to produce cholesterol endogenously, therefore reducing serum LDL-cholesterol. This reduced endogenous cholesterol production triggers the body to then pull cholesterol from other cellular sources, enhancing serum HDL-cholesterol. These data are primarily in middle-age men and the conclusions are less clear for women and people over the age of 70.

Surgery
When atherosclerosis has become severe and caused irreversible ischemia, such as tissue loss in the case of peripheral artery disease, surgery may be indicated. Vascular bypass surgery can re-establish flow around the diseased segment of artery, and angioplasty with or without stenting can reopen narrowed arteries and improve blood flow. Coronary artery bypass grafting without manipulation of the ascending aorta has demonstrated reduced rates of postoperative stroke and mortality compared to traditional on-pump coronary revascularization.

Other
There is evidence that some anticoagulants, particularly warfarin, which inhibit clot formation by interfering with Vitamin K metabolism, may actually promote arterial calcification in the long term despite reducing clot formation in the short term. Also, single peptides such as 3-hydroxybenzaldehyde and protocatechuic aldehyde have shown vasculoprotective effects to reduce risk of atherosclerosis.

Epidemiology
Cardiovascular disease, which is predominantly the clinical manifestation of atherosclerosis, is one of the leading causes of death worldwide.

Etymology
The following terms are similar, yet distinct, in both spelling and meaning, and can be easily confused: arteriosclerosis, arteriolosclerosis, and atherosclerosis.  Arteriosclerosis is a general term describing any hardening (and loss of elasticity) of medium or large arteries (from Greek  ἀρτηρία (artēria) artery, and  σκλήρωσις (sklerosis) hardening); arteriolosclerosis is any hardening (and loss of elasticity) of arterioles (small arteries); atherosclerosis is a hardening of an artery specifically due to an atheromatous plaque (from Ancient Greek   ἀθήρα (athḗra) gruel). The term atherogenic is used for substances or processes that cause formation of atheroma.

Economics
In 2011, coronary atherosclerosis was one of the top ten most expensive conditions seen during inpatient hospitalizations in the US, with aggregate inpatient hospital costs of $10.4 billion.

Research
Lipids
An indication of the role of high-density lipoprotein (HDL) on atherosclerosis has been with the rare Apo-A1 Milano human genetic variant of this HDL protein. A small short-term trial using bacterial synthesized human Apo-A1 Milano HDL in people with unstable angina produced a fairly dramatic reduction in measured coronary plaque volume in only six weeks vs. the usual increase in plaque volume in those randomized to placebo. The trial was published in JAMA in early 2006.  Ongoing work starting in the 1990s may lead to human clinical trials—probably by about 2008.  These may use synthesized Apo-A1 Milano HDL directly, or they may use gene-transfer methods to pass the ability to synthesize the Apo-A1 Milano HDLipoprotein.Methods to increase HDL particle concentrations, which in some animal studies largely reverses and removes atheromas, are being developed and researched. However, increasing HDL by any means is not necessarily helpful. For example, the drug torcetrapib is the most effective agent currently known for raising HDL (by up to 60%). However, in clinical trials, it also raised deaths by 60%.  All studies regarding this drug were halted in December 2006.The actions of macrophages drive atherosclerotic plaque progression.
Immunomodulation of atherosclerosis is the term for techniques that modulate immune system function to suppress this macrophage action.Involvement of lipid peroxidation chain reaction in atherogenesis triggered research on the protective role of the heavy isotope (deuterated) polyunsaturated fatty acids (D-PUFAs) that are less prone to oxidation than ordinary PUFAs (H-PUFAs). PUFAs are essential nutrients – they are involved in metabolism in that very form as they are consumed with food. In transgenic mice, that are a model for human-like lipoprotein metabolism, adding D-PUFAs to diet indeed reduced body weight gain, improved cholesterol handling and reduced atherosclerotic damage to the aorta.

miRNA
MicroRNAs (miRNAs) have complementary sequences in the 3 UTR and 5 UTR of target mRNAs of protein-coding genes, and cause mRNA cleavage or repression of translational machinery. In diseased vascular vessels, miRNAs are dysregulated and highly expressed. miR-33 is found in cardiovascular diseases. It is involved in atherosclerotic initiation and progression including lipid metabolism, insulin signaling and glucose homeostatis, cell type progression and proliferation, and myeloid cell differentiation. It was found in rodents that the inhibition of miR-33 will raise HDL level and the expression of miR-33 is down-regulated in humans with atherosclerotic plaques.miR-33a and miR-33b are located on intron 16 of human sterol regulatory element-binding protein 2 (SREBP2) gene on chromosome 22 and intron 17 of SREBP1 gene on chromosome 17. miR-33a/b regulates cholesterol/lipid homeostatis by binding in the 3UTRs of genes involved in cholesterol transport such as ATP binding cassette (ABC) transporters and enhance or represses its expression. Study have shown that ABCA1 mediates transport of cholesterol from peripheral tissues to Apolipoprotein-1 and it is also important in the reverse cholesterol transport pathway, where cholesterol is delivered from peripheral tissue to the liver, where it can be excreted into bile or converted to bile acids prior to excretion. Therefore, we know that ABCA1 plays an important role in preventing cholesterol accumulation in macrophages. By enhancing miR-33 function, the level of ABCA1 is decreased, leading to decrease cellular cholesterol efflux to apoA-1. On the other hand, by inhibiting miR-33 function, the level of ABCA1 is increased and increases the cholesterol efflux to apoA-1. Suppression of miR-33 will lead to less cellular cholesterol and higher plasma HDL level through the regulation of ABCA1 expression.The sugar, cyclodextrin, removed cholesterol that had built up in the arteries of mice fed a high-fat diet.

DNA damage
Aging is the most important risk factor for cardiovascular problems.  The causative basis by which aging mediates its impact, independently of other recognized risk factors, remains to be determined.  Evidence has been reviewed for a key role of DNA damage in vascular aging.8-oxoG, a common type of oxidative damage in DNA, is found to accumulate in plaque vascular smooth muscle cells, macrophages and endothelial cells, thus linking DNA damage to plaque formation. DNA strand breaks also increased in atherosclerotic plaques.  Werner syndrome (WS) is a premature aging condition in humans </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Supraclavicular lymph nodes and can you explain it in depth? [/INST] Supraclavicular lymph nodes are lymph nodes found above the clavicle, that can be felt in the supraclavicular fossa. The supraclavicular lymph nodes on the left side are called Virchows nodes. It leads to an appreciable mass that can be recognized clinically, called Troisier sign.

Structure
A Virchows node is a left-sided supraclavicular lymph node.

Clinical significance
Malignancies of the internal organs can reach an advanced stage before giving symptoms. Stomach cancer, for example, can remain asymptomatic while metastasizing. One of the first visible spots where these tumors metastasize is one of the left supraclavicular lymph node.
Virchows nodes take their supply from lymph vessels in the abdominal cavity, and are therefore sentinel lymph nodes of cancer in the abdomen, particularly gastric cancer, ovarian cancer, testicular cancer and kidney cancer, that has spread through the lymph vessels, and Hodgkins lymphoma. Such spread typically results in Troisiers sign, which is the finding of an enlarged, hard Virchows node.The left supraclavicular nodes are the classical Virchows node because they receive lymphatic drainage of most of the body (from the thoracic duct) and enters the venous circulation via the left subclavian vein. The metastasis may block the thoracic duct leading to regurgitation into the surrounding Virchows nodes. Another concept is that one of the supraclavicular nodes corresponds to the end node along the thoracic duct and hence the enlargement.Differential diagnosis of an enlarged Virchows node includes lymphoma, various intra-abdominal malignancies, breast cancer, and infection (e.g. of the arm).  Similarly, an enlarged right supraclavicular lymph node tends to drain thoracic malignancies such as lung and esophageal cancer, as well as Hodgkins lymphoma.

History
Virchows nodes are named after Rudolf Virchow (1821–1902), the German pathologist who first described the nodes and their association with gastric cancer in 1848. The French pathologist Charles Emile Troisier noted in 1889 that other abdominal cancers, too, could spread to the nodes.

Additional images
References
This article incorporates text in the public domain from page 697 of the 20th edition of Grays Anatomy (1918)

Further reading
Cervin, J. R.; Silverman, J. F.; Loggie, B. W.; Geisinger, K. R. (1995). "Virchows node revisited. Analysis with clinicopathologic correlation of 152 fine-needle aspiration biopsies of supraclavicular lymph nodes". Archives of Pathology & Laboratory Medicine. 119 (8): 727–30. PMID 7646330. INIST:3670181 NAID 10026546830.
Negus, D; Edwards, J M; Kinmonth, J B (7 December 2005). "Filling of cervical and mediastinal nodes from the thoracic duct and the physiology of virchows node—studies by lymphography". British Journal of Surgery </s>


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<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Preureteric vena cava and can you explain it in depth? [/INST] A preureteric vena cava, also known as a retrocaval ureter, is a rare congenital malformation of the right human ureter, in which the ureter passes behind the inferior vena cava, causing compression possibly leading to hydronephrosis. The prevalence of this condition is approximately 1 per 1,000 persons, with males 2-3 times more likely than females to develop the condition. Symptoms often do not manifest until those with the condition are aged in their 20s or 30s.

References
"preureteric vena cava" (PDF). Retrieved 15 July 2019.
Morganstern, S </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Congenital blindness and can you explain it in depth? [/INST] Congenital blindness refers to a group of diseases and conditions occurring in childhood or early adolescence of below 16 years old, which, if left untreated, result in blindness or severe visual impairment that are likely to be permanent blindness later in life. Congenital blindness is a hereditary disease and can be cured by gene therapy. Visual loss in children or infant can occur either at the stage of prenatal (during the time of conception or intrauterine period) or postnatal stage (during birth). A variety of causes can promote congenital blindness but the most concern and highest cause of it is a genetic mutation. In general, 60% of congenital blindness cases are contributed from prenatal stage and 40% are contributed from inherited disease. However, most of the congenital blindness cases show that it can be avoidable or preventable with early treatment.

Causes
Prenatal stage

Premature Birth
Refractive error
Congenital cataract
Retinopathy of prematurity (ROP)
Infection such as Ophtalmia neonatorum that happen during time of conception or intrauterine period
Vitamin A deficiency
MeaslesPostnatal stage

Genetic mutationThe mutation can usually be an autosomal recessive condition and unusual condition of infant happened where it forms retinoblastoma result from autosomal dominant condition. The mutation of Retinal pigment epithelium-specific 65 kDa protein (RPE65) gene which function to produce retinoid isomerohydrolase which is an enzyme. RPE65 performs a key role in the trans-cis isomerization of retinol in the retinal pigment epithelium of the eye </s>


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Endocardial cushion defects are associated with abnormalities of the atrioventricular valves (the mitral valve and the tricuspid valve) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Spinocerebellar tract and can you explain it in depth? [/INST] The spinocerebellar tract is a nerve tract originating in the spinal cord and terminating in the same side (ipsilateral) of the cerebellum.

Origins of proprioceptive information
Proprioceptive information is obtained by Golgi tendon organs and muscle spindles.

Golgi tendon organs consist of a fibrous capsule enclosing tendon fascicles and bare nerve endings that respond to tension in the tendon by causing action potentials in type Ib afferents. These fibers are relatively large, myelinated, and quickly conducting.
Muscle spindles monitor the length within muscles and send information via faster Ia afferents. These axons are larger and faster than type Ib (from both nuclear bag fibers and nuclear chain fibers) and type II afferents (solely from nuclear chain fibers).All of these neurons are sensory (first order, or primary) and have their cell bodies in the dorsal root ganglia. They pass through Rexed laminae layers I-VI of the posterior grey column (dorsal horn) to form synapses with second order or secondary neurons in layer VII just beneath the dorsal horn.

Subdivisions of the tract
The tract is divided into:

Dorsal spinocerebellar tract
The dorsal spinocerebellar tract (posterior spinocerebellar tract, Flechsigs fasciculus, Flechsigs tract) conveys proprioceptive information from proprioceptors in the skeletal muscles and joints to the cerebellum.It is part of the somatosensory system and runs in parallel with the ventral spinocerebellar tract. It carries proprioceptive information from muscle spindles and Golgi tendon organs of ipsilateral part of trunk and lower limb.
Proprioceptive information is taken to the spinal cord via central processes of dorsal root ganglia (first order neurons). These central processes travel through the dorsal horn where they synapse with second order neurons of Clarkes nucleus. Axon fibers from Clarkes Nucleus convey this proprioceptive information in the spinal cord in the peripheral region of the funiculus posterior ipsilaterally. The fibers continue to course through the medulla oblongata of the brainstem, at which point they pass through the inferior cerebellar peduncle and into the cerebellum, where unconscious proprioceptive information is processed.
This tract involves two neurons and ends up on the same side of the body.
The terms Flechsigs fasciculus and Flechsigs tract are named after German neuroanatomist, psychiatrist and neuropathologist Paul Flechsig.

Ventral spinocerebellar tract
The ventral spinocerebellar tract (or anterior spinocerebellar tract) conveys proprioceptive information from the body to the cerebellum. Historically, it has also been known as Gowers column (or fasciculus or tract),  after Sir William Richard Gowers.
It is part of the somatosensory system and runs in parallel with the dorsal spinocerebellar tract. Both these tracts involve two neurons.
The ventral spinocerebellar tract will cross to the opposite side of the body first in the spinal cord as part of the anterior white commissure and then cross again to end in the cerebellum (referred to as a "double cross"), as compared to the dorsal spinocerebellar tract, which does not decussate, or cross sides, at all through its path.
The ventral tract (under L2/L3) gets its proprioceptive/fine touch/vibration information from a first order neuron, with its cell body in a dorsal ganglion. The axon runs via the fila radicularia to the dorsal horn of the grey matter. There it makes a synapse with the dendrites of two neurons: they send their axons bilaterally to the ventral border of the lateral funiculi. The fibers of the ventral spinocerebellar tract then enters the cerebellum via the superior cerebellar peduncle. This is in contrast with the dorsal spinocerebellar tract (C8 - L2/L3), which only has 1 unilateral axon that has its cell body in Clarkes column (only at the level of C8 - L2/L3).
Originates from ventral horn at lumbosacral spinal levels. Axons first cross midline in the spinal cord and run in the ventral border of the lateral funiculi. These axons ascend to the pons where they join the superior cerebellar peduncle to enter the cerebellum. Once in the deep white matter of the cerebellum, the axons recross the midline, give off collaterals to the globose and emboliform nuclei, and terminate in the cortex of the anterior lobe and vermis of the posterior lobe.

Comparison with dorsal spinocerebellar tract
When the dorsal roots are cut in a cat performing a step cycle, peripheral excitation is lost, and the dorsal spinocerebellar tract has no activity; the ventral spinocerebellar tract continues to show activity. This suggests that the dorsal spinocerebellar tract carries sensory information to the spinocerebellum through the inferior cerebellar peduncle during movement (since the inferior peduncle is known to contain fibres from the dorsal tract), and that the ventral spinocerebellar tract carries internally generated motor information about the movement through the superior cerebellar peduncle.

Posterior external arcuate fibers
The posterior external arcuate fibers (dorsal external arcuate fibers or cuneocerebellar tract) take origin in the accessory cuneate nucleus; they pass to the inferior cerebellar peduncle of the same side. The term "cuneocerebellar tract" is also used to describe an exteroceptive and proprioceptive components that take origin in the gracile and cuneate nuclei; they pass to the inferior cerebellar peduncle of the same side.The posterior external arcuate fibers carry proprioceptive information from the upper limbs and neck. It is an analogue to the dorsal spinocerebellar tract for the upper limbs. In this context, the "cuneo-" derives from the accessory cuneate nucleus, not the cuneate nucleus. (The two nuclei are related in space, but not in function.)
It is uncertain whether fibers are continued directly from the gracile and cuneate fasciculi into the inferior peduncle.

Rostral spinocerebellar tract
The rostral spinocerebellar tract is a tract which transmits information from the golgi tendon organs of the cranial half of the body to the cerebellum. It terminates bilaterally in the anterior lobe of the cerebellum (lower cerebellar peduncle) after travelling ipsilaterally from its origin in the cervical portion of the spinal cord. It reaches the cerebellum partly through the brachium conjunctivum (superior cerebellar peduncle) and partly through the restiform body (inferior cerebellar peduncle).

Pathway for dorsal and spinocuneocerebellar tracts
The sensory neurons synapse in an area known as Clarkes nucleus or "Clarkes column".
This is a column of relay neuron cell bodies within the medial gray matter within the spinal cord in layer VII (just beneath the dorsal horn), specifically between T1-L3 </s>


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<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Imperforate lacrimal punctum and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Post-encephalitic parkinsonism and can you explain it in depth? [/INST] Post-encephalitic parkinsonism is a disease believed to be caused by a viral illness that triggers degeneration of the nerve cells in the substantia nigra </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Actinic cheilitis and can you explain it in depth? [/INST] Actinic cheilitis  is cheilitis (lip inflammation) caused by long term sunlight exposure. Essentially it is a burn, and a variant of actinic keratosis which occurs on the lip. It is a premalignant condition, as it can develop into squamous cell carcinoma (a type of mouth cancer).

Signs and symptoms
AC almost always affects the lower lip and only rarely the upper lip, probably because the lower lip is more exposed to the sun. In the unusual cases reported where it affects the upper lip, this may be due to upper lip prominence. The commissures (corners of the mouth) are not usually involved.Affected individuals may experience symptoms such as a dry sensation and cracking of the lips.
It is usually painless and persistent.
The appearance is variable. White lesions indicate hyperkeratosis. Red, erosive or ulcerative lesions indicate atrophy, loss of epithelium and inflammation. Early, acute lesions may be erythematous (red) and edematous (swollen). With months and years of sun exposure, the lesion becomes chronic and may be grey-white in color and appear dry, scaly and wrinkled.There is thickening whitish discoloration of the lip at the border of the lip and skin.   There is also a loss of the usually sharp border between the red of the lip and the normal skin, known as the vermillion border. The lip may become scaly and indurated as AC progresses.
When palpated, the lip may have a texture similar to rubbing the gloved finger along sandpaper.AC may occur with skin lesions of actinic keratosis or skin cancer elsewhere, particularly on the head and neck since these are the most sun exposed areas. Rarely it may represent a genetic susceptibility to light damage (e.g. xeroderma pigmentosum or actinic prurigo).

Causes
AC is caused by chronic and excessive exposure to ultraviolet radiation in sunlight.
Risk factors include:

Outdoor lifestyle: e.g. farmers, sailors, fishermen, windsurfers, mountaineers, golfers, etc. This has given rise to synonyms for this condition such as "sailors lip" and "farmers lip". The prevalence in agricultural workers in a semi-arid region of Brazil is reported to be 16.7%.
Light skin complexion: the condition typically affects individuals with lighter skin tones, particularly Caucasians living in tropical regions. In one report, 96% of persons with AC had phenotype II according to the Fitzpatrick scale.
Age: AC typically affects older individuals, and rarely those under the age of 45.
Gender: the condition affects males more commonly than females. Sometimes this ratio is reported as high as 10:1.Additional factors may also play a role, including tobacco use, lip irritation, poor oral hygiene, and ill-fitting dentures.

Diagnosis
Tissue biopsy is indicated.

Prevention
To prevent AC from developing, protective measures could be undertaken such as avoiding mid-day sun, or use of a broad-brimmed hat, lip balm with anti UVA and UVB ingredients (e.g. para-aminobenzoic acid), or sun blocking agents (e.g. zinc oxide, titanium oxide) prior to sun exposure.

Treatment
This condition is considered premalignant because it may lead to squamous cell carcinoma in about 10% of all cases.  It is not possible to predict which cases will progress into SCC, so the current consensus is that all lesions should be treated.Treatment options include 5-fluorouracil, imiquimod, scalpel vermillionectomy, chemical peel, electrosurgery, and carbon dioxide laser vaporization.  These curative treatments attempt to destroy or remove the damaged epithelium.  All methods are associated with some degree of pain, edema, and a relatively low rate of recurrence.

Medication
Topical 5-fluorouracil (5-FU, Efudex, Carac) has been shown to be an effective therapy for diffuse, but minor actinic cheilitis.  5-fluorouracil works by blocking DNA synthesis. Cells that are rapidly growing need more DNA, so they accumulate more 5-fluorouracil, resulting in their death.  Normal skin is much less affected.  The treatment usually takes 2–4 weeks depending on the response.  The typical response includes an inflammatory phase, followed by redness, burning, oozing, and finally erosion.  Treatment is stopped when ulceration and crusting appear.  There is minimal scarring.  Complete clearance has been reported in about 50% of patients.Imiquimod (Aldara) is an immune response modifier that has been studied for the treatment of actinic cheilitis.  It promotes an immune response in the skin leading to apoptosis (death) of the tumor cells. It causes the epidermis to be invaded by macrophages, which leads to epidermal erosion. T-cells are also activated as a result of imiquimod treatment. Imiquimod appears to promote an "immune memory" that reduces the recurrence of lesions. There is minimal scarring.  Complete clearance has been demonstrated in up to 45% of patients with actinic keratoses.  However, the dose and duration of therapy, as well as the long-term efficacy, still need to be established in the treatment of actinic cheilitis.

Procedures
Both cryosurgery and electrosurgery are effective choices for small areas of actinic cheilitis.  Cryosurgery is accomplished by applying liquid nitrogen in an open spraying technique.  Local anesthesia is not required, but treatment of the entire lip can be quite painful.  Cure rates in excess of 96% have been reported.  Cryosurgery is the treatment of choice for focal areas of actinic cheilitis.  Electrosurgery is an alternate treatment, but local anesthesia is required, making it less practical than cryosurgery.  With both techniques, adjacent tissue damage can delay healing and promote scar formation.More extensive or recurring areas of actinic cheilitis may be treated with either a shave vermillionectomy or a carbon dioxide laser.  The shave vemillionectomy removes a portion of the vermillion border but leaves the underlying muscle intact.  Considerable bleeding can occur during the procedure due to the vascular nature of the lip </s>