<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 Hereditary hemorrhagic telangiectasia and can you explain it in depth? [/INST] Hereditary hemorrhagic telangiectasia (HHT), also known as Osler–Weber–Rendu disease and Osler–Weber–Rendu syndrome, is a rare autosomal dominant genetic disorder that leads to abnormal blood vessel formation in the skin, mucous membranes, and often in organs such as the lungs, liver, and brain.It may lead to nosebleeds, acute and chronic digestive tract bleeding, and various problems due to the involvement of other organs. Treatment focuses on reducing bleeding from blood vessel lesions, and sometimes surgery or other targeted interventions to remove arteriovenous malformations in organs. Chronic bleeding often requires iron supplements and sometimes blood transfusions. HHT is transmitted in an autosomal dominant fashion, and occurs in one in 5,000–8,000 people in North America.The disease carries the names of Sir William Osler, Henri Jules Louis Marie Rendu, and Frederick Parkes Weber, who described it in the late 19th and early 20th centuries.

Signs and symptoms
Telangiectasias
Telangiectasia (small vascular malformations) may occur in the skin and mucosal linings of the nose and gastrointestinal tract. The most common problem is nosebleeds (epistaxis), which happen frequently from childhood and affect about 90–95% of people with HHT. Lesions on the skin and in the mouth bleed less often but may be considered cosmetically displeasing; they affect about 80%. The skin lesions characteristically occur on the lips, the nose and the fingers, and on the skin of the face in sun-exposed areas. They appear suddenly, with the number increasing over time.About 20% are affected by symptomatic digestive tract lesions, although a higher percentage have lesions that do not cause symptoms. These lesions may bleed intermittently, which is rarely significant enough to be noticed (in the form of bloody vomiting or black stool), but can eventually lead to depletion of iron in the body, resulting in iron-deficiency anemia.

Arteriovenous malformation
Arteriovenous malformations (AVMs, larger vascular malformations) occur in larger organs, predominantly the lungs (pulmonary AVMs) (50%), liver (30–70%) and the brain (cerebral AVMs, 10%), with a very small proportion (<1%) of AVMs in the spinal cord.Vascular malformations in the lungs may cause a number of problems. The lungs normally "filter out" bacteria and blood clots from the bloodstream; AVMs bypass the capillary network of the lungs and allow these to migrate to the brain, where bacteria may cause a brain abscess and blood clots may lead to stroke. HHT is the most common cause of lung AVMs: out of all people found to have lung AVMs, 70–80% are due to HHT. Bleeding from lung AVMs is relatively unusual, but may cause hemoptysis (coughing up blood) or hemothorax (blood accumulating in the chest cavity). Large vascular malformations in the lung allow oxygen-depleted blood from the right ventricle to bypass the alveoli, meaning that this blood does not have an opportunity to absorb fresh oxygen. This may lead to breathlessness. Large AVMs may lead to platypnea, difficulty in breathing that is more marked when sitting up compared to lying down; this probably reflects changes in blood flow associated with positioning. Very large AVMs cause a marked inability to absorb oxygen, which may be noted by cyanosis (bluish discoloration of the lips and skin), clubbing of the fingernails (often encountered in chronically low oxygen levels), and a humming noise over the affected part of the lung detectable by stethoscope.The symptoms produced by AVMs in the liver depend on the type of abnormal connection that they form between blood vessels. If the connection is between arteries and veins, a large amount of blood bypasses the bodys organs, for which the heart compensates by increasing the cardiac output. Eventually congestive cardiac failure develops ("high-output cardiac failure"), with breathlessness and leg swelling among other problems. If the AVM creates a connection between the portal vein and the blood vessels of the liver, the result may be portal hypertension (increased portal vein pressure), in which collateral blood vessels form in the esophagus (esophageal varices), which may bleed violently; furthermore, the increased pressure may give rise to fluid accumulation in the abdominal cavity (ascites). If the flow in the AVM is in the other direction, portal venous blood flows directly into the veins rather than running through the liver; this may lead to hepatic encephalopathy (confusion due to portal waste products irritating the brain). Rarely, the bile ducts are deprived of blood, leading to severe cholangitis (inflammation of the bile ducts). Liver AVMs are detectable in over 70% of people with HHT, but only 10% experience problems as a result.In the brain, AVMs occasionally exert pressure, leading to headaches. They may also increase the risk of seizures, as would any abnormal tissue in the brain. Finally, hemorrhage from an AVM may lead to intracerebral hemorrhage (bleeding into the brain), which causes any of the symptoms of stroke such as weakness in part of the body or difficulty speaking. If the bleeding occurs into the subarachnoid space (subarachnoid hemorrhage), there is usually a severe, sudden headache and decreased level of consciousness and often weakness in part of the body.

Other problems
A very small proportion (those affected by SMAD4 (MADH4) mutations, see below) have multiple benign polyps in the large intestine, which may bleed or transform into colorectal cancer. A similarly small proportion experiences pulmonary hypertension, a state in which the pressure in the lung arteries is increased, exerting pressure on the right side of the heart and causing peripheral edema (swelling of the legs), fainting and attacks of chest pain. It has been observed that the risk of thrombosis (particularly venous thrombosis, in the form of deep vein thrombosis or pulmonary embolism) may be increased. There is a suspicion that those with HHT may have a mild immunodeficiency and are therefore at a slightly increased risk from infections.

Genetics
HHT is a genetic disorder with an autosomal dominant inheritance pattern. Those with HHT symptoms that have no relatives with the disease may have a new mutation. Homozygosity appears to be fatal in utero.Five genetic types of HHT are recognized. Of these, three have been linked to particular genes, while the two remaining have currently only been associated with a particular locus. More than 80% of all cases of HHT are due to mutations in either ENG or ACVRL1. A total of over 600 different mutations are known. There is likely to be a predominance of either type in particular populations, but the data are conflicting. MADH4 mutations, which cause colonic polyposis in addition to HHT, comprise about 2% of disease-causing mutations. Apart from MADH4, it is not clear whether mutations in ENG and ACVRL1 lead to particular symptoms, although some reports suggest that ENG mutations are more likely to cause lung problems while ACVRL1 mutations may cause more liver problems, and pulmonary hypertension may be a particular problem in people with ACVRL1 mutations. People with exactly the same mutations may have different nature and severity of symptoms, suggesting that additional genes or other risk factors may determine the rate at which lesions develop; these have not yet been identified.

Pathophysiology
Telangiectasias and arteriovenous malformations in HHT are thought to arise because of changes in angiogenesis, the development of blood vessels out of existing ones. The development of a new blood vessel requires the activation and migration of various types of cells, chiefly endothelium, smooth muscle and pericytes. The exact mechanism by which the HHT mutations influence this process is not yet clear, and it is likely that they disrupt a balance between pro- and antiangiogenic signals in blood vessels. The wall of telangiectasias is unusually friable, which explains the tendency of these lesions to bleed.All genes known so far to be linked to HHT code for proteins in the TGF-β signaling pathway. This is a group of proteins that participates in signal transduction of hormones of the transforming growth factor beta superfamily (the transforming growth factor beta, bone morphogenetic protein and growth differentiation factor classes), specifically BMP9/GDF2 and BMP10. The hormones do not enter the cell but link to receptors on the cell membrane; these then activate other proteins, eventually influencing cellular behavior in a number of ways such as cellular survival, proliferation (increasing in number) and differentiation (becoming more specialized). For the hormone signal to be adequately transduced, a combination of proteins is needed: two each of two types of serine/threonine-specific kinase type membrane receptors and endoglin. When bound to the hormone, the type II receptor proteins phosphorylate (transfer phosphate) onto type I receptor proteins (of which Alk-1 is one), which in turn phosphorylate a complex of SMAD proteins (chiefly SMAD1, SMAD5 and SMAD8). These bind to SMAD4 and migrate to the cell nucleus where they act as transcription factors and participate in the transcription of particular genes. In addition to the SMAD pathway, the membrane receptors also act on the MAPK pathway, which has additional actions on the behavior of cells. Both Alk-1 and endoglin are expressed predominantly in endothelium, perhaps explaining why HHT-causing mutations in these proteins lead predominantly to blood vessel problems. Both ENG and ACVRL1 mutations lead predominantly to underproduction of the related proteins, rather than misfunctioning of the proteins.

Diagnosis
Diagnostic tests may be conducted for various reasons. Firstly, some tests are needed to confirm or refute the diagnosis. Secondly, some are needed to identify any potential complications.

Telangiectasias
The skin and oral cavity telangiectasias are visually identifiable on physical examination, and similarly the lesions in the nose may be seen on endoscopy of the nasopharynx or on laryngoscopy. The severity of nosebleeds may be quantified objectively using a grid-like questionnaire in which the number of nosebleed episodes and their duration is recorded.Digestive tract telangiectasias may be identified on esophagogastroduodenoscopy (endoscopy of the esophagus, stomach and first part of the small intestine). This procedure will typically only be undertaken if there is anemia that is more marked than expected by the severity of nosebleeds, or if there is evidence of severe bleeding (vomiting blood, black stools). If the number of lesions seen on endoscopy is unexpectedly low, the remainder of the small intestine may be examined with capsule endoscopy, in which the patient swallows a capsule-shaped device containing a miniature camera which transmits images of the digestive tract to a portable digital recorder.

Arteriovenous malformations
Identification of AVMs requires detailed medical imaging of the organs most commonly affected by these lesions. Not all AVMs cause symptoms or are at risk of doing so, and hence there is a degree of variation between specialists as to whether such investigations would be performed, and by which modality; often, decisions on this issue are reached together with the patient.Lung AVMs may be suspected because of the abnormal appearance of the lungs on a chest X-ray, or hypoxia (low oxygen levels) on pulse oximetry or arterial blood gas determination. Bubble contrast echocardiography (bubble echo) may be used as a screening tool to identify abnormal connections between the lung arteries and veins. This involves the injection of agitated saline into a vein, followed by ultrasound-based imaging of the heart. Normally, the lungs remove small air bubbles from the circulation, and they are therefore only seen in the right atrium and the right ventricle. If an AVM is present, bubbles appear in the left atrium and left ventricle, usually 3–10 cardiac cycles after the right side; this is slower than in heart defects, in which there are direct connections between the right and left side of the heart. A larger number of bubbles is more likely to indicate the presence of an AVM. Bubble echo is not a perfect screening tool as it can miss smaller AVMs and does not identify the site of AVMs.  Often contrast-enhanced computed tomography (CT angiography) is used to identify lung lesions; this modality has a sensitivity of over 90%. It may be possible to omit contrast administration on modern CT scanners. Echocardiography is also used if there is a suspicion of pulmonary hypertension or high-output cardiac failure due to large liver lesions, sometimes followed by cardiac catheterization to measure the pressures inside the various chambers of the heart.

Liver AVMs may be suspected because of abnormal liver function tests in the blood, because the symptoms of heart failure develop, or because of jaundice or other symptoms of liver dysfunction. The most reliable initial screening test is Doppler ultrasonography of the liver; this has a very high sensitivity for identifying vascular lesions in the liver. If necessary, contrast-enhanced CT may be used to further characterize AVMs. It is extremely common to find incidental nodules on liver scans, most commonly due to focal nodular hyperplasia (FNH), as these are a hundredfold times more common in HHT compared to the general population. FNH is regarded as harmless. Generally, tumor markers and additional imaging modalities are used to differentiate between FNH and malignant tumors of the liver. Liver biopsy is discouraged in people with HHT as the risk of hemorrhage from liver AVMs may be significant. Liver scans may be useful if someone is suspected of HHT, but does not meet the criteria (see below) unless liver lesions can be demonstrated.Brain AVMs may be detected on computed tomography angiography (CTA or CT angio) or magnetic resonance angiography (MRA); CTA is better in showing the vessels themselves, and MRA provides more detail about the relationship between an AVM and surrounding brain tissue. In general, MRI is recommended. Various types of vascular malformations may be encountered: AVMs, micro-AVMs, telangiectasias and arteriovenous fistulas. If surgery, embolization, or other treatment is contemplated (see below), cerebral angiography may be required to get sufficient detail of the vessels. This procedure carries a small risk of stroke (0.5%) and is therefore limited to specific circumstances. Recent professional guidelines recommend that all children with suspected or definite HHT undergo a brain MRI early in life to identify AVMs that can cause major complications. Others suggest that screening for cerebral AVMs is probably unnecessary in those who are not experiencing any neurological symptoms, because most lesions discovered on screening scans would not require treatment, creating undesirable conundrums.

Genetic testing
Genetic tests are available for the ENG, ACVRL1 and MADH4 mutations. Testing is not always needed for diagnosis, because the symptoms are sufficient to distinguish the disease from other diagnoses. There are situations in which testing can be particularly useful. Firstly, children and young adults with a parent with definite HHT may have limited symptoms, yet be at risk from some of the complications mentioned above; if the mutation is known in the affected parent, absence of this mutation in the child would prevent the need for screening tests. Furthermore, genetic testing may confirm the diagnosis in those with limited symptoms who otherwise would have been labeled "possible HHT" (see below).Genetic diagnosis in HHT is difficult, as mutations occur in numerous different locations in the linked genes, without particular mutations being highly frequent (as opposed to, for instance, the ΔF508 mutation in cystic fibrosis). Sequence analysis of the involved genes is therefore the most useful approach (sensitivity 75%), followed by additional testing to detect large deletions and duplications (additional 10%). Not all mutations in these genes have been linked with disease.Mutations in the MADH4 gene is usually associated with juvenile polyposis, and detection of such a mutation would indicate a need to screen the patient and affected relatives for polyps and tumors of the large intestine.

Criteria
The diagnosis can be made depending on the presence of four criteria, known as the "Curaçao criteria". If three or four are met, a patient has "definite HHT", while two gives "possible HHT":

Spontaneous recurrent epistaxis
Multiple telangiectasias in typical locations (see above)
Proven visceral AVM (lung, liver, brain, spine)
First-degree family member with HHTDespite the designation "possible", someone with a visceral AVM and a family history but no nosebleeds or telangiectasias is still extremely likely to have HHT, because these AVMs are very uncommon in the general population. At the same time, the same cannot be said of nosebleeds and sparse telangiectasias, both of which occur in people without HHT, in the absence of AVMs. Someones diagnostic status may change in the course of life, as young children may not yet exhibit all the symptoms; at age 16, thirteen percent are still indeterminate, while at age 60 the vast majority (99%) have a definite diagnostic classification. The children of established HHT patients may therefore be labeled as "possible HHT", as 50% may turn out to have HHT in the course of their life.

Treatment
Treatment of HHT is symptomatic (it deals with the symptoms rather than the disease itself), as there is no therapy that stops the development of telangiectasias and AVMs directly. Furthermore, some treatments are applied to prevent the development of common complications. Chronic nosebleeds and digestive tract bleeding can both lead to anemia; if the bleeding itself cannot be completely stopped, the anemia requires treatment with iron supplements. Those who cannot tolerate iron tablets or solutions may require administration of intravenous iron, and blood transfusion if the anemia is causing severe symptoms that warrant rapid improvement of the blood count.Most treatments used in HHT have been described in adults, and the experience in treating children is more limited. Women with HHT who get pregnant are at an increased risk of complications, and are observed closely, although the absolute risk is still low (1%).

Nosebleeds
An acute nosebleed may be managed with a variety of measures, such as packing of the nasal cavity with absorbent swabs or gels. Removal of the packs after the bleeding may lead to reopening of the fragile vessels, and therefore lubricated or atraumatic packing is recommended. Some patients may wish to learn packing themselves to deal with nosebleeds without having to resort to medical help.Frequent nosebleeds can be prevented in part by keeping the nostrils moist, and by applying saline solution, estrogen-containing creams or tranexamic acid; these have few side effects and may have a small degree of benefit. A number of additional modalities has been used to prevent recurrent bleeding if simple measures are unsuccessful. Medical therapies include oral tranexamic acid and estrogen; the evidence for these is relatively limited, and estrogen is poorly tolerated by men and possibly carries risks of cancer and heart disease in women past the menopause. Nasal coagulation and cauterization may reduce the bleeding from telangiectasias, and is recommended before surgery is considered. However, it is highly recommended to use the least heat and time to prevent septal perforations and excessive trauma to the nasal mucosa that are already susceptible to bleeding. Sclerotherapy is another option to manage the bleeding. This process involves injecting a small amount of an aerated irritant (detergent such as sodium tetradecyl sulfate) directly into the telangiectasias. The detergent causes the vessel to collapse and harden, resulting in scar tissue residue. This is the same procedure used to treat varicose veins and similar disorders.It may be possible to embolize vascular lesions through interventional radiology; this requires passing a catheter through a large artery and locating the maxillary artery under X-ray guidance, followed by the injection into the vessel of particles that occlude the blood vessels. The benefit from the procedure tends to be short-lived, and it may be most appropriate in episodes of severe bleeding.To more effectively minimize recurrence and severity of epistaxis, other options may be used in conjunction with therapies listed above. Intravenously administered anti-VEGF substances such as bevacizumab (brand name Avastin), pazopinab and thalidomide or its derivatives interfere with the production of new blood vessels that are weak and therefore prone to bleeding. Due to the past experiences with prescribing thalidomide to pregnant women to alleviate symptoms of nausea and the terrible birth defects that followed, thalidomide is a last resort therapy. Additionally, thalidomide can cause neuropathy. Though this can be mitigated by tinkering with dosages and prescribing its derivatives such as lenolidomide and pomalidomide, many doctors prefer alternative VEGF inhibitors. Bevacizumab has been shown to significantly reduce the severity of epistaxis without side effects.If other interventions have failed, several operations have been reported to provide benefit. One is septal dermoplasty or Saunders procedure, in which skin is transplanted into the nostrils, and the other is Youngs procedure, in which the nostrils are sealed off completely.

Skin and digestive tract
The skin lesions of HHT can be disfiguring, and may respond to treatment with long-pulsed Nd:YAG laser. Skin lesions in the fingertips may sometimes bleed and cause pain. Skin grafting is occasionally needed to treat this problem.With regards to digestive tract lesions, mild bleeding and mild resultant anemia is treated with iron supplementation, and no specific treatment is administered. There is limited data on hormone treatment and tranexamic acid to reduce bleeding and anemia. Severe anemia or episodes of severe bleeding are treated with endoscopic argon plasma coagulation (APC) or laser treatment of any lesions identified; this may reduce the need for supportive treatment. The expected benefits are not such that repeated attempts at treating lesions are advocated. Sudden, very severe bleeding is unusual—if encountered, alternative causes (such as a peptic ulcer) need to be considered—but embolization may be used in such instances.

Lung AVMs
Lung lesions, once identified, are usually treated to prevent episodes of bleeding and more importantly embolism to the brain. This is particularly done in lesions with a feeding blood vessel of 3 mm or larger, as these are the most likely to cause long-term complications unless treated. The most effective current therapy is embolization with detachable metal coils or plugs. The procedure involves puncture of a large vein (usually under a general anesthetic), followed by advancing of a catheter through the right ventricle and into the pulmonary artery, after which radiocontrast is injected to visualize the AVMs (pulmonary angiography). Once the lesion has been identified, coils are deployed that obstruct the blood flow and allow the lesion to regress. In experienced hands, the procedure tends to be very effective and with limited side effects, but lesions may recur and further attempts may be required. CTA scans are repeated to monitor for recurrence. Surgical excision has now essentially been abandoned due to the success of embolotherapy.Those with either definite pulmonary AVMs or an abnormal contrast echocardiogram with no clearly visible lesions are deemed to be at risk from brain emboli. They are therefore counselled to avoid scuba diving, during which small air bubbles may form in the bloodstream that may migrate to the brain and cause stroke. Similarly, antimicrobial prophylaxis is advised during procedures in which bacteria may enter the bloodstream, such as dental work, and avoidance of air bubbles during intravenous therapy.

Liver AVMs
Given that liver AVMs generally cause high-output cardiac failure, the emphasis is on treating this with diuretics to reduce the circulating blood volume, restriction of salt and fluid intake, and antiarrhythmic agents in case of irregular heart beat. This may be sufficient in treating the symptoms of swelling and breathlessness. If this treatment is not effective or leads to side effects or complications, the only remaining option is liver transplantation. This is reserved for those with severe symptoms, as it carries a mortality of about 10%, but leads to good results if successful. The exact point at which liver transplantion is to be offered is not yet completely established. Embolization treatment has been attempted, but leads to severe complications in a proportion of patients and is discouraged.Other liver-related complications (portal hypertension, esophageal varices, ascites, hepatic encephalopathy) are treated with the same modalities as used in cirrhosis, although the use of transjugular intrahepatic portosystemic shunt treatment is discouraged due to the lack of documented benefit.

Brain AVMs
The decision to treat brain arteriovenous malformations depends on the symptoms that they cause (such as seizures or headaches). The bleeding risk is predicted by previous episodes of hemorrhage, and whether on the CTA or MRA scan the AVM appears to be deep-seated or have deep venous drainage. Size of the AVM and the presence of aneurysms appears to matter less. In HHT, some lesions (high-flow arteriovenous fistulae) tend to cause more problems, and treatment is warranted.  Other AVMs may regress over time without intervention. Various modalities are available, depending on the location of the AVM and its size: surgery, radiation-based treatment and embolization. Sometimes, multiple modalities are used on the same lesion.Surgery (by craniotomy, open brain surgery) may be offered based on the risks of treatment as determined by the Spetzler–Martin scale (grade I-V); this score is higher in larger lesions that are close to important brain structures and have deep venous drainage. High grade lesions (IV and V) have an unacceptably high risk and surgery is not typically offered in those cases. Radiosurgery (using targeted radiation therapy such as by a gamma knife) may be used if the lesion is small but close to vital structures. Finally, embolization may be used on small lesions that have only a single feeding vessel.

Experimental treatments
Several anti-angiogenesis drugs approved for other conditions, such as cancer, have been investigated in small clinical trials. The anti-VEGF antibody bevacizumab, for instance, has been used off-label in several studies. In a large clinical trial, bevacizumab infusion was associated with a decrease in cardiac output and reduced duration and number of episodes of epistaxis in treated HHT patients. Thalidomide, another anti-angiogenesis drug, was also reported to have beneficial effects in HHT patients. Thalidomide treatment was found to induce vessel maturation in an experimental mouse model of HHT and to reduce the severity and frequency of nosebleeds in the majority of a small group of HHT patients. The blood hemoglobin levels of these treated patients rose as a result of reduced hemorrhage and enhanced blood vessel stabilization.

Epidemiology
Population studies from numerous areas in the world have shown that HHT occurs at roughly the same rate in almost all populations: somewhere around 1 in 5000. In some areas, it is much more common; for instance, in the French region of Haut Jura the rate is 1:2351 - twice as common as in other populations. This has been attributed to a founder effect, in which a population descending from a small number of ancestors has a high rate of a particular genetic trait because one of these ancestors harbored this trait. In Haut Jura, this has been shown to be the result of a particular ACVRL1 mutation (named c.1112dupG or c.1112_1113insG). The highest rate of HHT is 1:1331, reported in Bonaire and Curaçao, two islands in the Caribbean belonging to the Netherlands Antilles.Most people with HHT have a normal lifespan. The skin lesions and nosebleeds tend to develop during childhood </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 Orotic aciduria and can you explain it in depth? [/INST] Orotic aciduria (AKA hereditary orotic aciduria) is a disease caused by an enzyme deficiency resulting in a decreased ability to synthesize pyrimidines </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 Herpes labialis and can you explain it in depth? [/INST] Herpes labialis, commonly known as cold sores or fever blisters, is a type of infection by the herpes simplex virus that affects primarily the lip. Symptoms typically include a burning pain followed by small blisters or sores. The first attack may also be accompanied by fever, sore throat, and enlarged lymph nodes. The rash usually heals within ten days, but the virus remains dormant in the trigeminal ganglion. The virus may periodically reactivate to create another outbreak of sores in the mouth or lip.The cause is usually herpes simplex virus type 1 (HSV-1) and occasionally herpes simplex virus type 2 (HSV-2). The infection is typically spread between people by direct non-sexual contact. Attacks can be triggered by sunlight, fever, psychological stress, or a menstrual period. Direct contact with the genitals can result in genital herpes. Diagnosis is usually based on symptoms but can be confirmed with specific testing.Prevention includes avoiding kissing or using the personal items of a person who is infected. A zinc oxide, anesthetic, or antiviral cream appears to decrease the duration of symptoms by a small amount. Antiviral medications may also decrease the frequency of outbreaks.About 2.5 per 1000 people are affected with outbreaks in any given year. After one episode about 33% of people develop subsequent episodes. Onset often occurs in those less than 20 years old and 80% develop antibodies for the virus by this age. In those with recurrent outbreaks, these typically happen less than three times a year. The frequency of outbreaks generally decreases over time.

Signs and symptoms
Herpes infections usually show no symptoms; when symptoms do appear they typically resolve within two weeks.  The main symptom of oral infection is inflammation of the mucosa of the cheek and gums—known as acute herpetic gingivostomatitis—which occurs within 5–10 days of infection. Other symptoms may also develop, including headache, nausea, dizziness and painful ulcers—sometimes confused with canker sores—fever, and sore throat.Primary HSV infection in adolescents frequently manifests as severe pharyngitis with lesions developing on the cheek and gums. Some individuals develop difficulty in swallowing (dysphagia) and swollen lymph nodes (lymphadenopathy). Primary HSV infections in adults often results in pharyngitis similar to that observed in glandular fever (infectious mononucleosis), but gingivostomatitis is less likely.Recurrent oral infection is more common with HSV-1 infections than with HSV-2. Symptoms typically progress in a series of eight stages:

Latent (weeks to months incident-free):  The remission period; After initial infection, the viruses move to sensory nerve ganglia (trigeminal ganglion), where they reside as lifelong, latent viruses.  Asymptomatic shedding of contagious virus particles can occur during this stage.
Prodromal (day 0–1): Symptoms often precede a recurrence.  Symptoms typically begin with tingling (itching) and reddening of the skin around the infected site.  This stage can last from a few days to a few hours preceding the physical manifestation of an infection and is the best time to start treatment.
Inflammation (day 1):  Virus begins reproducing and infecting cells at the end of the nerve.  The healthy cells react to the invasion with swelling and redness displayed as symptoms of infection.
Pre-sore (day 2–3): This stage is defined by the appearance of tiny, hard, inflamed papules and vesicles that may itch and are painfully sensitive to touch.  In time, these fluid-filled blisters form a cluster on the lip (labial) tissue, the area between the lip and skin (vermilion border), and can occur on the nose, chin, and cheeks.
Open lesion (day 4): This is the most painful and contagious of the stages. All the tiny vesicles break open and merge to create one big, open, weeping ulcer.  Fluids are slowly discharged from blood vessels and inflamed tissue.  This watery discharge is teeming with active viral particles and is highly contagious. Depending on the severity, one may develop a fever and swollen lymph glands under the jaw.
Crusting (day 5–8): A honey/golden crust starts to form from the syrupy exudate. This yellowish or brown crust or scab is not made of active virus but from blood serum containing useful proteins such as immunoglobulins. This appears as the healing process begins. The sore is still painful at this stage, but, more painful, however, is the constant cracking of the scab as one moves or stretches their lips, as in smiling or eating.  Virus-filled fluid will still ooze out of the sore through any cracks.
Healing (day 9–14): New skin begins to form underneath the scab as the virus retreats into latency. A series of scabs will form over the sore (called Meier Complex), each one smaller than the last. During this phase irritation, itching, and some pain are common.
Post-scab (12–14 days): A reddish area may linger at the site of viral infection as the destroyed cells are regenerated. Virus shedding can still occur during this stage.The recurrent infection is thus often called herpes simplex labialis. Rare reinfections occur inside the mouth (intraoral HSV stomatitis) affecting the gums, alveolar ridge, hard palate, and the back of the tongue, possibly accompanied by herpes labialis.A lesion caused by herpes simplex can occur in the corner of the mouth and be mistaken for angular cheilitis of another cause. Sometimes termed "angular herpes simplex". A cold sore at the corner of the mouth behaves similarly to elsewhere on the lips. Rather than utilizing antifungal creams, angular herpes simplex is treated in the same way as a cold sore, with topical antiviral drugs.

Causes
Herpes labialis infection occurs when the herpes simplex virus comes into contact with oral mucosal tissue or abraded skin of the mouth. Infection by the type 1 strain of herpes simplex virus (HSV-1) is most common; however, cases of oral infection by the type 2 strain are increasing.Oral HSV-2 shedding is rare, and "usually noted in the context of first episode genital herpes." In general, both types can cause oral or genital herpes.Cold sores are the result of the virus reactivating in the body. Once HSV-1 has entered the body, it never leaves. The virus moves from the mouth to remain latent in the central nervous system. In approximately one-third of people, the virus can "wake up" or reactivate to cause disease. When reactivation occurs, the virus travels down the nerves to the skin where it may cause blisters (cold sores) around the lips or mouth area.In case of Herpes zoster the nose can be affected.Cold sore outbreaks may be influenced by stress, menstruation, sunlight, sunburn, fever, dehydration, or local skin trauma. Surgical procedures such as dental or neural surgery, lip tattooing, or dermabrasion are also common triggers. HSV-1 can in rare cases be transmitted to newborn babies by family members or hospital staff who have cold sores; this can cause a severe disease called neonatal herpes simplex.
The colloquial term for this condition, "cold sore" comes from the fact that herpes labialis is often triggered by fever, for example, as may occur during an upper respiratory tract infection (i.e. a cold).People can transfer the virus from their cold sores to other areas of the body, such as the eye, skin, or fingers; this is called autoinoculation. Eye infection, in the form of conjunctivitis or keratitis, can happen when the eyes are rubbed after touching the lesion. Finger infection (herpetic whitlow) can occur when a child with cold sores or primary HSV-1 infection sucks their fingers.Blood tests for herpes may differentiate between type 1 and type 2. When a person is not experiencing any symptoms, a blood test alone does not reveal the site of infection. Genital herpes infections occurred with almost equal frequency as type 1 or 2 in younger adults when samples were taken from genital lesions. Herpes in the mouth is more likely to be caused by type 1, but (see above) also can be type  2. The only way to know for certain if a positive blood test for herpes is due to infection of the mouth, genitals, or elsewhere, is to sample from lesions. This is not possible if the affected individual is asymptomatic. The bodys immune system typically fight the virus.

Prevention
Primary Infection
The likelihood of the infection can be reduced through avoidance of touching an area with active infection and contact sports and frequent hand washing, use of mouth rinsing (anti-viral, anti-bacterial) products.</ref> During active infection (outbreaks with oral lesions) avoid oral-to-oral kissing and oral-genital sex without protection. HSV1 can be transmitted to uninfected partners through oral sex, resulting in genital lesions. Healthcare workers working with patients who have active lesions are advised to use gloves, eye protection, and mouth protection during physical, mucosal, and bronchoscopic procedures and examinations.

Recurrent Infection
In some cases, sun exposure can lead to HSV-1 reactivation, therefore use of zinc-based sunscreen or topical and oral therapeutics such as acyclovir and valacyclovir may prove helpful. Other triggers for recurrent herpetic infection includes fever, common cold, fatigue, emotional stress, trauma, sideropenia, oral cancer therapy, immunosuppression, chemotherapy, oral and facial surgery, menstruation, and epidural morphine, and upset GI. Surgical procedures like nerve root decompression, facial dermabrasion, and ablative laser resurfacing can increase risks of reactivation by 50-70%.

Treatment
Despite no cure or vaccine for the virus, a human bodys immune system and specific antibodies typically fight the virus. Treatment options include no treatment, topical creams (indifferent, antiviral, and anaesthetic), and oral antiviral medications. Indifferent topical creams include zinc oxide and glycerin cream, which can have itching and burning sensation as side effects and docosanoll. Docosanol, a saturated fatty alcohol was approved by the United States Food and Drug Administration for herpes labialis in adults with properly functioning immune systems.  It is comparable in effectiveness to prescription topical antiviral agents.  Due to docosanols mechanism of action, there is little risk of drug resistance. Antivirals creams include acyclovir and penciclovir, which can speed healing by as much as 10%. Oral antivirals include acyclovir, valaciclovir, and famciclovir.  Famciclovir or valacyclovir, taken in pill form, can be effective using a single day, high-dose application and is more cost effective and convenient than the traditional treatment of lower doses for 5–7 days. Anaesthetic creams include lidocaine and prilocaine which has shown reduction in duration of subjective symptoms and eruptions.Treatment recommendations vary on the severity of the symptoms and chronicity of the infection. Treatment with oral antivirals such as acyclovir in children within 72 hours of illness onset has shown to shorten duration of fever, odynophagia, and lesions, and to reduce viral shedding. For patient with mild to moderate symptoms, local anaesthetic such as lidocaine for pain without antiviral may be sufficient </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 Heterotopic ossification and can you explain it in depth? [/INST] Heterotopic ossification (HO) is the process by which bone tissue forms outside of the skeleton in muscles and soft tissue.

Symptoms
In traumatic heterotopic ossification (traumatic myositis ossificans), the patient may complain of a warm, tender, firm swelling in a muscle and decreased range of motion in the joint served by the muscle involved.  There is often a history of a blow or other trauma to the area a few weeks to a few months earlier.  Patients with traumatic neurological injuries, severe neurologic disorders or severe burns who develop heterotopic ossification experience limitation of motion in the areas affected.

Causes
Heterotopic ossification of varying severity can be caused by surgery or trauma to the hips and legs. About every third patient who has total hip arthroplasty (joint replacement) or a severe fracture of the long bones of the lower leg will develop heterotopic ossification, but is uncommonly symptomatic.  Between 50% and 90% of patients who developed heterotopic ossification following a previous hip arthroplasty will develop additional heterotopic ossification.Heterotopic ossification often develops in patients with traumatic brain or spinal cord injuries, other severe neurologic disorders or severe burns, most commonly around the hips.  The mechanism is unknown.  This may account for the clinical impression that traumatic brain injuries cause accelerated fracture healing.There are also rare genetic disorders causing heterotopic ossification such as fibrodysplasia ossificans progressiva (FOP), a condition that causes injured bodily tissues to be replaced by heterotopic bone. Characteristically exhibiting in the big toe at birth, it causes the formation of heterotopic bone throughout the body over the course of the sufferers life, causing chronic pain and eventually leading to the immobilisation and fusion of most of the skeleton by abnormal growths of bone.Another rare genetic disorder causing heterotopic ossification is progressive osseous heteroplasia (POH), is a condition characterized by cutaneous or subcutaneous ossification.

Diagnosis
During the early stage, an x-ray will not be helpful because there is no calcium in the matrix. (In an acute episode which is not treated, it will be 3– 4 weeks after onset before the x-ray is positive.) Early laboratory tests are not very helpful.  Alkaline phosphatase will be elevated at some point, but initially may be only slightly elevated, rising later to a high value for a short time.  Unless weekly tests are done, this peak value may not be detected. It is not useful in patients who have had fractures or spine fusion recently, as they will cause elevations.The only definitive diagnostic test in the early acute stage is a bone scan, which will show heterotopic ossification 7 – 10 days earlier than an x-ray.  The three-phase bone scan may be the most sensitive method of detecting early heterotopic bone formation.  However, an abnormality detected in the early phase may not progress to the formation of heterotopic bone.  Another finding, often misinterpreted as early heterotopic bone formation, is an increased (early) uptake around the knees or the ankles in a patient with a very recent spinal cord injury.  It is not clear exactly what this means, because these patients do not develop heterotopic bone formation </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 Hirsutism and can you explain it in depth? [/INST] Hirsutism is excessive body hair on parts of the body where hair is normally absent or minimal. The word is from early 17th century: from Latin hirsutus meaning "hairy". It may refer to a "male" pattern of hair growth that may be a sign of a more serious medical condition, especially if it develops well after puberty. Cultural stigma against hirsutism can cause much psychological distress and social difficulty. Discrimination based on facial hirsutism often leads to the avoidance of social situations and to symptoms of anxiety and depression.Hirsutism is usually the result of an underlying endocrine imbalance, which may be adrenal, ovarian, or central. It can be caused by increased levels of androgen hormones. The amount and location of the hair is measured by a Ferriman-Gallwey score. It is different from hypertrichosis, which is excessive hair growth anywhere on the body.Treatments may include birth control pills that contain estrogen and progestin, antiandrogens, or insulin sensitizers.Hirsutism affects between 5–15% of women across all ethnic backgrounds. Depending on the definition and the underlying data, approximately 40% of women have some degree of facial hair.

Causes
The causes of hirsutism can be divided into endocrine imbalances and non-endocrine etiologies. It is important to begin by first determining the distribution of body hair growth. If hair growth follows a male distribution, it could indicate the presence of increased androgens or hyperandrogenism. However, there are other hormones not related to androgens that can lead to hirsutism. A detailed history is taken by a provider in search of possible causes for hyperandrogenism or other non-endocrine-related causes. If the distribution of hair growth occurs throughout the body, this is referred to as hypertrichosis, not hirsutism.

Endocrine causes
Ovarian cysts such as in polycystic ovary syndrome (PCOS), the most common cause in women.
Adrenal gland tumors, adrenocortical adenomas, and adrenocortical carcinoma, as well as adrenal hyperplasia due to pituitary adenomas (as in Cushings disease).
Inborn errors of steroid metabolism such as in congenital adrenal hyperplasia, most commonly caused by 21-hydroxylase deficiency.
Acromegaly and gigantism (growth hormone and IGF-1 excess), usually due to pituitary tumors.

Causes of hirsutism not related to hyperandrogenism include
Familial: Family history of hirsutism with normal androgen levels.
Drug-induced: medications were used before the onset of hirsutism. The recommendation is to stop the medication and replace it with another.Minoxidil
Testosterone, danazol, progestins, anabolic steroids, valproic acid, methyldopa
Pregnancy or post-menopause: moderate hirsutism due to prolactin secretion and hyperandrogenism due to decrease estrogen production, respectively.
Idiopathic: When no other cause can be attributed to an individuals hirsutism, the cause is considered idiopathic by exclusion. In these cases, mensuration cycles and androgen levels are normal.

Diagnosis
Hirsutism is a clinical diagnosis of excessive androgenic, terminal hair growth. A complete physical evaluation should be done prior to initiating more extensive studies, the examiner should differentiate between widespread body hair increase and male pattern virilization. One method of evaluating hirsutism is the Ferriman-Gallwey Score which gives a score based on the amount and location of hair growth. The Ferriman-Gallwey Score has various cutoffs due to variable expressivity of hair growth based on ethnic background.Diagnosis of patients with even mild hirsutism should include assessment of ovulation and ovarian ultrasound, due to the high prevalence of polycystic ovary syndrome (PCOS), as well as 17α-hydroxyprogesterone (because of the possibility of finding nonclassic 21-hydroxylase deficiency). People with hirsutism may present with an elevated serum dehydroepiandrosterone sulfate (DHEA-S) level, however, additional imaging is required to discriminate between malignant and benign etiologies of adrenal hyperandrogenism.  Levels greater than 700 μg/dL are indicative of adrenal gland dysfunction, particularly congenital adrenal hyperplasia due to 21-hydroxylase deficiency. However, PCOS and idiopathic hirsutism make up 90% of cases.

Treatment
Treatment of hirsutism is indicated when hair growth causes patient distress. The two main approaches to treatment are pharmacologic therapies targeting androgen production/action, and direct hair removal methods including electrolysis and photoepilaiton. These may be used independently or in combination.

Pharmacologic therapies
Common medications consist of antiandrogens, insulin sensitizers, and oral contraceptive pills. All three types of therapy have demonstrated efficacy on their own, however insulin sensitizers are shown to be less effective than antiandrogens and oral contraceptive pills. The therapies may be combined, as directed by a physician, in line with the patients medical goals. Antiandrogens are drugs that block the effects of androgens like testosterone and dihydrotestosterone (DHT) in the body. They are the most effective pharmacologic treatment for patient-important hirsutism, however they have teratogenic potential, and are therefore not recommended in people who are pregnant or desire pregnancy. Current data does not favor any one type of oral contraceptive over another.List of medications:

Spironolactone: An antimineralocorticoid with additional antiandrogenic activity at high dosages
Cyproterone acetate: A dual antiandrogen and progestogen. In addition to single form, it is also available in some formulations of combined oral contraceptives at a low dosage (see below). It has a risk of liver damage.
Flutamide: A pure antiandrogen. It has been found to possess equivalent or greater effectiveness than spironolactone, cyproterone acetate, and finasteride in the treatment of hirsutism. However, it has a high risk of liver damage and hence is no longer recommended as a first- or second-line treatment. Flutamide is safe and effective.
Bicalutamide: A pure antiandrogen </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 Hookworm infection and can you explain it in depth? [/INST] Hookworm infection is an infection by a type of intestinal parasite known as a hookworm. Initially, itching and a rash may occur at the site of infection. Those only affected by a few worms may show no symptoms. Those infected by many worms may experience abdominal pain, diarrhea, weight loss, and tiredness. The mental and physical development of children may be affected. Anemia may result.Two common hookworm infections in humans are ancylostomiasis and necatoriasis, caused by the species Ancylostoma duodenale and Necator americanus respectively. Hookworm eggs are deposited in the stools of infected people. If these end up in the environment, they can hatch into larvae (immature worms), which can then penetrate the skin. One type can also be spread through contaminated food. Risk factors include walking barefoot in warm climates, where sanitation is poor. Diagnosis is by examination of a stool sample with a microscope.The disease can be prevented on an individual level by not walking barefoot in areas where the disease is common. At a population level, decreasing outdoor defecation, not using raw feces as fertilizer, and mass deworming is effective. Treatment is typically with the medications albendazole or mebendazole for one to three days. Iron supplements may be needed in those with anemia.Hookworms infected about 428 million people in 2015. Heavy infections can occur in both children and adults, but are less common in adults. They are rarely fatal. Hookworm infection is a soil-transmitted helminthiasis and classified as a neglected tropical disease.

Signs and symptoms
No symptoms or signs are specific for hookworm infection, but they give rise to a combination of intestinal inflammation and progressive iron-deficiency anemia and protein deficiency. Coughing, chest pain, wheezing, and fever sometimes result from severe infection. Epigastric pains, indigestion, nausea, vomiting, constipation, and diarrhea can occur early or in later stages, as well, although gastrointestinal symptoms tend to improve with time. Signs of advanced severe infection are those of anemia and protein deficiency, including emaciation, cardiac failure, and abdominal distension with ascites.Larval invasion of the skin (mostly in the Americas) can produce a skin disease called cutaneous larva migrans also known as creeping eruption. The hosts of these worms are not human and the larvae can only penetrate the upper five layers of the skin, where they give rise to intense, local itching, usually on the foot or lower leg, known as ground itch. This infection is due to larvae from the A. braziliense hookworm. The larvae migrate in tortuous tunnels between the stratum basale and stratum corneum of the skin, causing serpiginous vesicular lesions. With advancing movement of the larvae, the rear portions of the lesions become dry and crusty. The lesions are typically intensely itchy.

Incubation period
The incubation period can vary between a few weeks to many months, and is largely dependent on the number of hookworm parasites an individual is infected with.

Cause
Hookworm infections in humans include ancylostomiasis and necatoriasis. Ancylostomiasis is caused by Ancylostoma duodenale, which is the more common type found in the Middle East, North Africa, India, and (formerly) in southern Europe. Necatoriasis is caused by Necator americanus, the more common type in the Americas, sub-Saharan Africa, Southeast Asia, China, and Indonesia.Other animals such as birds, dogs, and cats may also be affected. A. tubaeforme infects cats, A. caninum infects dogs, and A. braziliense and Uncinaria stenocephala infect both cats and dogs. Some of these infections can be transmitted to humans.

Morphology
A. duodenale worms are grayish white or pinkish with the head slightly bent in relation to the rest of the body. This bend forms a definitive hook shape at the anterior end for which hookworms are named. They possess well-developed mouths with two pairs of teeth. While males measure approximately one centimeter by 0.5 millimeter, the females are often longer and stouter. Additionally, males can be distinguished from females based on the presence of a prominent posterior copulatory bursa.N. americanus is very similar in morphology to A. duodenale. N. americanus is generally smaller than A. duodenale with males usually 5 to 9 mm long and females about 1 cm long. Whereas A. duodenale possesses two pairs of teeth, N. americanus possesses a pair of cutting plates in the buccal capsule. Additionally, the hook shape is much more defined in Necator than in Ancylostoma.

Life cycle
The hookworm thrives in warm soil where temperatures are over 18 °C (64 °F). They exist primarily in sandy or loamy soil and cannot live in clay or muck. Rainfall averages must be more than 1,000 mm (39 in) a year for them to survive. Only if these conditions exist can the eggs hatch. Infective larvae of N. americanus can survive at higher temperatures, whereas those of A. duodenale are better adapted to cooler climates. Generally, they live for only a few weeks at most under natural conditions, and die almost immediately on exposure to direct sunlight or desiccation.Infection of the host is by the larvae, not the eggs. While A. duodenale can be ingested, the usual method of infection is through the skin; this is commonly caused by walking barefoot through areas contaminated with fecal matter. The larvae are able to penetrate the skin of the foot, and once inside the body, they migrate through the vascular system to the lungs, and from there up the trachea, and are swallowed. They then pass down the esophagus and enter the digestive system, finishing their journey in the intestine, where the larvae mature into adult worms.Once in the host gut, Necator tends to cause a prolonged infection, generally 1 to 5 years (many worms die within a year or two of infecting), though some adult worms have been recorded to live for 15 years or more. Ancylostoma adults are short-lived, surviving on average for only about 6 months. However, the infection can be prolonged because dormant larvae can be "recruited" sequentially from tissue "stores" (see Pathology, above) over many years, to replace expired adult worms. This can give rise to seasonal fluctuations in infection prevalence and intensity (apart from normal seasonal variations in transmission).

They mate inside the host, females laying up to 30,000 eggs per day and some 18 to 54 million eggs during their lifetimes, which pass out in feces. Because 5 to 7 weeks are needed for adult worms to mature, mate, and produce eggs, in the early stages of very heavy infection, acute symptoms might occur without any eggs being detected in the patients feces. This can make diagnosis very difficult.N. americanus and A. duodenale eggs can be found in warm, moist soil where they eventually hatch into first-stage larvae, or L1. L1, the feeding noninfective rhabditoform stage, will feed on soil microbes and eventually molt into second-stage larvae, L2, which is also in the rhabditoform stage. It will feed for about 7 days and then molt into the third-stage larvae, or L3. This is the filariform stage of the parasite, that is, the nonfeeding infective form of the larvae. The L3 larvae are extremely motile and seek higher ground to increase their chances of penetrating the skin of a human host. The L3 larvae can survive up to 2 weeks without finding a host. While N. americanus larvae only infect through penetration of skin, A. duodenale can infect both through penetration and orally. After the L3 larvae have successfully entered the host, they then travel through the subcutaneous venules and lymphatic vessels of the human host. Eventually, the L3 larvae enter the lungs through the pulmonary capillaries and break out into the alveoli. They then travel up the trachea to be coughed and swallowed by the host. After being swallowed, the L3 larvae are then found in the small intestine, where they molt into the L4, or adult worm stage. The entire process from skin penetration to adult development takes about 5–9 weeks. The female adult worms release eggs (N. americanus about 9,000–10,000 eggs/day and A. duodenale 25,000–30,000 eggs/day), which are passed in the feces of the human host. These eggs hatch in the environment within several days and the cycle starts anew.

Pathophysiology
Hookworm infection is generally considered to be asymptomatic, but as Norman Stoll described in 1962, it is an extremely dangerous infection because its damage is "silent and insidious." An individual may experience general symptoms soon after infection. Ground-itch, which is an allergic reaction at the site of parasitic penetration and entry, is common in patients infected with N. americanus. Additionally, cough and pneumonitis may result as the larvae begin to break into the alveoli and travel up the trachea. Then once the larvae reach the small intestine of the host and begin to mature, the infected individual will experience diarrhea and other gastrointestinal discomfort. However, the "silent and insidious" symptoms referred to by Stoll are related to chronic, heavy-intensity hookworm infections. Major morbidity associated with hookworm infection is caused by intestinal blood loss, iron deficiency anemia, and protein malnutrition. They result mainly from adult hookworms in the small intestine ingesting blood, rupturing erythrocytes, and degrading hemoglobin in the host. This long-term blood loss can manifest itself physically through facial and peripheral edema; eosinophilia and pica/geophagy caused by iron deficiency anemia are also experienced by some hookworm-infected patients. Recently, more attention has been given to other important outcomes of hookworm infection that play a large role in public health. It is now widely accepted that children who have chronic hookworm infection can experience growth retardation as well as intellectual and cognitive impairments. Additionally, recent research has focused on the potential of adverse maternal-fetal outcomes when the mother is infected with hookworm during pregnancy.The disease was linked to nematode worms (Ankylostoma duodenalis) from one-third to half an inch long in the intestine chiefly through the labours of Theodor Bilharz and Griesinger in Egypt (1854).The symptoms can be linked to inflammation in the gut stimulated by feeding hookworms, such as nausea, abdominal pain and intermittent diarrhea, and to progressive anemia in prolonged disease: capricious appetite, pica/geophagy (or dirt-eating), obstinate constipation followed by diarrhea, palpitations, thready pulse, coldness of the skin, pallor of the mucous membranes, fatigue and weakness, shortness of breath and in cases running a fatal course, dysentery, hemorrhages and edema. The worms suck blood and damage the mucosa. However, the blood loss in the stools is not visibly apparent.
Blood tests in early infection often show a rise in numbers of eosinophils, a type of white blood cell that is preferentially stimulated by worm infections in tissues (large numbers of eosinophils are also present in the local inflammatory response). Falling blood hemoglobin levels will be seen in cases of prolonged infection with anemia.
In contrast to most intestinal helminthiases, where the heaviest parasitic loads tend to occur in children, hookworm prevalence and intensity can be higher among adult males. The explanation for this is that hookworm infection tends to be occupational, so that coworkers and other close groups maintain a high prevalence of infection among themselves by contaminating their work environment. However, in most endemic areas, adult women are the most severely affected by anemia, mainly because they have much higher physiological needs for iron (menstruation, repeated pregnancy).An interesting consequence of this in the case of Ancylostoma duodenale infection is translactational transmission of infection: the skin-invasive larvae of this species do not all immediately pass through the lungs and on into the gut, but spread around the body via the circulation, to become dormant inside muscle fibers. In a pregnant woman, after childbirth some or all of these larvae are stimulated to re-enter the circulation (presumably by sudden hormonal changes), then to pass into the mammary glands, so that the newborn baby can receive a large dose of infective larvae through its mothers milk. This accounts for otherwise inexplicable cases of very heavy, even fatal, hookworm infections in children a month or so of age, in places such as China, India and northern Australia.
An identical phenomenon is much more commonly seen with Ancylostoma caninum infections in dogs, where the newborn pups can even die of hemorrhaging from their intestines caused by massive numbers of feeding hookworms. This also reflects the close evolutionary link between the human and canine parasites, which probably have a common ancestor dating back to when humans and dogs first started living closely together.
Filariform larvae is the infective stage of the parasite: infection occurs when larvae in soil penetrate the skin, or when they are ingested through contaminated food and water following skin penetration.

Diagnosis
Diagnosis depends on finding characteristic worm eggs on microscopic examination of the stools, although this is not possible in early infection. Early signs of infection in most dogs include limbular limping and anal itching. The eggs are oval or elliptical, measuring 60 by 40 µm, colorless, not bile stained and with a thin transparent hyaline shell membrane. When released by the worm in the intestine, the egg contains an unsegmented ovum. During its passage down the intestine, the ovum develops and thus the eggs passed in feces have a segmented ovum, usually with 4 to 8 blastomeres.
As the eggs of both Ancylostoma and Necator (and most other hookworm species) are indistinguishable, to identify the genus, they must be cultured in the lab to allow larvae to hatch out. If the fecal sample is left for a day or more under tropical conditions, the larvae will have hatched out, so eggs might no longer be evident. In such a case, it is essential to distinguish hookworms from Strongyloides larvae, as infection with the latter has more serious implications and requires different management. The larvae of the two hookworm species can also be distinguished microscopically, although this would not be done routinely, but usually for research purposes. Adult worms are rarely seen (except via endoscopy, surgery or autopsy), but if found, would allow definitive identification of the species. Classification can be performed based on the length of the buccal cavity, the space between the oral opening and the esophagus: hookworm rhabditoform larvae have long buccal cavities whereas Strongyloides rhabditoform larvae have short buccal cavities.Recent research has focused on the development of DNA-based tools for diagnosis of infection, specific identification of hookworm, and analysis of genetic variability within hookworm populations. Because hookworm eggs are often indistinguishable from other parasitic eggs, PCR assays could serve as a molecular approach for accurate diagnosis of hookworm in the feces.

Prevention
The infective larvae develop and survive in an environment of damp dirt, particularly sandy and loamy soil. They cannot survive in clay or muck. The main lines of precaution are those dictated by good hygiene behaviors:

Do not defecate in the open, but rather in toilets.
Do not use untreated human excreta or raw sewage as fertilizer in agriculture.
Do not walk barefoot in known infected areas.
Deworm pet dogs and cats. Canine and feline hookworms rarely develop to adulthood in humans. Ancylostoma caninum, the common dog hookworm, occasionally develops into an adult to cause eosinophilic enteritis in people, but their invasive larvae can cause an itchy rash called cutaneous larva migrans.Moxidectin is available in the United States as (imidacloprid + moxidectin) topical solution for dogs and cats. It utilizes moxidectin for control and prevention of roundworms, hookworms, heartworms, and whipworms.

Children
Most of these public health concerns have focused on children who are infected with hookworm. This focus on children is largely due to the large body of evidence that has demonstrated strong associations between hookworm infection and impaired learning, increased absences from school, and decreased future economic productivity. In 2001, the 54th World Health Assembly passed a resolution demanding member states to attain a minimum target of regular deworming of at least 75% of all at-risk school children by the year 2010. A 2008 World Health Organization publication reported on these efforts to treat at-risk school children. Some of the interesting statistics were as follows: 1) only 9 out of 130 endemic countries were able to reach the 75% target goal; and 2) less than 77 million school-aged children (of the total 878 million at risk) were reached, which means that only 8.78% of at-risk children are being treated for hookworm infection.

School-based mass deworming
School-based mass deworming programs have been the most popular strategy to address the issue of hookworm infection in children. School-based programs are extremely cost-effective as schools already have an available, extensive, and sustained infrastructure with a skilled workforce that has a close relationship with the community. With little training from a local health system, teachers can easily administer the drugs which often cost less than US$0.50 per child per year.Recently, many people have begun to question if the school-based programs are necessarily the most effective approach. An important concern with school-based programs is that they often do not reach children who do not attend school, thus ignoring a large number of at-risk children. A 2008 study by Massa et al. continued the debate regarding school-based programs. They examined the effects of community-directed treatments versus school-based treatments in the Tanga Region of Tanzania. A major conclusion was that the mean infection intensity of hookworm was significantly lower in the villages employing the community-directed treatment approach than the school-based approach. The community-directed treatment model used in this specific study allowed villagers to take control of the childs treatment by having villagers select their own community drug distributors to administer the antihelminthic drugs. Additionally, villagers organized and implemented their own methods for distributing the drugs to all children. The positive results associated with this new model highlight the need for large-scale community involvement in deworming campaigns.

Public health education
Many mass deworming programs also combine their efforts with a public health education. These health education programs often stress important preventative techniques such as: washing your hands before eating, and staying away from water/areas contaminated by human feces. These programs may also stress that shoes must be worn, however, these come with their own health risks and may not be effective. Shoe wearing patterns in towns and villages across the globe are determined by cultural beliefs, and the levels of education within that society. The wearing of shoes will prevent the entry of hookworm infections from the surrounding soils into tender skin regions; such as areas between the toes.

Sanitation
Historical examples, such as the hookworm campaigns in Mississippi and Florida from 1943 to 1947 have shown that the primary cause of hookworm infection is poor sanitation, which can be solved by building and maintaining toilets. But while these may seem like simple tasks, they raise important public health challenges. Most infected populations are from poverty-stricken areas with very poor sanitation. Thus, it is most likely that at-risk children do not have access to clean water to wash their hands and live in environments with no proper sanitation infrastructure. Health education, therefore, must address preventive measures in ways that are both feasible and sustainable in the context of resource-limited settings.

Integrated approaches
Evaluation of numerous public health interventions has generally shown that improvement in each individual component ordinarily attributed to poverty (for example, sanitation, health education and underlying nutrition status) often have minimal impact on transmission. For example, one study found that the introduction of latrines into a resource-limited community only reduced the prevalence of hookworm infection by four percent. However, another study in Salvador, Brazil found that improved drainage and sewerage had a significant impact on the prevalence of hookworm infection but no impact at all on the intensity of hookworm infection. This seems to suggest that environmental control alone has a limited but incomplete effect on the transmission of hookworms. It is imperative, therefore, that more research is performed to understand the efficacy and sustainability of integrated programs that combine numerous preventive methods including education, sanitation, and treatment.

Treatment
Anthelmintic drugs
The most common treatment for hookworm are benzimidazoles, specifically albendazole and mebendazole. BZAs kill adult worms by binding to the nematodes β-tubulin and subsequently inhibiting microtubule polymerization within the parasite. In certain circumstances, levamisole and pyrantel pamoate may be used. A 2008 review found that the efficacy of single-dose treatments for hookworm infections were as follows: 72% for albendazole, 15% for mebendazole, and 31% for pyrantel pamoate. This substantiates prior claims that albendazole is much more effective than mebendazole for hookworm infections. Also of note is that the World Health Organization does recommend anthelmintic treatment in pregnant women after the first trimester. It is also recommended that if the patient also has anemia that ferrous sulfate (200 mg) be administered three times daily at the same time as anthelmintic treatment; this should be continued until hemoglobin values return to normal which could take up to 3 months.Hookworm infection can be treated with local cryotherapy when the hookworm is still in the skin.Albendazole is effective both in the intestinal stage and during the stage the parasite is still migrating under the skin.In case of anemia, iron supplementation can cause relief symptoms of iron-deficiency anemia. However, as red blood cell levels are restored, shortage of other essentials such as folic acid or vitamin B12 may develop, so these might also be supplemented.
During the 1910s, common treatments for hookworm included thymol, 2-naphthol, chloroform, gasoline, and eucalyptus oil. By the 1940s, the treatment of choice used tetrachloroethylene, given as 3 to 4 cc in the fasting state, followed by 30 to 45 g of sodium sulfate. Tetrachloroethylene was reported to have a cure rate of 80 percent for Necator infections, but 25 percent in Ancylostoma infections, and often produced mild intoxication in the patient.

Reinfection and drug resistance
Other important issues related to the treatment of hookworm are reinfection and drug resistance. It has been shown that reinfection after treatment can be extremely high. Some studies even show that 80% of pretreatment hookworm infection rates can be seen in treated communities within 30–36 months. While reinfection may occur, it is still recommended that regular treatments be conducted as it will minimize the occurrence of chronic outcomes. There are also increasing concerns about the issue of drug resistance. Drug resistance has appeared in front-line anthelmintics used for livestock nematodes. Generally human nematodes are less likely to develop resistance due to longer reproducing times, less frequent treatment, and more targeted treatment. Nonetheless, the global community must be careful to maintain the effectiveness of current anthelmintic as no new anthelmintic drugs are in the late-stage development.

Epidemiology
It is estimated that between 576 and 740 million individuals are infected with hookworm. Of these infected individuals, about 80 million are severely affected. The major cause of hookworm infection is N. americanus which is found in the Americas, sub-Saharan Africa, and Asia. A. duodenale is found in more scattered focal environments, namely Europe and the Mediterranean. Most infected individuals are concentrated in sub-Saharan Africa and East Asia/the Pacific Islands with each region having estimates of 198 million and 149 million infected individuals, respectively. Other affected regions include: South Asia (50 million), Latin America and the Caribbean (50 million), South Asia (59 million), Middle East/North Africa (10 million). A majority of these infected individuals live in poverty-stricken areas with poor sanitation. Hookworm infection is most concentrated among the worlds poorest who live on less than $2 a day.While hookworm infection may not directly lead to mortality, its effects on morbidity demand immediate attention. When considering disability-adjusted life years (DALYs), neglected tropical diseases, including hookworm infection, rank among diarrheal diseases, ischemic heart disease, malaria, and tuberculosis as one of the most important health problems of the developing world.
It has been estimated that as many as 22.1 million DALYs have been lost due to hookworm infection. Recently, there has been increasing interest to address the public health concerns associated with hookworm infection. For example, the Bill & Melinda Gates Foundation recently donated US$34 million to fight Neglected Tropical Diseases including hookworm infection. Former US President Clinton also announced a mega-commitment at the Clinton Global Initiative (CGI) 2008 Annual Meeting to de-worm 10 million children.Many of the numbers regarding the prevalence of hookworm infection are estimates as there is no international surveillance mechanism currently in place to determine prevalence and global distribution. Some prevalence rates have been measured through survey data in endemic regions around the world. The following are some of the most recent findings on prevalence rates in regions endemic with hookworm.
Darjeeling, Hooghly District, West Bengal, India (Pal et al. 2007)
43% infection rate of predominantly N. americanus although with some A. duodenale infection
Both hookworm infection load and degree of anemia in the mild rangeXiulongkan Village, Hainan Province, China (Gandhi et al. 2001)
60% infection rate of predominantly N. americanus
Important trends noted were that prevalence increased with age (plateau of about 41 years) and women had higher prevalence rates than menHòa Bình, Northwest Vietnam (Verle et al. 2003)
52% of a total of 526 tested households infected
Could not identify species, but previous studies in North Vietnam reported N. americanus in more than 95% of hookworm larvaeMinas Gerais, Brazil (Fleming et al. 2006)
63% infection rate of predominantly N. americanusKwaZulu-Natal, South Africa (Mabaso et al. 2004)
Inland areas had a prevalence rate of 9% of N. americanus
Coastal plain areas had a prevalence rate of 63% of N. americanusLowndes County, Alabama, United States
35% infection rate of predominantly N. americanusThere have also been technological developments that may facilitate more accurate mapping of hookworm prevalence. Some researchers have begun to use geographical information systems (GIS) and remote sensing (RS) to examine helminth ecology and epidemiology. Brooker et al. utilized this technology to create helminth distribution maps of sub-Saharan Africa. By relating satellite derived environmental data with prevalence data from school-based surveys, they were able to create detailed prevalence maps. The study focused on a wide range of helminths, but interesting conclusions about hookworm specifically were found. As compared to other helminths, hookworm is able to survive in much hotter conditions and was highly prevalent throughout the upper end of the thermal range.Improved molecular diagnostic tools are another technological advancement that could help improve existing prevalence statistics. Recent research has focused on the development of a DNA-based tool that can be used for diagnosis of infection, specific identification of hookworm, and analysis of genetic variability in hookworm populations. Again this can serve as a major tool for different public health measures against hookworm infection. Most research regarding diagnostic tools is now focused on the creation of a rapid and cost-effective assay for the specific diagnosis of hookworm infection. Many are hopeful that its development can be achieved within the next five years.

History
Discovery
The symptoms now attributed to hookworm appear in papyrus papers of ancient Egypt (c. 1500 BC), described as a derangement characterized by anemia. Avicenna, a Persian physician of the eleventh century, discovered the worm in several of his patients and related it to their disease. In later times, the condition was noticeably prevalent in the mining industry in England, France, Germany, Belgium, North Queensland, and elsewhere.Italian physician Angelo Dubini was the modern-day discoverer of the worm in 1838 after an autopsy of a peasant woman. Dubini published details in 1843 and identified the species as A. duodenale. Working in the Egyptian medical system in 1852 German physician Theodor Bilharz, drawing upon the work of colleague Wilhelm Griesinger, found these worms during autopsies and went a step further in linking them to local endemic occurrences of chlorosis, which would probably be called iron-deficiency anemia today.
A breakthrough came 25 years later following a diarrhea and anemia epidemic that took place among Italian workmen employed on the Gotthard Rail Tunnel. In an 1880 paper, physicians Camillo Bozzolo, Edoardo Perroncito, and Luigi Pagliani correctly hypothesized that hookworm was linked to the fact that workers had to defecate inside the 15 km tunnel, and that many wore worn-out shoes. The work environment often contained standing water, sometimes knee-deep, and the larvae were capable of surviving several weeks in the water, allowing them to infect many of the workers. In 1897, it was established that the skin was the principal avenue of infection and the biological life cycle of the hookworm was clarified.

Eradication programmes
In 1899, American zoologist Charles Wardell Stiles identified progressive pernicious anemia seen in the southern United States as being caused by the hookworm A. duodenale. Testing in the 1900s revealed very heavy infestations in school-age children. In Puerto Rico, Dr. Bailey K. Ashford, a US Army physician, organized and conducted a parasite treatment campaign, which cured approximately 300,000 people (one-third of the Puerto Rican population) and reduced the death rate from this anemia by 90 percent during the years 1903–04.

On October 26, 1909, the Rockefeller Sanitary Commission for the Eradication of Hookworm Disease was organized as a result of a gift of US$1 million from John D. Rockefeller, Sr. The five-year program was a remarkable success and a great contribution to the United States public health, instilling public education, medication, field work and modern government health departments in eleven southern states.
The hookworm exhibit was a prominent part of the 1910 Mississippi state fair.
The commission found that an average of 40% of school-aged children were infected with hookworm. Areas with higher levels of hookworm infection prior to the eradication program experienced greater increases in school enrollment, attendance, and literacy after the intervention. Econometric studies have shown that this effect cannot be explained by a variety of alternative factors, including differential trends across areas, changing crop prices, shifts in certain educational and health policies and the effect of malaria eradication. No significant contemporaneous results were found for adults who should have benefited less from the intervention owing to their substantially lower (prior) infection rates. The program nearly eradicated hookworm and would flourish afterward with new funding as the Rockefeller Foundation International Health Division.The RFs hookworm campaign in Mexico showed how science and politics play a role in developing health policies. It brought together government officials, health officials, public health workers, Rockefeller officials and the community. This campaign was launched to eradicate hookworms in Mexico. Although the campaign did not focus on long-term treatments, it did set the terms of the relationship between Mexico and the Rockefeller Foundation. The scientific knowledge behind this campaign helped shape public health policies, improved public health and built a strong relationship between US and Mexico.In the 1920s, hookworm eradication reached the Caribbean and Latin America, where great mortality was reported among people in the West Indies towards the end of the 18th century, as well as through descriptions sent from Brazil and various other tropical and sub-tropical regions.

Treatments
Treatment in the early 20th century relied on the use of Epsom salt to reduce protective mucus, followed by thymol to kill the worms. By the 1940s, tetrachloroethylene was the leading method. It was not until later in the mid-20th century when new organic drug compounds were developed.

Research
Anemia in pregnancy
It is estimated that a third of all pregnant women in developing countries are infected with hookworm, 56% of all pregnant women in developing countries experience anemia, 20% of all maternal deaths are either directly or indirectly related to anemia. Numbers like this have led to an increased interest in the topic of hookworm-related anemia during pregnancy. With the understanding that chronic hookworm infection can often lead to anemia, many people are now questioning if the treatment of hookworm could effect change in severe anemia rates and thus also on maternal and child health as well. Most evidence suggests that the contribution of hookworm to maternal anemia merits that all women of child-bearing age living in endemic areas be subject to periodic anthelmintic treatment. The World Health Organization even recommends that infected pregnant women be treated after their first trimester. Regardless of these suggestions, only Madagascar, Nepal and Sri Lanka have added deworming to their antenatal care programs.This lack of deworming of pregnant women is explained by the fact that most individuals still fear that anthelmintic treatment will result in adverse birth outcomes. But a 2006 study by Gyorkos et al. found that when comparing a group of pregnant women treated with mebendazole with a control placebo group, both illustrated rather similar rates in adverse birth outcomes. The treated group demonstrated 5.6% adverse birth outcomes, while the control group had 6.25% adverse birth outcomes. Furthermore, Larocque et al. illustrated that treatment for hookworm infection actually led to positive health results in the infant. This study concluded that treatment with mebendazole plus iron supplements during antenatal care significantly reduced the proportion of very low birth weight infants when compared to a placebo control group. Studies so far have validated recommendations to treat infected pregnant women for hookworm infection during pregnancy.
A review found that a single dose of antihelminthics (anti-worm drugs) given in the second trimester of pregnancy "may reduce maternal anaemia and worm prevalence when used in settings with high prevalence of maternal helminthiasis".The intensity of hookworm infection as well as the species of hookworm have yet to be studied as they relate to hookworm-related anemia during pregnancy. Additionally, more research must be done in different regions of the world to see if trends noted in completed studies persist.

Malaria co-infection
Co-infection with hookworm and Plasmodium falciparum is common in Africa. Although exact numbers are unknown, preliminary analyses estimate that as many as a quarter of African schoolchildren (17.8–32.1 million children aged 5–14 years) may be coincidentally at-risk of both P. falciparum and hookworm. While original hypotheses stated that co-infection with multiple parasites would impair the hosts immune response to a single parasite and increase susceptibility to clinical disease, studies have yielded contrasting results. For example, one study in Senegal showed that the risk of clinical malaria infection was increased in helminth-infected children in comparison to helminth-free children while other studies have failed to reproduce such results, and even among laboratory mouse experiments the effect of helminths on malaria is variable.Some hypotheses and studies suggest that helminth infections may protect against cerebral malaria due to the possible modulation of pro-inflammatory and anti-inflammatory cytokines responses. Furthermore, the mechanisms underlying this supposed increased susceptibility to disease are unknown. For example, helminth infections cause potent and highly polarized immune response characterized by increased T-helper cell type 2 (Th2) cytokine and Immunoglobulin E (IgE) production. However, the effect of such responses on the human immune response is unknown. Additionally, both malaria and helminth infection can cause anemia, but the effect of co-infection and possible enhancement of anemia is poorly understood.

Hygiene hypothesis and hookworm as therapy
The hygiene hypothesis states that infants and children who lack exposure to infectious agents are more susceptible to allergic diseases via modulation of immune system development. The theory was first proposed by David P. Strachan who noted that hay fever and eczema were less common in children who belonged to large families. Since then, studies have noted the effect of gastrointestinal worms on the development of allergies in the developing world. For example, a study in Gambia found that eradication of worms in some villages led to increased skin reactions to allergies among children.

Vaccines
While annual or semi-annual mass antihelminthic administration is a critical aspect of any public health intervention, many have begun to realize how unsustainable it is due to aspects such as poverty, high rates of re-infection, and diminished efficacy of drugs with repeated use. Current research, therefore, has focused on the development of a vaccine that could be integrated into existing control programs. The goal of vaccine development is not necessarily to create a vaccine with sterilizing immunity or complete protection against immunity. A vaccine that reduces the likelihood of vaccinated individuals developing severe infections and thus reduced blood and nutrient levels could still have a significant impact on the high burden of disease throughout the world.
Current research focuses on targeting two stages in the development of the worm: the larval stage and the adult stage. Research on larval antigens has focused on proteins that are members of the pathogenesis-related protein superfamily, Ancylostoma Secreted Proteins. Although they were first described in Anyclostoma, these proteins have also been successfully isolated from the secreted product of N. americanus. N. americanus ASP-2 (Na-ASP-2) is currently the leading larval-stage hookworm vaccine candidate. A randomized, double-blind, placebo-controlled study has already been performed; 36 healthy adults without a history of hookworm infection were given three intramuscular injections of three different concentrations of Na-ASP-2 and observed for six months after the final vaccination. The vaccine induced significant anti-Na-ASP-2 IgG and cellular immune responses. In addition, it was safe and produced no debilitating side effects. The vaccine is now in a phase one trial; healthy adult volunteers with documented evidence of previous infection in Brazil are being given the same dose concentration on the same schedule used in the initial study </s>