<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 Marburg virus disease and can you explain it in depth? [/INST] Marburg virus disease (MVD; formerly Marburg hemorrhagic fever) is a viral hemorrhagic fever in humans and primates caused by either of the two Marburgviruses: Marburg virus (MARV) and Ravn virus (RAVV). Its clinical symptoms are very similar to those of Ebola virus disease (EVD).Egyptian fruit bats are believed to be the normal carrier in nature and Marburg virus RNA has been isolated from them.

Signs and symptoms
The most detailed study on the frequency, onset, and duration of MVD clinical signs and symptoms was performed during the 1998–2000 mixed MARV/RAVV disease outbreak. A maculopapular rash, petechiae, purpura, ecchymoses, and hematomas (especially around needle injection sites) are typical hemorrhagic manifestations. However, contrary to popular belief, hemorrhage does not lead to hypovolemia and is not the cause of death (total blood loss is minimal except during labor). Instead, death occurs due to multiple organ dysfunction syndrome (MODS) due to fluid redistribution, hypotension, disseminated intravascular coagulation, and focal tissue necroses.Clinical phases of Marburg Hemorrhagic Fevers presentation are described below. Note that phases overlap due to variability between cases.

Incubation: 2–21 days, averaging 5–9 days.
Generalization Phase: Day 1 up to Day 5 from the onset of clinical symptoms. MHF presents with a high fever 104 °F (~40˚C) and a sudden, severe headache, with accompanying chills, fatigue, nausea, vomiting, diarrhea, pharyngitis, maculopapular rash, abdominal pain, conjunctivitis, and malaise.
Early Organ Phase: Day 5 up to Day 13. Symptoms include prostration, dyspnea, edema, conjunctival injection, viral exanthema, and CNS symptoms, including encephalitis, confusion, delirium, apathy, and aggression. Hemorrhagic symptoms typically occur late and herald the end of the early organ phase, leading either to eventual recovery or worsening and death. Symptoms include bloody stools, ecchymoses, blood leakage from venipuncture sites, mucosal and visceral hemorrhaging, and possibly hematemesis.
Late Organ Phase: Day 13 up to Day 21+. Symptoms bifurcate into two constellations for survivors and fatal cases. Survivors will enter a convalescence phase, experiencing myalgia, fibromyalgia, hepatitis, asthenia, ocular symptoms, and psychosis. Fatal cases continue to deteriorate, experiencing continued fever, obtundation, coma, convulsions, diffuse coagulopathy, metabolic disturbances, shock and death, with death typically occurring between days 8 and 16.

Causes
MVD is caused by two viruses; Marburg virus (MARV) and Ravn virus (RAVV), family Filoviridae.Marburgviruses are endemic in arid woodlands of equatorial Africa. Most marburgvirus infections were repeatedly associated with people visiting natural caves or working in mines. In 2009, the successful isolation of infectious MARV and RAVV was reported from healthy Egyptian fruit bat caught in caves. This isolation strongly suggests that Old World fruit bats are involved in the natural maintenance of marburgviruses and that visiting bat-infested caves is a risk factor for acquiring marburgvirus infections. Further studies are necessary to establish whether Egyptian rousettes are the actual hosts of MARV and RAVV or whether they get infected via contact with another animal and therefore serve only as intermediate hosts. Another risk factor is contact with nonhuman primates, although only one outbreak of MVD (in 1967) was due to contact with infected monkeys.Contrary to Ebola virus disease (EVD), which has been associated with heavy rains after long periods of dry weather, triggering factors for spillover of marburgviruses into the human population have not yet been described.

Diagnosis
MVD is clinically indistinguishable from Ebola virus disease (EVD), and it can also easily be confused with many other diseases prevalent in Equatorial Africa, such as other viral hemorrhagic fevers, falciparum malaria, typhoid fever, shigellosis, rickettsial diseases such as typhus, cholera, gram-negative sepsis, borreliosis such as relapsing fever or EHEC enteritis. Other infectious diseases that ought to be included in the differential diagnosis include leptospirosis, scrub typhus, plague, Q fever, candidiasis, histoplasmosis, trypanosomiasis, visceral leishmaniasis, hemorrhagic smallpox, measles, and fulminant viral hepatitis. Non-infectious diseases that can be confused with MVD are acute promyelocytic leukemia, hemolytic uremic syndrome, snake envenomation, clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura, hereditary hemorrhagic telangiectasia, Kawasaki disease, and even warfarin intoxication. The most important indicator that may lead to the suspicion of MVD at clinical examination is the medical history of the patient, in particular the travel and occupational history (which countries and caves were visited?) and the patients exposure to wildlife (exposure to bats or bat excrements?). MVD can be confirmed by isolation of marburgviruses from or by detection of marburgvirus antigen or genomic or subgenomic RNAs in patient blood or serum samples during the acute phase of MVD. Marburgvirus isolation is usually performed by inoculation of grivet kidney epithelial Vero E6 or MA-104 cell cultures or by inoculation of human adrenal carcinoma SW-13 cells, all of which react to infection with characteristic cytopathic effects. Filovirions can easily be visualized and identified in cell culture by electron microscopy due to their unique filamentous shapes, but electron microscopy cannot differentiate the various filoviruses alone despite some overall length differences. Immunofluorescence assays are used to confirm marburgvirus presence in cell cultures. During an outbreak, virus isolation and electron microscopy are most often not feasible options. The most common diagnostic methods are therefore RT-PCR in conjunction with antigen-capture ELISA, which can be performed in field or mobile hospitals and laboratories. Indirect immunofluorescence assays (IFAs) are not used for diagnosis of MVD in the field anymore.

Classification
Marburg virus disease (MVD) is the official name listed in the World Health Organizations International Statistical Classification of Diseases and Related Health Problems 10 (ICD-10) for the human disease caused by any of the two marburgviruses Marburg virus (MARV) and Ravn virus (RAVV). In the scientific literature, Marburg hemorrhagic fever (MHF) is often used as an unofficial alternative name for the same disease. Both disease names are derived from the German city Marburg, where MARV was first discovered.

Transmission
The details of the initial transmission of MVD to humans remain incompletely understood. Transmission most likely occurs from Egyptian fruit bats or another natural host, such as non-human primates or through the consumption of bush meat, but the specific routes and body fluids involved are unknown. Human-to-human transmission of MVD occurs through direct contact with infected bodily fluids such as blood.

Prevention
There are currently no Food and Drug Administration-approved vaccines for the prevention of MVD. Many candidate vaccines have been developed and tested in various animal models. Of those, the most promising ones are DNA vaccines or based on Venezuelan equine encephalitis virus replicons, vesicular stomatitis Indiana virus (VSIV) or filovirus-like particles (VLPs) as all of these candidates could protect nonhuman primates from marburgvirus-induced disease. DNA vaccines have entered clinical trials. Marburgviruses are highly infectious, but not very contagious. They do not get transmitted by aerosol during natural MVD outbreaks. Due to the absence of an approved vaccine, prevention of MVD therefore relies predominantly on quarantine of confirmed or high probability cases, proper personal protective equipment, and sterilization and disinfection.

Endemic zones
The natural maintenance hosts of marburg viruses remain to be identified unequivocally. However, the isolation of both MARV and RAVV from bats and the association of several MVD outbreaks with bat-infested mines or caves strongly suggests that bats are involved in marburg virus transmission to humans. Avoidance of contact with bats and abstaining from visits to caves is highly recommended, but may not be possible for those working in mines or people dependent on bats as a food source.

During outbreaks
Since marburgviruses are not spread via aerosol, the most straightforward prevention method during MVD outbreaks is to avoid direct (skin-to-skin) contact with patients, their excretions and body fluids, and any possibly contaminated materials and utensils. Patients should be isolated, but still are safe to be visited by family members. Medical staff should be trained in and apply strict barrier nursing techniques (disposable face mask, gloves, goggles, and a gown at all times). Traditional burial rituals, especially those requiring embalming of bodies, should be discouraged or modified, ideally with the help of local traditional healers.

In the laboratory
Marburgviruses are World Health Organization Risk Group 4 Pathogens, requiring Biosafety Level 4-equivalent containment, laboratory researchers have to be properly trained in BSL-4 practices and wear proper personal protective equipment.

Treatment
There is currently no effective marburgvirus-specific therapy for MVD. Treatment is primarily supportive in nature and includes minimizing invasive procedures, balancing fluids and electrolytes to counter dehydration, administration of anticoagulants early in infection to prevent or control disseminated intravascular coagulation, administration of procoagulants late in infection to control hemorrhaging, maintaining oxygen levels, pain management, and administration of antibiotics or antifungals to treat secondary infections.

Prognosis
Prognosis is generally poor. If a patient survives, recovery may be prompt and complete, or protracted with sequelae, such as orchitis, hepatitis, uveitis, parotitis, desquamation, or alopecia. Importantly, MARV is known to be able to persist in some survivors and to either reactivate and cause a secondary bout of MVD or to be transmitted via sperm, causing secondary cases of infection and disease.Of the 252 people who contracted Marburg during the 2004–2005 outbreak of a particularly virulent serotype in Angola, 227 died, for a case fatality rate of 90%.
Although all age groups are susceptible to infection, children are rarely infected. In the 1998–2000 Congo epidemic, only 8% of the cases were children less than 5 years old.

Epidemiology
Below is a table of outbreaks concerning MVD from 1967 to 2021:

1967 outbreak
MVD was first documented in 1967, when 31 people became ill in the German towns of Marburg and Frankfurt am Main, and in Belgrade, Yugoslavia. The outbreak involved 25 primary MARV infections and seven deaths, and six nonlethal secondary cases. The outbreak was traced to infected grivets (species Chlorocebus aethiops) imported from an undisclosed location in Uganda and used in developing poliomyelitis vaccines. The monkeys were received by Behringwerke, a Marburg company founded by the first winner of the Nobel Prize in Medicine, Emil von Behring. The company, which at the time was owned by Hoechst, was originally set up to develop sera against tetanus and diphtheria. Primary infections occurred in Behringwerke laboratory staff while working with grivet tissues or tissue cultures without adequate personal protective equipment. Secondary cases involved two physicians, a nurse, a post-mortem attendant, and the wife of a veterinarian. All secondary cases had direct contact, usually involving blood, with a primary case. Both physicians became infected through accidental skin pricks when drawing blood from patients. A popular science account of this outbreak can be found in Laurie Garrett’s book The Coming Plague.

1975 cases
In 1975, an Australian tourist became infected with MARV in Rhodesia (today Zimbabwe). He died in a hospital in Johannesburg, South Africa. His girlfriend and an attending nurse were subsequently infected with MVD, but survived.

1980 cases
A case of MARV infection occurred in 1980 in Kenya. A French man, who worked as an electrical engineer in a sugar factory in Nzoia (close to Bungoma) at the base of Mount Elgon (which contains Kitum Cave), became infected by unknown means and died on 15 January shortly after admission to Nairobi Hospital. The attending physician contracted MVD, but survived. A popular science account of these cases can be found in Richard Preston’s book The Hot Zone (the French man is referred to under the pseudonym “Charles Monet”, whereas the physician is identified under his real name, Shem Musoke).

1987 case
In 1987, a single lethal case of RAVV infection occurred in a 15-year-old Danish boy, who spent his vacation in Kisumu, Kenya. He had visited Kitum Cave on Mount Elgon prior to travelling to Mombasa, where he developed clinical signs of infection. The boy died after transfer to Nairobi Hospital. A popular science account of this case can be found in Richard Preston’s book The Hot Zone (the boy is referred to under the pseudonym “Peter Cardinal”).

1988 laboratory infection
In 1988, researcher Nikolai Ustinov infected himself lethally with MARV after accidentally pricking himself with a syringe used for inoculation of guinea pigs. The accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor") in Koltsovo, USSR (today Russia). Very little information is publicly available about this MVD case because Ustinovs experiments were classified. A popular science account of this case can be found in Ken Alibek’s book Biohazard.

1990 laboratory infection
Another laboratory accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor") in Koltsovo, USSR, when a scientist contracted MARV by unknown means.

1998–2000 outbreak
A major MVD outbreak occurred among illegal gold miners around Goroumbwa mine in Durba and Watsa, Democratic Republic of Congo from 1998 to 2000, when co-circulating MARV and RAVV caused 154 cases of MVD and 128 deaths. The outbreak ended with the flooding of the mine.

2004–2005 outbreak
In early 2005, the World Health Organization (WHO) began investigating an outbreak of viral hemorrhagic fever in Angola, which was centered in the northeastern Uíge Province but also affected many other provinces. The Angolan government had to ask for international assistance, pointing out that there were only approximately 1,200 doctors in the entire country, with some provinces having as few as two. Health care workers also complained about a shortage of personal protective equipment such as gloves, gowns, and masks. Médecins Sans Frontières (MSF) reported that when their team arrived at the provincial hospital at the center of the outbreak, they found it operating without water and electricity. Contact tracing was complicated by the fact that the countrys roads and other infrastructure were devastated after nearly three decades of civil war and the countryside remained littered with land mines. Americo Boa Vida Hospital in the Angolan capital Luanda set up a special isolation ward to treat infected people from the countryside. Unfortunately, because MVD often results in death, some people came to view hospitals and medical workers with suspicion and treated helpers with hostility. For instance, a specially-equipped isolation ward at the provincial hospital in Uíge was reported to be empty during much of the epidemic, even though the facility was at the center of the outbreak. WHO was forced to implement what it described as a "harm reduction strategy", which entailed distributing disinfectants to affected families who refused hospital care. Of the 252 people who contracted MVD during outbreak, 227 died.

2007 cases
In 2007, four miners became infected with marburgviruses in Kamwenge District, Uganda. The first case, a 29-year-old man, became symptomatic on July 4, 2007, was admitted to a hospital on July 7, and died on July 13. Contact tracing revealed that the man had had prolonged close contact with two colleagues (a 22-year-old man and a 23-year-old man), who experienced clinical signs of infection before his disease onset. Both men had been admitted to hospitals in June and survived their infections, which were proven to be due to MARV. A fourth, 25-year-old man, developed MVD clinical signs in September and was shown to be infected with RAVV. He also survived the infection.

2008 cases
On July 10, 2008, the Netherlands National Institute for Public Health and the Environment reported that a 41-year-old Dutch woman, who had visited Python Cave in Maramagambo Forest during her holiday in Uganda had MVD due to MARV infection, and had been admitted to a hospital in the Netherlands. The woman died under treatment in the Leiden University Medical Centre in Leiden on July 11. The Ugandan Ministry of Health closed the cave after this case. On January 9 of that year an infectious diseases physician notified the Colorado Department of Public Health and the Environment that a 44-year-old American woman who had returned from Uganda had been hospitalized with a fever of unknown origin. At the time, serologic testing was negative for viral hemorrhagic fever. She was discharged on January 19, 2008. After the death of the Dutch patient and the discovery that the American woman had visited Python Cave, further testing confirmed the patient demonstrated MARV antibodies and RNA.

2017 Uganda outbreak
In October 2017 an outbreak of Marburg virus disease was detected in Kween District, Eastern Uganda. All three initial cases (belonging to one family – two brothers and one sister) had died by 3 November. The fourth case – a health care worker – developed symptoms on 4 November and was admitted to a hospital. The first confirmed case traveled to Kenya before the death </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 Berlins edema and can you explain it in depth? [/INST] Berlins edema (commotio retinae) a common condition caused by blunt injury to the eye.  It is characterized by decreased vision in the injured eye a few hours after the injury </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 Localized granuloma annulare 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 Sarcopenia and can you explain it in depth? [/INST] Sarcopenia is a type of muscle loss (muscle atrophy) that occurs with aging and/or immobility.  It is characterized by the degenerative loss of skeletal muscle mass, quality, and strength. The rate of muscle loss is dependent on exercise level, co-morbidities, nutrition and other factors. The muscle loss is related to changes in muscle synthesis signalling pathways. It is distinct from cachexia, in which muscle is degraded through cytokine-mediated degradation, although both conditions may co-exist. Sarcopenia is considered a component of frailty syndrome. Sarcopenia can lead to reduced quality of life, falls, fracture, and disability.Sarcopenia is a factor in changing body composition associated with aging populations; and certain muscle regions are expected to be affected first, specifically the anterior thigh and abdominal muscles. In population studies, body mass index (BMI) is seen to decrease in aging populations while bioelectrical impedance analysis (BIA) shows body fat proportion rising.The term sarcopenia is from Greek σάρξ sarx, "flesh" and πενία penia, "poverty". This was first proposed by Rosenberg in 1989, who wrote that "there may be no single feature of age-related decline that could more dramatically affect ambulation, mobility, calorie intake, and overall nutrient intake and status, independence, breathing, etc."

Signs and symptoms
The hallmark sign of sarcopenia is loss of lean muscle mass, or muscle atrophy. The change in body composition may be difficult to detect due to obesity, changes in fat mass, or edema. Changes in weight, limb or waist circumference are not reliable indicators of muscle mass changes. Sarcopenia may also cause reduced strength, functional decline and increased risk of falling. Sarcopenia may also have no symptoms until it is severe and is often unrecognized. Research has shown, however, that hypertrophy may occur in the upper parts of the body to compensate for this loss of lean muscle mass Therefore, one early indicator of the onset of sarcopenia can be significant loss of muscle mass in the anterior thigh and abdominal muscles.

Causes
There are many proposed causes of sarcopenia and it is likely the result of multiple interacting factors. Understanding of the causes of sarcopenia is incomplete, however changes in hormones, immobility, age-related muscle changes, nutrition and neurodegenerative changes have all been recognized as potential causative factors.The degree of sarcopenia is determined by two factors: initial amount of muscle mass and rate at which muscle mass declines. Due to variations in these factors across the population, the rate of progression and the threshold at which muscle loss becomes apparent is variable. Immobility dramatically increases the rate of muscle loss, even in younger people. Other factors that can increase rate of progression of sarcopenia include decreased nutrient intake, low physical activity, or chronic disease. Additionally, epidemiological research has indicated that early environmental influences may have long-term effects on muscle health. For example, low birth weight, a marker of a poor early environment, is associated with reduced muscle mass and strength in adult life.

Pathophysiology
There are multiple theories proposed to explain the mechanisms of muscle changes of sarcopenia including changes in satellite cell recruitment, changes in anabolic signalling, protein oxidation, inflammation, and developmental factors. The pathologic changes of sarcopenia include a reduction in muscle tissue quality as reflected in the replacement of muscle fibers with fat, an increase in fibrosis, changes in muscle metabolism, oxidative stress, and degeneration of the neuromuscular junction.The distribution of muscle fibers types also changes in sarcopenic muscle causing a decrease in type II muscle fibers, or "fast twitch," with little to no decrease in type I muscle fibers, or "slow-twitch" muscle fibers. Deinervated type II fibers are often converted to type I fibers by reinnervation by slow type I fiber motor nerves.The failure to activate satellite cells upon injury or exercise is also thought to contribute to the pathophysiology of sarcopenia. Additionally, oxidized proteins can lead to a buildup of lipofuscin and cross-linked proteins causing an accumulation of non-contractile material in the skeletal muscle and contribute to sarcopenic muscle.An apparent protective factor is sufficient levels of the protein BNIP3, which prevents cells buildup of damaged mitochondria. Deficiency of BNIP3 leads to muscle inflammation and atrophy.

Diagnosis
Multiple diagnostic criteria have been proposed by various expert groups and continues to be an area of research and debate. Despite the lack of a widely accepted definition, sarcopenia was assigned an ICD-10 code (M62.84) in 2016, recognizing it as a disease state.Sarcopenia can be diagnosed when a patient has muscle mass that is at least two standard deviations below the relevant population mean and has a slow walking speed. The European Working Group on Sarcopenia in Older People (EWGSOP) developed a broad clinical definition for sarcopenia, designated as the presence of low muscle mass and either low muscular strength or low physical performance. Other international groups have proposed criteria that include metrics on walking speed, distance walked in 6 minutes, or grip strength. Hand grip strength alone has also been advocated as a clinical marker of sarcopenia that is simple and cost effective and has good predictive power, although it does not provide comprehensive information.There are screening tools for sarcopenia that assess patient reported difficulty in doing daily activities such as walking, climbing stairs or standing from a chair and have been shown to predict sarcopenia and poor functional outcomes.

Management
Exercise
Exercise remains the intervention of choice for sarcopenia, but translation of research findings into clinical practice is challenging. The type, duration and intensity of exercise are variable between studies, preventing a standardized exercise prescription for sarcopenia. Lack of exercise is a significant risk factor for sarcopenia and exercise can dramatically slow the rate of muscle loss. Exercise can be an effective intervention because aging skeletal muscle retains ability to synthesize proteins in response to short-term resistance exercise. Progressive resistance training in older adults can improve physical performance (gait speed) and muscular strength.

Medication
There are currently no approved medications for the treatment of sarcopenia. Testosterone or other anabolic steroids have also been investigated for treatment of sarcopenia, and seem to have some positive effects on muscle strength and mass, but cause several side effects and raise concerns of prostate cancer in men and virilization in women. Additionally, recent studies suggest testosterone treatments may induce adverse cardiovascular events.DHEA and human growth hormone have been shown to have little to no effect in this setting. Growth hormone increases muscle protein synthesis and increases muscle mass, but does not lead to gains in strength and function in most studies. This, and the similar lack of efficacy of its effector insulin-like growth factor 1 (IGF-1), may be due to local resistance to IGF-1 in aging muscle, resulting from inflammation and other age changes.Other medications under investigation as possible treatments for sarcopenia include ghrelin, vitamin D, angiotensin converting enzyme inhibitors, and eicosapentaenoic acid.

Nutrition
Intake of calories and protein are important stimuli for muscle protein synthesis. Older adults may not utilize protein so efficiently as younger people and may require higher amounts to prevent muscle atrophy. A number of expert groups have proposed an increase in dietary protein recommendations for older age groups to 1.0-1.2 g/kg body weight per day.
Ensuring adequate nutrition in older adults is of interest in the prevention of sarcopenia and frailty, since it is a simple, low-cost treatment approach without major side effects.

Supplements
A component of sarcopenia is the loss of ability for aging skeletal muscle to respond to anabolic stimuli such as amino acids, especially at lower concentrations. However, aging muscle retains the ability of an anabolic response to protein or amino acids at larger doses. Supplementation with larger doses of amino acids, particularly leucine has been reported to counteract muscle loss with aging. Exercise may work synergistically with amino acid supplementation.β-hydroxy β-methylbutyrate (HMB) is a metabolite of leucine that acts as a signalling molecule to stimulate protein synthesis. It is reported to have multiple targets, including stimulating mTOR and decreasing proteasome expression. Its use to prevent the loss of lean body mass in older adults is consistently supported in clinical trials. More research is needed to determine the precise effects of HMB on muscle strength and function in this age group.

Epidemiology
The prevalence of sarcopenia depends on the definition used in each epidemiological study. Estimated prevalence in people between the ages of 60-70 is 5-13% and increases to 11-50% in people more than 80 years of age. This equates to >50 million people and is projected to affect >200 million in the next 40 years given the rising population of older adults.

Public health impact
Sarcopenia is emerging as a major public health concern given the increased longevity of industrialized populations and growing geriatric population. Sarcopenia is a predictor of many adverse outcomes including increased disability, falls and mortality. Immobility or bed rest in populations predisposed to sarcopenia can cause dramatic impact on functional outcomes. In the elderly, this often leads to decreased biological reserve and increased vulnerability to stressors known as the "frailty syndrome". Loss of lean body mass is also associated with increased risk of infection, decreased immunity, and poor wound healing. The weakness that accompanies muscle atrophy leads to higher risk of falls, fractures, physical disability, need for institutional care, reduced quality of life, increased mortality, and increased healthcare costs. This represents a significant personal and societal burden and its public health impact is increasingly recognized.

Research directions
There are significant opportunities to better understand the causes and consequences of sarcopenia and help guide clinical care. This includes elucidation of the molecular and cellular mechanisms of sarcopenia, further refinement of reference populations by ethnic groups, validation of diagnostic criteria and clinical tools, as well as tracking of incidence of hospitalization admissions, morbidity, and mortality. Identification and research on potential therapeutic approaches and timing of interventions is also needed.New pharmaceutical therapies in clinical development include myostatin and the selective androgen receptor modulators (SARMs). Nonsteriodal SARMs are of particular interest, given they exhibit significant selectivity between the anabolic effects of testosterone on muscle, but with little to no evidence of androgenic effects (such as prostate stimulation in men).

See also
Cachexia
Ageing
Frailty syndrome
Geriatrics
Dynapenia

References
Further reading
Fujita S, Volpi E (January 2006). "Amino acids and muscle loss with aging". The Journal of Nutrition (Review). 136 (1 Suppl): 277S–80S. doi:10.1093/jn/136.1.277S. PMC 3183816 </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 Transvestic fetishism 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 Megalencephaly and can you explain it in depth? [/INST] Megalencephaly (or macrencephaly; abbreviated MEG) is a growth development disorder in which the brain is abnormally large. It is characterized by a brain with an average weight that is 2.5 standard deviations above the mean of the general population. Approximately 1 out of 50 children (2%) are said to have the characteristics of megalencephaly in the general population.A mutation in the PI3K-AKT pathway is believed to be the primary cause of brain proliferation and ultimately the root cause of megalencephaly. This mutation has produced a classification of brain overdevelopment that consists of two syndromes including megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH). Megalencephaly is usually diagnosed at birth and is confirmed with an MRI.
There are several neuropsychiatric disorders linked with megalencephaly; however, studies have shown that autism is the most prevalent association with the malformation of MEG. Although no treatment currently exists for megalencephaly, management methods are focused at reducing deficits linked with autism. Most recent research is targeted at creating inhibitors to reduce the mutational pathway that causes megalencephaly.

Classification
Macrocephaly
Macrocephaly is a term used to refer to a person who has an abnormally large head. The circumference of the head must be above the 95th percentile or at least 2.5 standard deviations from the mean of normal weight and gender groups in the United States. A person with macrocephaly does not necessarily indicate that megalencephaly is also present. Large skulls usually exhibit no neurodevelopment conditions at all, meaning most individuals with macrocephaly are healthy.

Hemimegalencephaly
Hemimegalencephaly is an extremely rare form of macrocephaly and is characterized by uneven development of brain hemispheres (one-half of brain is larger than other). The syndrome can be presented by itself or in association with phakomatosis or hemigigantism. Additionally, hemimegalencephaly will frequently cause severe epilepsy, focal neuro-logical deficits, macrocrania, and mild to severe intellectual disability.

MCAP
Megalencephaly-capillary (MCAP) is one of the two major syndromes of megalencephaly. Typically, MCAP and MPPH can be distinguished by somatic features. MCAP includes many characteristics that are observed at birth including: cutaneous vascular malformations, especially capillary malformations of the face and cutis marmorata, polydactyly, connective tissue dysplasia, and focal or segmental body overgrowth. Furthermore, MCAP can occasionally be linked with asymmetric brain overgrowth (hemimegalencephaly) as well as segmental overgrowth of the body (hemihypertrophy).

MPPH
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) is one of the two major syndromes contributing to megalencephaly. Typically MCAP and MPPH can be distinguished by somatic features. In differentiation to MCAP, MPPH lacks consistent somatic features other than postaxial polydactyly. Furthermore, brain and body development is normally symmetric in the majority of patients that appear to have MPPH symptoms.

Presentation
Autism
There is an extremely high association between megalencephaly and autism. Approximately 20% of autistic children have megalencephaly, making it the most common physical characteristic of autism. People who present both megalencephaly and autistic characteristics usually also show signs of hyperactivity as a major symptom. However, there is no definitive evidence that autism is the primary cause/result of megalencephaly.Since most children with megalencephaly also have autism, the goal of treatment for MEG is focused on managing the signs and symptoms associated with autism.

Other associations
Achondroplasia
Beckwith–Wiedemann syndrome
Neurofibromatosis type I (NF1)
Tuberous sclerosis (TS)
Klippel–Trénaunay syndrome
Epidermal nevus syndrome

Causes
Although very little is still known as to the direct cause of megalencephaly, recent studies have begun to provide early indications of possible sources for its formation. Recent research has shown that there is a strong link between genetic pathways that cause brain develop and mutations in that pathway that result in brain overgrowth.

PI3K-AKT
Recent studies have shown that mutations in phosphoinositide 3-kinase (PI3K) and AKT (also known as protein kinase B) pathway have been identified in MCAP and MPPH. This pathway has proven to be an integral part of brain growth and development and is an area of interest to many researchers who study the cause of megalencephaly. Mutations in this pathway have been shown to cause a gain of function in the activation of the PI3K-AKT pathway. This cellular pathway is critical in the regulation of diverse cell functions including, cell growth, proliferation, metabolism, survival, apoptosis, angiogenesis, tumorigenesis and most importantly in regards to megalencephaly, brain development. AKT is a crucial signaling molecule part of the PI3K pathway and is also involved in many cellular functions. These functions include, brain development, synaptic plasticity and neurodevelopment. Loss of function in AKT can cause microcephaly in humans while inactivation of the pathway can cause hemimegalencephaly. There are also several cancers that have been shown to be linked with mutations in the AKT pathway, including melanoma and lung cancer.

Pur-alpha
Pur-alpha (purα) is a sequence-specific single-stranded DNA and RNA-binding protein. Studies have shown that the protein is primarily active during early development and is believed to have a role in brain enlargement. Although the exact function is still controversial, it is believed that pur-alpha is responsible for neuronal proliferation during neurogenesis as well as the maturation of dendrites. Thus, pur-alpha is also considered a potential root cause of megalencephaly and brain overgrowth.

Pathophysiology
One impact of megalencephaly is the complete lack of motor development. One medical study assessed three patients presenting megalencephaly who showed severely impaired motor and speech development as well as distinct facial abnormalities including skull bossing, a low nasal bridge and large eyes.

Diagnoses
Diagnosis of megalencephaly has changed over the years, however, with the development of more advanced equipment, physicians have been able to confirm the disorder with better accuracy. Usually, a physical exam is first performed when characteristics of megalencephaly have appeared. This typically occurs at birth or during early child development. A physician will then take head measurements in order to determine the circumference. This is known as the head circumference. Then a family background will be recorded in order to determine if there has been a history of megalencephaly in the family.A neurological exam will then be performed using the technology of an MRI machine in order to confirm the diagnosis of megalencephaly. These imaging tests give detailed information regarding brain size, volume asymmetry and other irregular developments linked with MCAP, MPPH and hemimegalencephaly.There is also a strong correlation of epilepsy and megalencephaly and this can aid doctors in their diagnosis.If a diagnosis of megalencephaly is confirmed, the child is referred to a specialist who focuses on managing the symptoms and improving lifestyle. Since megalencephaly is usually presented with autism, the goal of treatment is to improve deficiencies associated with autistic causes. Additionally, since each patient has unique symptoms, there is no one specific treatment method and therefore is heavily reliant on symptoms associated with an individual.

Prevention
Since there are very few treatment methods focused on managing megalencephaly, future research is targeted at inhibiting mutation of the pathway </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 Spinal muscular atrophy with progressive myoclonic epilepsy 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 Onychophosis 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 Congestive hepatopathy and can you explain it in depth? [/INST] Congestive hepatopathy, is liver dysfunction due to venous congestion, usually due to congestive heart failure. The gross pathological appearance of a liver affected by chronic passive congestion is "speckled" like a grated nutmeg kernel; the dark spots represent the dilated and congested hepatic venules and small hepatic veins. The paler areas are unaffected surrounding liver tissue. When severe and longstanding, hepatic congestion can lead to fibrosis; if congestion is due to right heart failure, it is called cardiac cirrhosis.

Signs and symptoms
Signs and symptoms depend largely upon the primary lesions giving rise to the condition. In addition to the heart or lung symptoms, there will be a sense of fullness and tenderness in the right hypochondriac region. Gastrointestinal catarrh is usually present, and vomiting of blood may occur </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 Erythema gyratum repens 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 Thrombin and can you explain it in depth? [/INST] Thrombin (EC 3.4.21.5, fibrinogenase, thrombase, thrombofort, topical, thrombin-C, tropostasin, activated blood-coagulation factor II, blood-coagulation factor IIa, factor IIa, E thrombin, beta-thrombin, gamma-thrombin) is a serine protease, an enzyme that, in humans, is encoded by the F2 gene. Prothrombin (coagulation factor II) is proteolytically cleaved to form thrombin in the clotting process. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.

History
After the description of fibrinogen and fibrin, Alexander Schmidt hypothesised the existence of an enzyme that converts fibrinogen into fibrin in 1872.Prothrombin was discovered by Pekelharing in 1894.

Physiology
Synthesis
Thrombin is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa). The activity of factor Xa is greatly enhanced by binding to activated Factor V (Va), termed the prothrombinase complex. Prothrombin is produced in the liver and is co-translationally modified in a vitamin K-dependent reaction that converts 10-12 glutamic acids in the N terminus of the molecule to gamma-carboxyglutamic acid (Gla). In the presence of calcium, the Gla residues promote the binding of prothrombin to phospholipid bilayers. Deficiency of vitamin K or administration of the anticoagulant warfarin inhibits the production of gamma-carboxyglutamic acid residues, slowing the activation of the coagulation cascade.
In human adults, the normal blood level of antithrombin activity has been measured to be around 1.1 units/mL. Newborn levels of thrombin steadily increase after birth to reach normal adult levels, from a level of around 0.5 units/mL 1 day after birth, to a level of around 0.9 units/mL after 6 months of life.

Mechanism of action
In the blood coagulation pathway, thrombin acts to convert factor XI to XIa, VIII to VIIIa, V to Va, fibrinogen to fibrin, and XIII to XIIIa. In the conversion of fibrinogen into fibrin, thrombin catalyzes the cleavage of fibrinopeptides A and B from the respective Aα and Bβ chains of fibrinogen to form fibrin monomers.Factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. The covalent bonds increase the stability of the fibrin clot. Thrombin interacts with thrombomodulin.As part of its activity in the coagulation cascade, thrombin also promotes platelet activation and aggregation via activation of protease-activated receptors on the cell membrane of the platelet.

Negative feedback
Thrombin bound to thrombomodulin activates protein C, an inhibitor of the coagulation cascade. The activation of protein C is greatly enhanced following the binding of thrombin to thrombomodulin, an integral membrane protein expressed by endothelial cells. Activated protein C inactivates factors Va and VIIIa. Binding of activated protein C to protein S leads to a modest increase in its activity. Thrombin is also inactivated by antithrombin, a serine protease inhibitor.

Structure
The molecular weight of prothrombin is approximately 72,000 Da. The catalytic domain is released from prothrombin fragment 1.2 to create the active enzyme thrombin, which has a molecular weight of 36,000 Da. Structurally, it is a member of the large PA clan of proteases.
Prothrombin is composed of four domains; an N-terminal Gla domain, two kringle domains and a C-terminal trypsin-like serine protease domain.
Factor Xa with factor V as a cofactor leads to cleavage of the Gla and two Kringle domains (forming together a fragment called fragment 1.2) and leave thrombin, consisting solely of the serine protease domain.As is the case for all serine proteases, prothrombin is converted to active thrombin by proteolysis of an internal peptide bond, exposing a new N-terminal Ile-NH3. The historic model of activation of serine proteases involves insertion of this newly formed N-terminus of the heavy chain into the β-barrel promoting the correct conformation of the catalytic residues. Contrary to crystal structures of active thrombin, hydrogen-deuterium exchange mass spectrometry studies indicate that this N-terminal Ile-NH3 does not become inserted into the β-barrel in the apo form of thrombin. However, binding of the active fragment of thrombomodulin appears to allosterically promote the active conformation of thrombin by inserting this N-terminal region.

Gene
The thrombin (prothrombin) gene is located on the eleventh chromosome (11p11-q12).There are an estimated 30 people in the world that have been diagnosed with the congenital form of Factor II deficiency, which should not be confused with the prothrombin G20210A mutation, which is also called the factor II mutation. Prothrombin G20210A is congenital.Prothrombin G20210A is not usually accompanied by other factor mutations (i.e., the most common is factor V Leiden). The gene may be inherited heterozygous (1 pair), or much more rarely, homozygous (2 pairs), and is not related to gender or blood type. Homozygous mutations increase the risk of thrombosis more than heterozygous mutations, but the relative increased risk is not well documented. Other potential risks for thrombosis, such as oral contraceptives may be additive. The previously reported relationship of inflammatory bowel disease (i.e., Crohns disease or ulcerative colitis) and prothrombin G20210A or factor V Leiden mutation have been contradicted by research.

Role in disease
Activation of prothrombin is crucial in physiological and pathological coagulation. Various rare diseases involving prothrombin have been described (e.g., hypoprothrombinemia). Anti-prothrombin antibodies in autoimmune disease may be a factor in the formation of the lupus anticoagulant (also known as antiphospholipid syndrome). Hyperprothrombinemia can be caused by the G20210A mutation.
Thrombin, a potent vasoconstrictor and mitogen, is implicated as a major factor in vasospasm following subarachnoid hemorrhage. Blood from a ruptured cerebral aneurysm clots around a cerebral artery, releasing thrombin. This can induce an acute and prolonged narrowing of the blood vessel, potentially resulting in cerebral ischemia and infarction (stroke).
Beyond its key role in the dynamic process of thrombus formation, thrombin has a pronounced pro-inflammatory character, which may influence the onset and progression of atherosclerosis. Acting via its specific cell membrane receptors (protease activated receptors: PAR-1, PAR-3 and PAR-4), which are abundantly expressed in all arterial vessel wall constituents, thrombin has the potential to exert pro-atherogenic actions such as inflammation, leukocyte recruitment into the atherosclerotic plaque, enhanced oxidative stress, migration and proliferation of vascular smooth muscle cells, apoptosis and angiogenesis.Thrombin is implicated in the physiology of blood clots. Its presence indicates the existence of a clot. In 2013 a system for detecting the presence of thrombin was developed in mice. It combines peptide-coated iron oxide attached to "reporter chemicals". When a peptide binds to a thrombin molecule, the report is released and appears in the urine where it can be detected. Human testing has not been conducted.

Applications
Research tool
Due to its high proteolytic specificity, thrombin is a valuable biochemical tool. The thrombin cleavage site (Leu-Val-Pro-Arg-Gly-Ser) is commonly included in linker regions of recombinant fusion protein constructs. Following purification of the fusion protein, thrombin can be used to selectively cleave between the arginine and glycine residues of the cleavage site, effectively removing the purification tag from the protein of interest with a high degree of specificity.

Medicine and surgery
Prothrombin complex concentrate and fresh frozen plasma are prothrombin-rich coagulation factor preparations that can be used to correct deficiencies (usually due to medication) of prothrombin. Indications include intractable bleeding due to warfarin.
Manipulation of prothrombin is central to the mode of action of most anticoagulants. Warfarin and related drugs inhibit vitamin K-dependent carboxylation of several coagulation factors, including prothrombin. Heparin increases the affinity of antithrombin to thrombin (as well as factor Xa). The direct thrombin inhibitors, a newer class of medication, directly inhibit thrombin by binding to its active site.
Recombinant thrombin is available as a powder for reconstitution into aqueous solution. It can be applied topically during surgery, as an aid to hemostasis. It can be useful for controlling minor bleeding from capillaries and small venules, but ineffective and not indicated for massive or brisk arterial bleeding.

Food production
Thrombin, combined with fibrinogen, is sold under the brand name Fibrimex for use as a binding agent for meat </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 Vitreous hemorrhage and can you explain it in depth? [/INST] Vitreous hemorrhage is the extravasation, or leakage, of blood into the areas in and around the vitreous humor of the eye. The vitreous humor is the clear gel that fills the space between the lens and the retina of the eye. A variety of conditions can result in blood leaking into the vitreous humor, which can cause impaired vision, floaters, and photopsia.

Symptoms
Common symptoms of vitreous hemorrhage include:

Blurred vision
Floaters – faint cobweb-like apparitions floating through the field of vision
Reddish tint to vision
Photopsia – brief flashes of light in the peripheral visionSmall vitreous hemorrhage often manifests itself as "floaters." A moderate case will often result in dark streaks in the vision, while dense vitreous hemorrhage can significantly inhibit vision.

Causes
There are many factors known to cause vitreous hemorrhage.

Diabetic retinopathy
The most common cause found in adults is diabetic retinopathy. Abnormal blood vessels can form in the back of the eye of a person with diabetes. These new blood vessels are weaker and prone to breaking and causing hemorrhage. Diabetic retinopathy accounts for 31.5–54% of all cases of vitreous hemorrhage in adults in the United States.

Trauma
Some injuries can cause blood vessels in the back of the eye to bleed </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 Poroma and can you explain it in depth? [/INST] Poromas are rare, benign, cutaneous adnexal tumors. Cutaneous adnexal tumors are a group of skin tumors consisting of tissues that have differentiated (i.e. matured from stem cells) towards one or more of the four primary adnexal structures found in normal skin: hair follicles, sebaceous sweat glands, apocrine sweat glands, and eccrine sweat glands. Poromas are eccrine or apocrine sweat gland tumors derived from the cells in the terminal portion of these glands ducts. This part of the sweat gland duct is termed the acrosyringium and had led to grouping poromas in the acrospiroma class of skin tumors (syringofibroadenomas and syringoacanthomas are classified as acrospiromas). Here, poromas are regarded as distinct sweat gland tumors that differ from other sweat gland tumors by their characteristic clinical presentations, microscopic histopathology, and the genetic mutations that their neoplastic cells have recently been found to carry.As currently viewed, there are 4 poroma variants based on their predominant cell types and extent of the their tumor tissues presence in the epidermis and dermis: 1) Hidroacanthoma simplex poromas are confined to the epidermis, i.e. uppermost layer of the skin. 2) Dermal duct poromas are confined to the dermis, i.e. layer of skin between the epidermis and subcutaneous tissues. 3) Hidradenomas have recently been sub-classified into two groups; 95% are termed clear cell hidradenomas and have features suggesting that they derive from apocrine sweat glands while the remaining 5% are termed poroid hidradenomas and have features suggesting that they derive from eccrine sweat glands. And 4) eccrine poromas are eccrine sweat gland tumors that consist of three cell types (see Histopathology section).Poromas usually occur as single, small, skin tumors that develop in middle aged to elderly individuals. They may occur anywhere on the body, but are most commonly seen on the head, neck, and extremities. They seldom cause symptoms. While benign, long-standing poromas have, in very rare cases, progressed to malignant forms termed porocarcinomas. Poromas are treated by excision; their removal is almost always curative.

Presentation
Poromas are rare tumors that in two large review studies represented 0.0058% and 0.134% of all skin tumors; dermal duct tumors are the rarest form of the poromas, representing only 3.3% of these tumors in 3 studies examining 675 poroid neoplasms. They usually occur in the elderly population (mean age 65.1–66.6 in different studies) as small (<2 centimeters), solitary dome-shaped papules, plaques, or nodules, that are skin-colored, pink, red, white, or blue and range from smooth to wart-like, ulcerative,  or pyogenic granuloma-like lesions. They may be located on the palms of the hands, soles of the feet, trunk, face, neck, or other cutaneous surfaces such as the areola, nipple, or other areas of the breast, on the scrotum, or on the vulva. Rarely, individuals present with multiple poromas either in one or widespread areas; these cases are termed poromatosis.Poromas present more commonly in: pregnancy; patients treated with electron therapy for mycosis fungoides; sites of chronic radiation dermatitis caused by long-term radiation exposure; patients who received chemotherapy with or with radiation therapy (these patients have often presented with poromatosis); individuals with underlying skin conditions such as hypohidrotic ectodermal dysplasia and Bowen’s disease (i.e. a form of squamous cell carcinoma that is localized to the outermost layer of the skin); and skin plaques of individuals with the congenital disease, nevus sebaceous.Poromas are usually slow growing and asymptomatic but some individuals report that their lesions are itchy, mildly tender, or  painful. An existing poroma that develops spontaneous bleeding, ulceration, sudden itching, pain, or rapid growth over a short period of time may indicate that it has become a cancerous porocarcinoma. These cancers may metastasize to local lymph nodes, nearby or distal skin sites, bones, bladder, breast, retroperitoneum, ovary, liver, lung, brain, or stomach. However, the progression of a poroma to a porocarcinoma is very rare, i.e. less than 1% of cases.

Histopathology
Microscopic histopathological examinations of the tumor tissues of all poroma variants stained with hematoxylin and eosin dyes reveal: a) basophilic "poroid cells" (i.e. small, cuboid-shaped cells with oval nuclei which resemble cells in the peripheral layer of the distal portion of eccrine sweat gland ducts) that may form cords and broad columns extending downward from the epidermis; b) larger cuticular cells (i.e. squamous epithelial-like eosinophilic cells that resemble the luminal cells lining eccrine sweat gland ducts); and in some cases c) clear cells (i.e. cells with small nuclei surrounded by pale cytoplasm). Poroma tumor tissues may appear highly vascularized and/or have areas of necrosis, i.e. dead or dying cells. Hidroacanthoma simplex variants are mainly composed of poroid cells, few cuticular cells, and no clear cells and are confined to the epidermis; dermal ductal variants are mostly confined to the superficial dermis and are composed of small solid and cystic nodular aggregates of poroid, cuticular, and clear cells; poroid hidradenoma variants have large aggregates of solid and cystic components and extend deeper into the dermis or even subcutis; and eccrine poroma variants are composed of all three cell types but are primarily located in the epidermis and superficial dermis. Poromas may have 2 or more of these variants in the same tumor tissue and the variants typically have histopathology findings that are not clearly distinguishable from each other.

Immunohistochemistry
As detected by immunohistochemical analyses, the poroma tumor cells, regardless of variant type, test positive when probed with the AE1/AE3 antibody cocktail that detects various cytokeratin proteins. Tumor cells of the four variants also commonly express carcinoembryonic antigen (i.e. CEA) or MUC1 (also termed EMA) and, except for the hidroacanthoma simplex variant, the carcinoembryonic antigen and MUC1 protein.

Gene abnormalities
The four poroma variants contain at least one of two YAP1 fusion genes, i.e. abnormal genes caused by a mutation which merges a part of the YAP1 gene fused to part of either the Nuclear protein in testis gene (also termed the NUTM1 gene) or the MAML2 gene to form the YAP1::NUTM1 and YAP::MAML2 fusion genes, respectively. Rarely, they may also contain a WWTR1::NUTM1 fusion gene. The YAP1::MAML2 fusion gene is detected in ~63% of poromas, the YAP1::NUTM1 fusion in 20.2% to 66% of poromas, and the WWTR1::NUTM1 fusion gene in 1% of poromas. YAP1  and WNTR1 fusion genes have been implicated in the initiation, aggressiveness, metastasis, and/or therapy resistance of various neoplasms. Studies are needed to determine if they play a role in the development and/or progression of poromas.

Diagnosis
The great diversity, rarity, and complex terminology of poromas make their diagnosis challenging. They have been misdiagnosed as other types of skin tumors including porocarcinomas, basal cell carcinomas, pyogenic granulomas, skin tags, plantar warts (i.e </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 Tyrosinemia type I and can you explain it in depth? [/INST] Tyrosinemia type I is a genetic disorder that disrupts the metabolism of the amino acid tyrosine, resulting in damage primarily to the liver along with the kidneys and peripheral nerves. The inability of cells to process tyrosine can lead to chronic liver damage ending in liver failure, as well as renal disease and rickets. Symptoms such as poor growth and enlarged liver are associated with the clinical presentation of the disease. Clinical manifestation of disease occurs typically within the first two years of life. The severity of the disease is correlated with the timing of onset of symptoms, earlier being more severe.Tyrosinemia type I is an autosomal recessive disorder caused by mutations in both copies of the gene encoding the enzyme fumarylacetoacetate hydrolase (FAH). FAH is a metabolic enzyme that catalyzes the conversion of fumarylacetoacetate to fumarate and acetoacetate.  It is expressed primarily in the liver and kidney. Loss of FAH activity results in the accumulation of certain metabolic intermediates in the tyrosine catabolic pathway. These compounds are toxic to cells and lead to differential gene expression and apoptosis in high concentrations. HT1 is diagnosed when elevated levels of succinylacetone (SA), one of the metabolites in this pathway, is detected in blood and urine samples.While there is no cure for tyrosinemia type I, management of the disease is possible utilizing dietary restrictions and medications. A diet low in tyrosine and phenylalanine is utilized indefinitely once a diagnosis is suspected or confirmed. Additionally, the drug nitisinone (brand name Orfadin) is prescribed and continued indefinitely in order to combat liver and kidney damage, promoting normal function of these organs. Prior to the development of nitisinone, dietary restrictions and liver transplantation were the only forms of treatment for HT1.Tyrosinemia type I is especially prevalent in the Saguenay-Lac Saint-Jean region of Quebec, where the prevalence is 1 in 1,850 births. It is most common among those with French-Canadian ancestry and this frequency of infliction has been attributed to the founder effect. There are five other known types of tyrosinemia, all of which derange the metabolism of tyrosine in the human body. They are distinguished by their symptoms and genetic cause.

Signs and symptoms
Type 1 tyrosinemia typically presents in infancy as failure to thrive and hepatomegaly.  The primary effects are progressive liver and kidney dysfunction.  The liver disease causes cirrhosis, conjugated hyperbilirubinemia, elevated AFP, hypoglycemia and coagulation abnormalities.  This can lead to jaundice, ascites and hemorrhage.  There is also an increased risk of hepatocellular carcinoma.The kidney dysfunction presents as Fanconi syndrome: Renal tubular acidosis, hypophosphatemia and aminoaciduria.  Cardiomyopathy, neurologic and dermatologic manifestations are also possible. The urine has an odor of cabbage or rancid butter.The presentation of symptoms of tyrosinemia type 1 in terms of timing is broken into three categories: acute, sub-acute, and chronic.The acute classification typically is presented clinically between birth and 6 months of age. The common presentation in an acute case is synthetic liver failure, marked by the lack of formation of coagulation factors in blood. Patients are prone to infections at this stage accompanied by fever, vomiting, increased tendency to bleed, and diarrhea along with bloody feces as manifestations of sepsis. Other symptoms include enlarged liver, jaundice, and excess abdominal fluid.Sub-acute cases present between 6 months and the first year of life and the severity of liver disease is lessened to an extent. Again, synthetic function of the liver in terms of blood coagulation factors is impaired in addition to enlargement of the liver and spleen. The infant may also display a failure to thrive as their growth is limited by the disease. This growth impairment can manifest itself in rickets, which is the softening of bones.The final classification, chronic HT1, is detected with presentations occurring after one year of life. The course of the disease up to this point can lead to different ailments affecting the liver. Cirrhosis, liver failure, or cancer of the liver may present as a result of chronic liver disease. Additional symptoms common in this classification include cardiomyopathy, renal disease, and acute neurological crises.

Liver
The liver is the organ affected most by Tyrosinemia Type I due to the high level of expression of the gene for fumarylacetoacetate hydrolase (FAH) in liver cells. The production of blood coagulation factors by the liver is disrupted, causing hemophiliac-like symptoms. Acute liver failure is common, especially in early life. Additionally, the synthesis of albumin in the liver may be defective, therefore leading to hypoalbuminemia. As the disease progresses, cirrhosis is common. This can lead to a fatty liver and the development of tumors in areas affected by this scarring of liver tissue. These scars are known as nodules. There is a 37% chance of developing a hepatocellular carcinoma (HCC) for untreated patients.

Renal and neurological manifestations
Many patients display impaired kidney function and neurological symptoms. In addition to liver cells, kidney cell expression involves expression of the gene for FAH. Kidney failure is a potential result of impaired kidney function, but the most common symptom associated with renal dysfunction is hypophosphatemic rickets. Neurological manifestations are characterized by acute neurological crises due to overaccumulation of porphyrin. These crises are characterized by porphyria. They typically follow an infection. Patients can present with a variety of varied symptoms including paresthesias, abdominal pain, pain-induced seizures, and can result in self-mutilation in response to this pain. Episodes can last for 1–7 days and can lead to neuropathy.

Genetics
Tyrosinemia type I is an autosomal recessive inherited condition. Mutant alleles in the gene are inherited from both parents. The genetic mutation occurs to the fumarylacetoacetate hydrolase (FAH) enzyme gene, located on chromosome 15. The most common mutation is IVS12+5(G->A) which is a mutation in the splice site consensus sequence of intron 12, therefore affecting exon 12. A second allele is the IVS6-1(G-T) mutation. This mutation results in a nonfunctional enzyme.Type 1 tyrosinemia is inherited in an autosomal recessive pattern.

Pathophysiology
Fumarylacetoacetate hydrolase catalyzes the final step in the degradation of tyrosine - fumarylacetoacetate to fumarate, acetoacetate and succinate.  Fumarylacetoacetate accumulates in hepatocytes and proximal renal tubal cells and causes oxidative damage and DNA damage leading to cell death and dysfunctional gene expression which alters metabolic processes like protein synthesis and gluconeogenesis.  The increase in fumarylacetoacetate inhibits previous steps in tyrosine degradation leading to an accumulation of tyrosine in the body.  Tyrosine is not directly toxic to the liver or kidneys but causes dermatologic and neurodevelopmental problems.

Tyrosine metabolic pathway
Fumarylacetoacetate hydrolase (FAH) is the final enzyme in the tyrosine metabolic pathway. The mutation of FAH enzyme results in nonfunctional FAH in all cells expressing this gene and thus metabolizing tyrosine is impaired. FAH catalyzes the conversion of fumarylacetoacetate to fumarate and acetoacetate. Loss of FAH results in the accumulation of upstream compounds in the catabolic pathway. These include maleylacetoacetate (MAA) and fumarylacetoacetate (FAA). MAA and FAA are converted to succinylacetoacetate (SAA) which is then catabolized to succinylacetone (SA).The accumulation of MAA, FAA, and SA in cells inhibits the breakdown of thiol derivatives, leading to post-translational modifications to the antioxidant glutathione. This inhibits the antioxidant activity of glutathione, leading to reactive oxygen species (ROS) damaging cell components. Over time, the combined effect of accumulation of toxic metabolic intermediates and elevated ROS levels in liver and kidney cells leads to apoptosis in these tissues which ultimately results in organ failure. Accumulated SA in liver and kidney cells results in its release into the bloodstream, which leads to secondary effects. SA inhibits the enzyme 5-ALA dehydratase which converts aminolevulinic acid (5-ALA) into porphobilinogen, a precursor to porphyrin. Consequently, porphyrin deposits form in the bloodstream and cause neuropathic pain, leading to the acute neurological crises experienced by some patients. Additionally. SA can function to inhibit renal tubular function, the synthesis of heme, and the immune system.The accumulation of unprocessed tyrosine itself in the blood stream as a consequence of deficient catabolism can also lead to disruption of hormonal signaling and neurotransmission. Tyrosine is a precursor molecule required for synthesis of several neurotransmitters and hormones, mainly Dopamine, norepinephrine, and thryoxine. Excessive synthesis of these molecules due to elevated tyrosine levels can impair physical growth, motor function, and speech development.

Diagnosis
Beyond the identification of physical clinical symptoms outlined above, the definitive criterion for diagnostic assessment of Tyrosinemia Type I is elevated succinylacetone (SA) in blood and urine. Elevated SA levels are not associated with any other known medical condition, so there is minimal risk of misdiagnosis. Quantitation of tyrosine levels is also used as a diagnostic but is less reliable due to high false positive and false negative rates. Newborns are not generally screened for HT1 due to rarity of the condition and lack of apparent symptoms at time of birth. However, prompt assessment upon the manifestation of physical symptoms such as fever, vomiting, increased tendency to bleed, diarrhea along with bloody feces, and jaundice is critical for improving long term prognosis.

Management
The primary treatment for type 1 tyrosinemia is nitisinone and restriction of tyrosine in the diet. Nitisinone inhibits the conversion of 4-OH phenylpyruvate to homogentisic acid by 4-Hydroxyphenylpyruvate dioxygenase, the second step in tyrosine degradation.  By inhibiting this enzyme, the accumulation of the fumarylacetoacetate is prevented. Previously, liver transplantation was the primary treatment option and is still used in patients in whom nitisinone fails.Clinical treatment of HT1 relies on medications and strict regulation of diet. Nitisinone and dietary restrictions that decrease the amount of tyrosine and phenylalaine absorbed from the GI tract during protein digestion are used in combination as therapeutic measures that control the disease state if they are continued indefinitely. If not, there is a lack of control over the disease, resulting in continued liver and kidney damage, contributing to organ failure and death. In this case, a liver transplant may be required. Levels of SA are monitored throughout treatment in order to assess treatment effectiveness.

Diet
The prescribed diet for treatment of HT1 is low in protein. Patients received amino acid supplements lacking tyrosine and phenylalanine in order to acquire sufficient protein. It is recommended that tyrosine levels remain below 500 μmol/L. Phenylalnine is the precursor to tyrosine. The ideology behind maintaining low tyrosine levels is two-fold. Firstly, it prevents the toxic metabolic intermediates from accumulating as a result of the dysfunctional tyrosine metabolic pathway. Prior to the introduction of nitisinone, this was the main treatment measure. Secondly, the mechanism of action of nitisinone is prevention of any tyrosine metabolism, thus it is important to prevent tyrosine from accumulating. Dietary protein consumption while taking nitisinone can also lead to side effects affecting the ocular system, which are easily reversed by removing protein from the diet.

Medication
Nitisinone is prescribed ultimately to reduce the accumulation of toxic metabolic intermediates, such as succinylacetate, which are toxic to cells. It modifies the function of 4-hydrooxyphenylpyruvate dioxygenase by acting as a competitive inhibitor. 4-hydrooxyphenylpyruvate dioxygenase functions to convert 4-hydroxyphenylpyruvate to homogentisate as the second enzymatic reaction in the tyrosine catabolic pathway. This prevents the further catabolism of tyrosine. It is recommended that nitisinone treatment begins immediately following a confirmed or suspected case of HT1. It is supplied orally as a capsule or suspension in dose increments of 2 mg, 5 mg, 10 mg, or 20 mg or 4 mg/mL respectively. The starting dose is 1 mg/kg one time daily or 2 mg/kg one time daily for 48 hours if the patient is experiencing acute liver failure. Patient responsiveness to nitisinone is assessed by measuring blood coagulation activity and SA levels in blood and urine. Patients should display a positive response within 24–48 hours of first dose. Establishment of the long-term dosage will vary from patient to patient. It is recommended that nitisinone levels be maintained at 30-50 μM in the blood stream.

Prognosis
Prior to the development of nitisinone, dietary restrictions and liver transplantation were the only forms of treatment for HT1. A study regarding the efficacy of treatment with nitisinone and dietary restrictions found that 93% of people survived at two years, four years, and six years indicating the prognosis of stabilizing the HT1 disease state is positive.

Epidemiology
Tyrosinemia type I affects males and females in equal numbers. Its prevalence has been estimated to be 1 in 100,000 to 120,000 births worldwide. HT1 is especially prevalent in the Saguenay-Lac Saint-Jean region of Quebec is one in 1,850 births. The elevated frequency of this disorder within individuals of French-Canadian ancestry in Quebec is believed to be due to reduced genetic heterogeneity within the original founder population for the Saguenay-Lac Saint-Jean region. The initial settlement of Saguenay Lac-Saint-Jean (SLSJ) occurred between 1838 and 1911. From a total of 28,656 settlers, 75 percent originated from the neighboring Charlevoix region. The settling of the Charlevoix region itself started in 1675 when 599 founders of mostly French descent moved to this region from the Quebec City area.Worldwide, type I tyrosinemia affects about 1 person in 100,000. This type of tyrosinemia is much more common in Quebec, Canada. The overall incidence in Quebec is about 1 in 16,000 individuals. In the Saguenay-Lac-Saint-Jean region of Quebec, type 1 tyrosinemia affects 1 person in 1,846. The carrier rate has been estimated to be between 1 in 20 and 1 in 31.

History
Nitisinone was first used to clinically treat tyrosinemia type I in 1991. Nitisinone was approved by the European Medicine Agency (EMA) under exceptional circumstances in 2005. Originally, nitisinone was developed as a weed-killer by Zeneca Agrochemicals. It was epidemiologically observed that the growth of plants and weeds was inhibited under the bottlebrush plant (Callistemon citrinus). It became clear that neither the shade nor the litterfall of these plants was responsible for the suppression of plant and weed growth. Rather, a substance – which was identified as leptospermone – in the soil under the bottlebrush plant was shown to have bleaching activity on the emerging plants. The allelochemical leptospermone was extracted from the bottlebrush plant and chemically characterized. Leptospermone belongs to the triketone family and inhibits chloroplast development due to a lack of plastoquinone secondary to hepatic 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibition; thus, it served as a blueprint for the synthesis of nitisinone.In 1932, Grace Medes first described "a new disorder of tyrosine metabolism," She coined the condition "tyrosinosis" after observing 4-hydroxyphenylpyruvate in the urine of a 49-year-old man with myasthenia gravis. She proposed that the metabolic defect in this patient was a deficiency of 4-hydroxyphenylpyruvate dioxygenase, but her case remains puzzling and has since been assigned a separate OMIM number. The first typical patient with hepatorenal tyrosinemia was described in 1956 by Margaret D Baber at Edgware General Hospital in Middlesex, England. Starting the following year, Kiyoshi Sakai and colleagues, at the Jikei University School of Medicine in Tokyo, published 3 reports describing the clinical, biochemical, and pathological findings of a 2-year-old boy with hepatorenal tyrosinemia who was then thought to have an "atypical" case of tyrosinosis. Between 1963 and 1965, Swedish pediatrician Rolf Zetterström and colleagues at the Karolinska Institute in Sweden published the first detailed clinical account of hepatorenal tyrosinemia and its variants </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 Cervical lymphadenopathy and can you explain it in depth? [/INST] Cervical lymphadenopathy refers to lymphadenopathy of the cervical lymph nodes (the glands in the neck). The term lymphadenopathy strictly speaking refers to disease of the lymph nodes, though it is often used to describe the enlargement of the lymph nodes. Similarly, the term lymphadenitis refers to inflammation of a lymph node, but often it is used as a synonym of lymphadenopathy.
Cervical lymphadenopathy is a sign or a symptom, not a diagnosis. The causes are varied, and may be inflammatory, degenerative, or neoplastic. In adults, healthy lymph nodes can be palpable (able to be felt), in the axilla, neck and groin. In children up to the age of 12 cervical nodes up to 1 cm in size may be palpable and this may not signify any disease. If nodes heal by resolution or scarring after being inflamed, they may remain palpable thereafter. In children, most palpable cervical lymphadenopathy is reactive or infective. In individuals over the age of 50, metastatic enlargement from cancers (most commonly squamous cell carcinomas) of the aerodigestive tract should be considered.

Classification
Cervical lymphadenopathy can be thought of as local where only the cervical lymph nodes are affected, or general where all the lymph nodes of the body are affected.

Causes
Infection
Pericoronitis
Staphylococcal lymphadenitis
Mycobacterial lymphadenitis
Rubella
Cat scratch fever
Infectious mononucleosis
Streptococcal pharyngitis
Viral respiratory infection
Toxoplasmosis
Tuberculosis
Brucellosis
Primary herpes simplex infection (primary herpetic gingivostomatitis)
Syphilis (secondary)
Cytomegalovirus
Human immunodeficiency virus
Histoplasmosis
Chicken pox

Malignancy
Lymph nodes may become enlarged in malignant disease. This cervical lymphadenopathy may be reactive or metastatic. Alternatively, enlarged lymph nodes may represent a primary malignancy of the lymphatic system itself, such as lymphoma (both Hodgkins and non-Hodgkins), lymphocytic leukemia, Lymphadenopathy that lasts less than two weeks or more than one year with no progressive size increase has a very low likelihood of being neoplastic.Metastatic lymph nodes are enlarged because tumor cells have detached from the primary tumor and started growing in the lymph node ("seeded"). Since cancer generally occurs more frequently in older people, this kind of lymphadenopathy is more common in older persons. Metastatic lymph nodes tend to feel hard and may be fixed to underlying tissues and may or may not be tender </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 African tick bite fever and can you explain it in depth? [/INST] African tick bite fever (ATBF) is a bacterial infection spread by the bite of a tick. Symptoms may include fever, headache, muscle pain, and a rash. At the site of the bite there is typically a red skin sore with a dark center. The onset of symptoms usually occurs 4–10 days after the bite. Complications are rare but may include joint inflammation. Some people do not develop symptoms.Tick bite fever is caused by the bacterium Rickettsia africae. The bacterium is spread by ticks of the Amblyomma type. These generally live in tall grass or bush rather than in cities. The diagnosis is typically based on symptoms. It can be confirmed by culture, PCR, or immunofluorescence.There is no vaccine. Prevention is by avoiding tick bites by covering the skin, using DEET, or using permethrin treated clothing. Evidence regarding treatment, however, is limited. The antibiotic doxycycline appears useful. Chloramphenicol or azithromycin may also be used. The disease will also tend to resolve without treatment.The disease occurs in sub-Saharan Africa, the West Indies, and Oceania. It is relatively common among travelers to sub-Saharan Africa. Most infections occur between November and April. Outbreaks of the disease may occur. The earliest descriptions of the condition are believed to be from 1911. African tick bite fever is a type of spotted fever. It has previously been confused with Mediterranean spotted fever.

Signs and symptoms
African tick bite fever is often asymptomatic or mild in clinical presentation and complications are rare. The onset of illness is typically 5–7 days after the tick bite, although in some cases it may take up to 10 days for symptoms to occur. Symptoms can persist for several days to up to three weeks.  Common presenting symptoms include:

Fever
Headache
Muscle aches
Inoculation eschar, which is dead, often black, tissue around a bite site (see photo above)
Eschars may or may not be present. Amblyomma ticks actively attack cattle or humans and can bite more than once. In African tick bite fever, unlike what is typically seen with other Rickettsial spotted fevers when only one eschar is identified, multiple eschars may be seen and are considered pathognomonic.
Swollen lymph nodes near the site of the bite
Maculopapular and/or vesicular rash

Complications
Complications are rare and are not life-threatening. No deaths due to African tick bite fever have been reported. Reported complications include:

Prolonged fever > 3 weeks in duration
Reactive arthritis
Moderate to severe headache

Cause
Bacteriology
Rickettsia africae is a gram-negative, obligate intracellular, pleomorphic bacterium. It belongs to the genus Rickettsia, which includes many bacterial species that are transmitted to humans by arthropods.

Vectors
Two species of hard ticks, Amblyoma variegatum and Amblyomma hebraeum are the most common vectors of R. africae. Typically, Amblyomma hebraeum transmits the bacteria in South Africa while Amblyoma variegatum carries R. africae throughout West, Central and East Africa and through the French West Indies. Other species of Amblyomma in sub-Saharan Africa can also transmit R. africae and it may be that up to 100% of Amblyomma ticks in sub-Saharan Africa carry R. africae. Amblyomma ticks are most active from November to April. These tick species frequently feed on cattle and other livestock, but can also be found feeding on wild animals in areas where farm animals are not found. Unlike other hard tick species, which passively seek hosts by clinging to plants and waiting for a potential host to brush by in passing, the Amblyomma hard ticks actively seek out hosts.Groups of tourists visiting Africa have returned to their own countries and were diagnosed there as having been infected.Up until 1998, it was thought that only ticks in sub-Saharan Africa carried R. africae. However, a case of locally transmitted African tick bite fever in the French West Indies led to the discovery of R. africae carried by Amblyomma varigatum ticks introduced through cattle shipped from Senegal to Gaudeluope more than a century ago. R. africae has been isolated from ticks on several Caribbean islands, though the only cases in humans in the Caribbean have occurred in the French West Indies. R. africae has also been found in Amblyomma loculosum ticks in Oceania.

Pathogenesis
After the rickettsia bacteria infects humans through a tick bite, it invades endothelial cells in the circulatory system (veins, arteries, capillaries). The body then releases chemicals that cause inflammation, resulting in the characteristic symptoms like headache and fever. The hallmark of all rickettsial diseases is a histology (cellular) finding called lymphohistiocytic vasculitis that involves immune cell deposition into the endothelial cells that make up vessels. This occurs secondary to the chemicals mentioned above, as well as damage from the infection, and involves signals to immune cells (T cells and macrophages) to come to the site of the infection.Rickettsia bacteria species like R. africae replicate around the area of the initial tick bite, causing necrosis (cell death) and lymph node inflammation. This is the cause of the characteristic eschar.

Diagnosis
Many patients with ATBF who live in areas with a high number of infections (Africa and the West Indies) do not visit a doctor, as most patients only have mild symptoms. This disease can, however, cause more serious symptoms in travelers who have never been exposed to the Rickettsia africae bacterium before and are not immune. Travelers who present to a doctor after a trip to affected areas can be hard to diagnose, as many tropical diseases cause a fever similar to that of ATBF. Other diseases that may look similar are malaria, dengue fever, tuberculosis, acute HIV and respiratory infections. In addition to questions about symptoms, doctors will ask patients for an accurate travel history and whether he/she was near animals or ticks. Microbiological tests are available for doctors, but are expensive and often must be done by special laboratories.The antibiotic treatment available for rickettsiae infections has very few side effects, so if a doctor has a high suspicion of the disease, he or she may simply treat without doing more laboratory tests.

Blood tests
Diagnosis of ATBF is mostly based on symptoms, as many laboratory tests are not specific for ATBF. Common laboratory test signs of ATBF are a low white blood cell count (lymphopenia) and low platelet count (thrombocytopenia), a high C-reactive protein, and mildly high liver function tests.

Microbiological tests
Biopsies or cultures of a persons tick wound (eschar) are used to diagnose ATBF. However, this requires special culture media and can only be done by a laboratory with biohazard protection. There are more specialized laboratory tests available that use quantitative polymerase chain reactions (qPCR), but can only be done by laboratories with special equipment. Immunofluorescence assays can also be used, but are hard to interpret because of cross-reactions with other rickettsiae bacteria.

Prevention
Prevention of ATBF centers around protecting oneself from tick bites by wearing long pants and shirt, and using insecticides like DEET on the skin. Travelers to rural areas in Africa and the West Indies should be aware that they may come in contact with ATBF tick vectors. Infection is more likely to occur in people who are traveling to rural areas or plan to spend time participating in outdoor activities. Extra caution should be taken in November - April, when Amblyomma ticks are more active </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 Acute zonal occult outer retinopathy and can you explain it in depth? [/INST]  </s>