<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Aggressive periodontitis and explain in detail? [/INST] Aggressive periodontitis describes a type of periodontal disease and includes two of the seven classifications of periodontitis as defined by the 1999 classification system:
Localized aggressive periodontitis (LAP)
Generalized aggressive periodontitis (GAP)LAP is localised to first molar or incisor interproximal attachment loss, whereas GAP is the interproximal attachment loss affecting at least three permanent teeth other than incisors and first molar. The prevalence of LAP is less than 1% and that of GAP is 0.13%. Approximately 0.1% of white Caucasians (with 0.1% in northern and in central Europe, 0.5% in southern Europe, and 0.1-0.2% in North America) and 2.6% of black Africans may have LAP. Estimates of the disease prevalence are 1-5% in the African population and in groups of African descent, 2.6% in African-Americans, 0.5-1.0% in Hispanics in North America, 0.3-2.0% in South America, and 0.2-1.0% in Asia. On the other hand, in Asia, the prevalence rate of 1.2% for LAP and 0.6% for GAP in Baghdad and Iran population, and 0.47% in Japanese population.Therefore, the prevalence of LAP varies considerably between continents, and differences in race or ethnicity seem to be a major contributing factor.Aggressive periodontitis is much less common than chronic periodontitis and generally affects younger patients than does the chronic form.[2][3] Around 1 in every 1000 patients experience more rapid loss of attachment. Males seem to be at higher risk of GAP than femalesThe localized and generalized forms are not merely different in extent; they differ in etiology and pathogenesis.

Etiology
Microbiology
Of the microflora characterised in aggressive periodontitis, approximately 65-75% of bacteria are Gram-negative bacilli, with few spirochaetes or motile rods present. Aggressive periodontitis is often characterised by a rapid loss of periodontal attachment associated with highly pathogenic bacteria and an impaired immune response. Various studies have associated Aggregatibacter actinomycetemcomitans, formerly known as Actinobacillus actinomycetemcomitans, with aggressive periodontitis. An early study dating back to 1983 explains its prevalence and documents its role in localised aggressive periodontitis.Virulence factors are the attributes of microorganisms that enable it to colonise a particular niche in its host, overcome the host defences and initiate a disease process. Fives Taylor et al. (2000) have categorised the virulence factors of Aggregatibacter actinomycetemcomitans as follows.
Samaranayake notes the evidence for the specific involvement of Aggregatibacter actinomycetemcomitans includes: an increased incidence of it found in subgingival plaque obtained from lesional sites, high level of its antibody which tends to fall following successful treatment, its possession of a wide range of potentially pathogenic products and its elimination with concordant disease regression, following treatment with successful periodontal therapy and adjunctive tetracycline.Porphyromonas gingivalis is a Gram-negative anaerobe associated with the pathogenicity of periodontal disease, and aggressive periodontitis is no exception. Greater numbers of both Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans were found in active, destructive periodontal lesions in comparison to non-active sites.Capnocytophaga spp are implicated as prime periodontal pathogens, especially in localised aggressive periodontitis. Both Capnocytophaga spp and Prevotella intermedia were the most frequently detected microorganisms in a study, which also noted that Capnocytophaga spp was the most prominent bacteria in subgingival samples of patients with aggressive periodontitis.An impaired ability of peripheral blood lymphocytes to react to chemotactic stimuli is found in the majority of patients with aggressive periodontitis. As well as Aggregatibacter actinomycetemcomitans being associated with this, the synergism of the disease also accounts for both Capnocytophaga spp and Porphyromonas gingivalis.

Pathophysiology
Aggressive periodontitis is a multifactorial disease with many complex interactions including host factors, microbiology and genetics.
Host defences involve multiple factors; saliva, epithelium, inflammatory response, immune response and chemical mediators. The inflammatory exudate in the gingival tissues and gingival crevicular fluid is mostly polymorph neutrophils but also includes B cells and plasma cells. The neutrophils may show an intrinsic functional defect and respond abnormally when challenged by certain pathogens. The plasma cells produce specific antibodies in response to the periodontal pathogens, which diffuse into the gingival crevicular fluid. They produce mainly IgG, with some IgA. It has been suggested that these gingival crevicular fluid antibody levels could be potentially useful in the development of a vaccine. Patients with localised aggressive periodontitis have large amount of Aggregatibacter actinomycetemcomitans specific IgG2. This is suggested to be protective against wider spread periodontal breakdown. However, patients with generalized aggressive periodontitis have decreased ability to mount high titres of IgG to Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans.
It has also been found that a low T-helper to T-suppressor ratio is found in aggressive periodontitis which may alter local immune regulation. Monocytes respond to bacterial and inflammatory stimuli with very high levels of local release inflammatory mediators and induce hyper-inflammatory reaction with activation of tissue degrading matrix-metalloproteinases. These is also evidence they produce increased amounts IL-1α and IL-1β which cause osteoclastic bone resorption. These amounts are greatly reduced following treatment.Studies of families, twins and sibling pairs have provided strong evidence for a genetic basis for aggressive periodontitis. A persons genetic predisposition to the condition is determined by a single gene of major effect, inherited as an autosomal dominant trait. However, for the disease process to initiate the person must be exposed to the presence of periodontal pathogens and potentially also various environmental factors.
Smoking is a generalized risk factor for generalized forms of aggressive periodontitis. Studies found that smokers have more affected teeth than non-smokers and high levels of attachment loss. This is due to the suppression of serum IgG2 and antibody against Aggregatibacter actinomycetemcomitans found in smokers.

Features
According to the 1999 International Workshop for the Classification of Periodontal Diseases, aggressive periodontitis was defined according to 3 primary features, in contrast to chronic periodontitis. These features are common for both localized and generalized form of disease.

Primary features
Patients are clinically healthy.Patients do not have any underlying systemic disease that would contribute to aggressive periodontitis. For instance, diabetes is proved to be associated with periodontitis- it is a major risk factor when glycaemic control is poor.
The rate of loss of attachment and bone loss is rapid.Loss of attachment refers to the destruction of periodontium whereas the bone refers to the alveolar bone supporting the teeth. The loss can be determined by using a calibrated periodontal probe and taking radiographs of the dentition. Usually the loss of attachment is greater than 2mm per year.

Aggressive periodontitis runs in the patients family.Familial aggregation of aggressive periodontitis is often discovered by taking a thorough medical history of the patient. The patient is said to have a high genetic susceptibility to aggressive periodontitis. Many studies have shown that genetic factors contribute to the pathogenesis of this disease. In this case, the manifestation of aggressive periodontitis is believed to be the result of genetic mutation, combined with environmental factors.

Secondary features
Secondary features are characteristics which are frequently seen but not always present in every patient diagnosed with aggressive periodontitis.

The severity of periodontal tissue destruction is out of proportion to amount of bacteria present.The amount of bacteria is often indicated by the level of dental plaque. This feature implies that when aggressive periodontitis is present, loss of attachment and bone loss tend to occur even if the plaque level is low.

High levels of Aggregatibacter (or Actinobacillus) actinomycetemcomitans and, in some populations, Porphyromonas gingivalis.These gram-negative microbes are considered the chief aetiological agent of aggressive periodontitis. They are implicated in the development of aggressive periodontitis by triggering inflammatory response in periodontal tissue.

There are abnormalities associated with phagocytes.Phagocytes are essential in resolving inflammation. The impairment of their phagocytic activity results in persistent inflammation in periodontal tissues.
Hyper-responsive macrophage phenotype.Due to the increased responsiveness, the macrophages produce excessive levels of inflammatory mediator and cytokine, such as prostaglandin E2 (PGE2) and interleukin-1β (IL-1B). Their hyperactivity is associated with periodontal tissue destruction and bone loss.
Progression of attachment loss and bone loss may be self-arresting.In some patients, the disease may burnout without any cause-related therapy.
Caries levels have seen to be lower in cases of aggressive periodontitis.Staging
Cases of aggressive periodontitis have been staged into Stage I, II and III based on the severity of the cases. The staging index was proposed based on clinical features, radiological features and possible risk factors. The proposed index was validated with 10 cases of aggressive periodontitis followed for 10 years.

Clinical and radiographic features
Localized aggressive periodontitis
Clinical features
LAP begins around the age of puberty where there is interproximal loss of attachment of the first molar, and or incisors. on at least two permanent teeth (one which is a first molar) and no involvement of more than two teeth other than the first molars and incisors, lack of inflammation and evidence of deep periodontal pocket with advanced bone loss. There is also a relatively fast progression of periodontal tissue loss.With an increase in the age of the patient, there may be progression of the disease involving the adjacent teeth and lead to the patient developing GAP. The periodontal tissue also exhibits minimal signs of inflammation clinically and show a robust response with serum antibodies to pathogens.The amount of plaque present is inconsistent with the amount and severity of tissue destruction  but with a high plaque pathogenicity due to the presence of increased levels of bacteria like Aggregatibacter actinomycetemcomitans (A.a) and Porphyromonas Gingivalis (P.g).Secondary features of LAP may also be present including;
diastema formation with disto-labial migration of the incisors
increased mobility of the affected teeth, sensitivity due to exposed root,
deep dull pain that radiates to the jaw
periodontal abscess with lymph node enlargement

Radiographic features
Radiographically, the periodontal lesion often presents with alveolar bone loss in a horizontal  pattern at the interproximal surface of the permanent first molars  and usually horizontal bone pattern of bone loss at the interproximal surface of the incisors as the bone is thinner than at the interproximal surface of the molars.The alveolar bone loss patterns are usually bilateral and similar on both sides and has been referred to as being a mirror-image pattern.In advanced cases the alveolar bone loss may be depicted as a horizontal bone loss pattern radiographically.

Generalized aggressive periodontitis
Clinical features
Mostly in individuals under 30 years oldIn GAP, the clinical appearance of the disease resembles chronic periodontitis. The difference is that individuals affected by GAP are much younger and the progression of disease appears more rapid.
There is a poor serum response against infecting agentsDestruction is present that is not in balance with the amount of local irritants present
Generalized inter-proximal attachment loss on 3 or more permanent teeth, excluding the first molars or incisorsThe main distinction between the localized and generalized form of AgP lies in the number of teeth affected. GAP brings about attachment loss involving more than 30% of sites on teeth; effectively being at least three permanent teeth other than the first molars or incisors.
Episodic nature of attachment loss Two main tissue responses have been found in GAP cases:Tissue may have severe acute inflammation and often presents with an angry red appearance and ulceration. There may be spontaneous bleeding or suppuration. This response is known to be present in the destructive phase, where there is presence of bone and attachment loss.
The other response is known as a period of quiescence, where gingival tissue may appear with no inflammation, pink appearance with some possible stippling. In addition to this mild appearance there may be deep pockets upon probing.

Radiographic features
The key diagnostic feature of AgP is vertical bone loss around teeth including the first molars and incisors. This tends to begin around puberty in otherwise healthy individuals. There may be an appearance of "arc-shaped loss of alveolar bone extending from the distal surface of the second premolar to the mesial surface of the second molar".
In GAP, generalized bone destruction is present that ranges from mild crestal bone resorption to severe alveolar bone destruction, depending on the severity of the disease. There may be a combination of vertical and horizontal bone loss defects.

Screening
Early diagnosis of aggressive periodontitis is important as it can cause rapid permanent destruction of the periodontal tissues. It is essential that all patients undergo a routine periodontal examination to screen for any form of periodontal disease during a dental checkup.

Clinical examination
At the start of the clinical examination of the gingival and periodontal tissues, the dental practitioner would look at the appearance of the gingiva first. A healthy periodontium in a Caucasian would appear stippled and pink with a knife edge margin where it abuts the tooth (pigmentation may differ in other races). After that, gingival probing depths would be checked. This would normally be carried out using a basic periodontal probe (WHO CPI). On probing, patients with AgP should have evidence of significant periodontal pocket depths and loss of attachment (LOA). Dental practitioners should also be aware of false pocketing around erupting/newly erupted teeth in the mixed dentition phase and also in the presence of gingival inflammation. The presence of bleeding on probing (BOP) should be noted which is an indicator of active disease.

Radiographs
Radiographic assessment should be carried out for patients with evidence of periodontitis to observe alveolar bone levels which can help to identify signs of AgP. In healthy periodontal tissues, the distance from the amelocemental junction (ACJ) to the alveolar bone crest is typically in the order of 1mm in young people. If the distance between the ACJ and alveolar bone crest is more than 2-3mm then there is a possible suggestion of AgP. In addition to that, presence of angular or vertical bone loss (especially at 6s) and arrowhead or furcation lesions are also a strong suggestion of AgP.

Strong family association
It is also important for a dental practitioner to check for family history of periodontal disease for each patient. This is because AgP may have an autosomal dominant inheritance pattern which suggests that up to 50% of siblings could be affected if one parent has the disease. Careful interpretation of the history is required but it may provide vital evidence in diagnosing AgP. If a case of Agp is diagnosed, it is important to screen the patients family members as well for AgP. Early detection of AgP allows intervention to be carried out before extensive periodontal destruction has taken place which further simplifies treatment.

Treatment
Following the initial assessment and diagnosis of AgP, a treatment plan is usually developed for each individual undergoing therapy. As the overall treatment concepts and goals for AgP are not significantly different from that of chronic periodontitis, the different treatment phases (cause related therapy; re-examination for response to therapy; definitive therapy; and maintenance) are similar for both types of periodontitis.
Nevertheless, the considerable amount of bone loss relative to the young age of the individual in AgP necessitates an often more aggressive treatment approach, to halt further periodontal destruction and regain as much periodontal attachment as possible. The objective of treatment is to create a conducive clinical condition for retaining as many teeth, for as long as possible.

Cause Related Therapy
This stage involves discussion of the disease with the patient.

Oral Hygiene Instructions: The clinician should advise the patient of his intrinsic susceptibility to plaque, which his body induces a strong, pro-inflammatory response to. It is thus essential to keep his oral hygiene immaculate. This involve going over both smooth surfaces (tooth brushing instructions) and the use of interproximal aids (e.g. floss).
Smoking cessation (if applicable): Smoking is a significant risk factor for AgP, with patients who smoke having more affected teeth with loss of clinical attachment and more bone loss than non-smoking patients with AgP. Non-smokers also tend to have a better response to periodontal therapy as compared to smokers. As such, individuals must be advised of the benefits of smoking cessation and the otherwise potential risks of a worsening periodontal condition.
Removal of plaque retentive factors: Local plaque retentive factors such as mal-positioned teeth, overhanging restorations, crown and bridgework, partial dentures and fixed/removable orthodontic appliances can increase the risk of periodontal disease and prevent successful treatment and resolution of associated pockets. Prior to starting periodontal treatment, any overhanging or poorly contoured restorations should be modified or replaced. Instructions should also be given on how to clean adequately around fixed restorations and appliances, and how to clean removable prostheses. These intra-oral appliances should also be well-designed and fitting.The periodontal therapy carried out at this stage is of a non-surgical approach, which is aimed at the removal of supra- and sub-gingival plaque and calculus deposits, to decrease the microbial load, bacteria biofilm, and calculus from the periodontally involved sites.
Scale and Polish
Root Surface Debridement (RSD)
Antibiotics: There is evidence that the additional use of systemic antibiotics in conjunction with non-surgical periodontal treatment results in a more favourable clinical response, as compared to just periodontal treatment alone, as it helps to suppress pathogenic bacteria and create a health-associated biofilm. There have been many antibiotic regimes proposed for the treatment of AgP. However, the combination of choice according to current research is a combination of amoxicillin (500 mg, thrice/day) and metronidazole (200 mg, thrice/day), for 7 days, starting on the day of the final debridement. Doxycycline (100 mg, once/day, with a starting first dose of 200 mg) is the choice of antibiotics for patients allergic to penicillin.
Light Amplification by Stimulated Emission of Radiation (LASER) Therapy
Photodynamic Therapy (PDT): This potentially has all the advantages of low-level LASER therapy, which allows the disinfection of periodontal pocket and the eradication of bacteria in areas of difficult access, without the thermal damage to tissues associated with the high-powered LASER. A significant reduction in the aggregatibacter actinomycetemcomitans count following PDT suggests that the use of PDT in conjunction with conventional non-surgical periodontal treatment can potentially result in a more effective treatment. Considering the global issue of antibiotic resistance, further development and research in PDT successes may prove to present it an ideal adjunct to conventional non-surgical periodontal therapy, as compared to the use of systemic antibiotics.

Re-examination/Response to Therapy
This stage of treatment involves the reassessment of the individuals compliance (i.e </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Spondyloepiphyseal dysplasia congenita and explain in detail? [/INST] Spondyloepiphyseal dysplasia congenita (abbreviated to SED more often than SDC) is a rare disorder of bone growth that results in dwarfism, characteristic skeletal abnormalities, and occasionally problems with vision and hearing. The name of the condition indicates that it affects the bones of the spine (spondylo-) and the ends of bones (epiphyses), and that it is present from birth (congenital). The signs and symptoms of spondyloepiphyseal dysplasia congenita are similar to, but milder than, the related skeletal disorders achondrogenesis type 2 and hypochondrogenesis. Spondyloepiphyseal dysplasia congenita is a subtype of collagenopathy, types II and XI.

Presentation
People with spondyloepiphyseal dysplasia are short-statured from birth, with a very short trunk and neck and shortened limbs. Their hands and feet, however, are usually average-sized. This type of dwarfism is characterized by a normal spinal column length relative to the femur bone. Adult height ranges from 0.9 meters (35 inches) to just over 1.4 meters (55 inches). Curvature of the spine (such as kyphoscoliosis and lordosis) progresses during childhood and can cause problems with breathing. Changes in the spinal bones (vertebrae) in the neck may also increase the risk of spinal cord damage </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Cyclotropia and explain in detail? [/INST] Cyclotropia is a form of strabismus in which, compared to the correct positioning of the eyes, there is a torsion of one eye (or both) about the eyes visual axis. Consequently, the visual fields of the two eyes appear tilted relative to each other. The corresponding latent condition – a condition in which torsion occurs only in the absence of appropriate visual stimuli – is called cyclophoria.
Cyclotropia is often associated with other disorders of strabism, can result in double vision, and can cause other symptoms, in particular head tilt.In some cases, subjective and objective cyclodeviation may result from surgery for oblique muscle disorders; if the visual system cannot compensate for it, cyclotropia and rotational double vision (cyclodiplopia) may result. The role of cyclotropia in vision disorders is not always correctly identified </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Pederasty and explain in detail? [/INST] Pederasty or paederasty (US:  or UK: ) is a sexual relationship between an adult man and a pubescent or adolescent boy. The term pederasty is primarily used to refer to historical practices of certain cultures, particularly ancient Greece and ancient Rome.
In most countries today such relationships are illegal. The local age of consent determines whether a person is considered legally competent to consent to sexual acts, and whether such contact is child sexual abuse or statutory rape. An adult engaging in sexual activity with a minor may be considered abusive by medical authorities for a variety of reasons, including the age of the minor, the likelihood of the minor developing one or more mental disorders, such as post-traumatic stress disorder, physical injury to the minor, and the minors propensity for further victimization in adulthood.

Etymology and usage
Pederasty derives from the combination of Ancient Greek: παίδ-, romanized: paid-, lit. boy, child (stem) with ἐραστής, erastēs, lover (cf. eros). Late Latin pæderasta was borrowed in the 16th century directly from Platos classical Greek in The Symposium. (Latin transliterates αί as æ.) The word first appeared in the English language during the Renaissance, as pæderastie (e.g. in Samuel Purchas Pilgrimes), in the sense of sexual relations between men and boys.
The Oxford English Dictionary defines it as "Homosexual relations between a man and a boy; homosexual anal intercourse, usually with a boy or younger man as the passive partner".

History
Ancient Greece
Pederasty in ancient Greece was a socially acknowledged romantic relationship between an adult male (the erastes) and a younger male (the eromenos), usually in his teens </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Hypoaldosteronism and explain in detail? [/INST] Hypoaldosteronism is an endocrinological disorder characterized by decreased levels of the hormone aldosterone.  Similarly, isolated hypoaldosteronism is the condition of having lowered aldosterone without corresponding changes in cortisol. (The two hormones are both produced by the adrenals.)

Presentation
Causes
There are several causes for this condition, including adrenal insufficiency, congenital adrenal hyperplasia, and some medications such as certain diuretics, NSAIDs, and ACE inhibitors.
Primary aldosterone deficiencyPrimary adrenal insufficiency
Congenital adrenal hyperplasia (21 but not 11β and 17)
Aldosterone synthase deficiencySecondary aldosterone deficiencySecondary adrenal insufficiency
Diseases of the pituitary or hypothalamusHyporeninemic hypoaldosteronism (due to decreased angiotensin 2 production as well as intra-adrenal dysfunction)Renal dysfunction-most commonly diabetic nephropathy
NSAIDs
Ciclosporin

Mechanism
Hypoaldosteronism may result in high blood potassium and is the cause of type 4 renal tubular acidosis, sometimes referred to as hyperkalemic RTA or tubular hyperkalemia. However, the acidosis, if present, is often mild </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Multidrug-resistant tuberculosis and explain in detail? [/INST] Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs): isoniazid and rifampin. Some forms of TB are also resistant to second-line medications, and are called extensively drug-resistant TB (XDR-TB).Tuberculosis is caused by infection with the bacterium Mycobacterium tuberculosis. Almost one in four people in the world are infected with TB bacteria. Only when the bacteria become active do people become ill with TB. Bacteria become active as a result of anything that can reduce the persons immunity, such as HIV, advancing age, diabetes or other immunocompromising illnesses. TB can usually be treated with a course of four standard, or first-line, anti-TB drugs (i.e., isoniazid, rifampin, pyrazinamide and ethambutol).However, beginning with the first antibiotic treatment for TB in 1943, some strains of the TB bacteria developed resistance to the standard drugs through genetic changes (see mechanisms.) Currently the majority of multidrug-resistant cases of TB are due to one strain of TB bacteria called the Beijing lineage. This process accelerates if incorrect or inadequate treatments are used, leading to the development and spread of multidrug-resistant TB (MDR-TB). Incorrect or inadequate treatment may be due to use of the wrong medications, use of only one medication (standard treatment is at least two drugs), or not taking medication consistently or for the full treatment period (treatment is required for several months). Treatment of MDR-TB requires second-line drugs (i.e., fluoroquinolones, aminoglycosides, and others), which in general are less effective, more toxic and much more expensive than first-line drugs. Treatment schedules for MDR-TB involving fluoroquinolones and aminoglycosides can run for 2 years, compared to the 6 months of first-line drug treatment, and cost over US$100,000. If these second-line drugs are prescribed or taken incorrectly, further resistance can develop leading to XDR-TB.
Resistant strains of TB are already present in the population, so MDR-TB can be directly transmitted from an infected person to an uninfected person. In this case a previously untreated person develops a new case of MDR-TB. This is known as primary MDR-TB, and is responsible for up to 75% of cases. Acquired MDR-TB develops when a person with a non-resistant strain of TB is treated inadequately, resulting in the development of antibiotic resistance in the TB bacteria infecting them. These people can in turn infect other people with MDR-TB.MDR-TB caused an estimated 600,000 new TB cases and 240,000 deaths in 2016 and MDR-TB accounts for 4.1% of all new TB cases and 19% of previously treated cases worldwide. Globally, most MDR-TB cases occur in South America, Southern Africa, India, China, and the former Soviet Union.Treatment of MDR-TB requires treatment with second-line drugs, usually four or more anti-TB drugs for a minimum of 6 months, and possibly extending for 18–24 months if rifampin resistance has been identified in the specific strain of TB with which the patient has been infected. Under ideal program conditions, MDR-TB cure rates can approach 70%.

Mechanism of drug resistance
The TB bacterium has natural defenses against some drugs, and can acquire drug resistance through genetic mutations. The bacterium does not have the ability to transfer genes for resistance between organisms through plasmids (see horizontal transfer). Some mechanisms of drug resistance include:
Cell wall: The cell wall of M. tuberculosis (TB) contains complex lipid molecules which act as a barrier to stop drugs from entering the cell.
Drug modifying & inactivating enzymes: The TB genome codes for enzymes (proteins) that inactivate drug molecules. These enzymes are usually phosphorylate, acetylate, or adenylate drug compounds.
Drug efflux systems: The TB cell contains molecular systems that actively pump drug molecules out of the cell.
Mutations: Spontaneous mutations in the TB genome can alter proteins which are the target of drugs, making the bacteria drug-resistant.One example is a mutation in the rpoB gene, which encodes the beta subunit of the bacteriums RNA polymerase. In non-resistant TB, rifampin binds the beta subunit of RNA polymerase and disrupt transcription elongation. Mutation in the rpoB gene changes the sequence of amino acids and eventual conformation of the beta subunit. In this case rifampin can no longer bind or prevent transcription, and the bacterium is resistant.Other mutations make the bacterium resistant to other drugs. For example, there are many mutations that confer resistance to isoniazid (INH), including in the genes katG, inhA, ahpC and others. Amino acid replacements in the NADH binding site of InhA apparently result in INH resistance by preventing the inhibition of mycolic acid biosynthesis, which the bacterium uses in its cell wall. Mutations in the katG gene make the enzyme catalase peroxidase unable to convert INH to its biologically active form. Hence, INH is ineffective and the bacterium is resistant. The discovery of new molecular targets is essential to overcome drug-resistance problems.In some TB bacteria, the acquisition of these mutations can be explained by other mutations in the DNA recombination, recognition and repair machinery. Mutations in these genes allow the bacteria to have a higher overall mutation rate and to accumulate mutations that cause drug resistance more quickly.

Extensively drug-resistant TB
MDR-TB can become resistant to the major second-line TB drug groups: fluoroquinolones (moxifloxacin, ofloxacin) and injectable aminoglycoside or polypeptide drugs (amikacin, capreomycin, kanamycin). When MDR-TB is resistant to at least one drug from each group, it is classified as extensively drug-resistant tuberculosis (XDR-TB).WHO has revised the definitions of pre-XDR-TB and XDR-TB in 2021 as following:Pre-XDR-TB: TB caused by Mycobacterium tuberculosis (M.tuberculosis) strains that fulfill the definition of MDR/RR-TB and which are also resistant to any fluoroquinolone.
XDR-TB: TB caused by Mycobacterium tuberculosis (M. tuberculosis) strains that fulfill the definition of MDR/RR-TB and which are also resistant to any fluoroquinolone and at least one additional Group A drug.
The Group A drugs are currently levofloxacin or moxifloxacin, bedaquiline and linezolid, therefore XDR-TB is MDR/RR-TB that is resistant to a fluoroquinolone and at least one of bedaquiline or linezolid (or both).
In a study of MDR-TB patients from 2005 to 2008 in various countries, 43.7% had resistance to at least one second-line drug. About 9% of MDR-TB cases are resistant to a drug from both classes and classified as XDR-TB.In the past 10 years TB strains have emerged in Italy, Iran, India, and South Africa which are resistant to all available first and second line TB drugs, classified as totally drug-resistant tuberculosis, though there is some controversy over this term. Increasing levels of resistance in TB strains threaten to complicate the current global public health approaches to TB control. New drugs are being developed to treat extensively resistant forms but major improvements in detection, diagnosis, and treatment will be needed.

Prevention
There are several ways that drug resistance to TB, and drug resistance in general, can be prevented:
Rapid diagnosis & treatment of TB: One of the greatest risk factors for drug-resistant TB is problems in treatment and diagnosis, especially in developing countries. If TB is identified and treated soon, drug resistance can be avoided.
Completion of treatment: Previous treatment of TB is an indicator of MDR TB. If the patient does not complete their antibiotic treatment, or if the physician does not prescribe the proper antibiotic regimen, resistance can develop. Also, drugs that are of poor quality or less in quantity, especially in developing countries, contribute to MDR TB.
Identifying and diagnosing patients with HIV/AIDS as soon as possible. They lack the immunity to fight the TB infection and are at great risk of developing drug resistance.
Identifying contacts who could have contracted TB: family members, people in close contact, etc.
Research: Much research and funding is needed in the diagnosis, prevention and treatment of TB and MDR TB."Opponents of a universal tuberculosis treatment, reasoning from misguided notions of cost-effectiveness, fail to acknowledge that MDRTB is not a disease of poor people in distant places. The disease is infectious and airborne. Treating only one group of patients looks inexpensive in the short run, but will prove disastrous for all in the long run."— Paul Farmer

DOTS-Plus
Community-based treatment programs such as DOTS-Plus, a MDR-TB-specialized treatment using the popular Directly Observed Therapy – Short Course (DOTS) initiative, have shown considerable success in the world. In these locales, these programs have proven to be a good option for proper treatment of MDR-TB in poor, rural areas. A successful example has been in Lima, Peru, where the program has seen cure rates of over 80%.However, TB clinicians have expressed concern in the DOTS program administered in the Republic of Georgia because it is anchored in a passive case finding. This means that the system depends on patients coming to health care providers, without conducting compulsory screenings. As medical anthropologists like Erin Koch have shown, this form of implementation does not suit all cultural structures. They urge that the DOTS protocol be constantly reformed in the context of local practices, forms of knowledge and everyday life.Erin Koch has used Paul Farmers concept of "structural" violence as a perspective for understanding how "institutions, environment, poverty, and power reproduce, solidify, and naturalize the uneven distribution of disease and access to resources". She has also studied the effectiveness of the DOTS protocol in the widespread disease of tuberculosis in the Georgian prison system. Unlike the DOTS passive case finding used for the general Georgian public, the multiple-level surveillance in the prison system has proven more successful in reducing the spread of tuberculosis while increasing rates of cure.Koch critically notes that because the DOTS protocol aims to change the individuals behavior without addressing the need to change the institutional, political, and economic contexts, certain limitations arise, such as MDR tuberculosis.

Treatment
Usually, multidrug-resistant tuberculosis can be cured with long treatments of second-line drugs, but these are more expensive than first-line drugs and have more adverse effects. The treatment and prognosis of MDR-TB are much more akin to those for cancer than to those for infection. MDR-TB has a mortality rate of about 15% with treatment, which further depends on a number of factors, including:
How many drugs the organism is resistant to (the fewer the better)
How many drugs the patient is given (patients treated with five or more drugs do better)
The expertise and experience of the physician responsible
How co-operative the patient is with treatment (treatment is arduous and long, and requires persistence and determination on the part of the patient)
Whether the patient is HIV-positive or not (HIV co-infection is associated with increased mortality).The majority of patients with multidrug-resistant tuberculosis do not receive treatment, as they are found in underdeveloped countries or in poverty. Denial of treatment remains a difficult human rights issue, as the high cost of second-line medications often precludes those who cannot afford therapy.A study of cost-effective strategies for tuberculosis control supported three major policies. First, the treatment of smear-positive cases in DOTS programs must be the foundation of any tuberculosis control approach, and should be a basic practice for all control programs. Second, there is a powerful economic case for treating smear-negative and extra-pulmonary cases in DOTS programs along with treating smear-negative and extra-pulmonary cases in DOTS programs as a new WHO "STOP TB" approach and the second global plan for tuberculosis control. Last, but not least, the study shows that significant scaling-up of all interventions is needed in the next 10 years if the millennium development goal and related goals for tuberculosis control are to be achieved. If the case detection rate can be improved, this will guarantee that people who gain access to treatment facilities are covered and that coverage is widely distributed to people who do not now have access.In general, treatment courses are measured in months to years; MDR-TB may require surgery, and death rates remain high despite optimal treatment. However, good outcomes for patients are still possible.The treatment of MDR-TB must be undertaken by physicians experienced in the treatment of MDR-TB. Mortality and morbidity in patients treated in non-specialist centers are significantly higher than those of patients treated in specialist centers. Treatment of MDR-TB must be done on the basis of sensitivity testing: it is impossible to treat such patients without this information. When treating a patient with suspected MDR-TB, pending the result of laboratory sensitivity testing, the patient could be started on SHREZ (Streptomycin+ isonicotinyl Hydrazine+ Rifampicin+Ethambutol+ pyraZinamide) and moxifloxacin with cycloserine. There is evidence that previous therapy with a drug for more than a month is associated with diminished efficacy of that drug regardless of in vitro tests indicating susceptibility. Hence, a detailed knowledge of the treatment history of each patient is essential. In addition to the obvious risks (i.e., known exposure to a patient with MDR-TB), risk factors for MDR-TB include HIV infection, previous incarceration, failed TB treatment, failure to respond to standard TB treatment, and relapse following standard TB treatment.
A gene probe for rpoB is available in some countries. This serves as a useful marker for MDR-TB, because isolated RMP resistance is rare (except when patients have a history of being treated with rifampicin alone). If the results of a gene probe (rpoB) are known to be positive, then it is reasonable to omit RMP and to use SHEZ+MXF+cycloserine. The reason for maintaining the patient on INH is that INH is so potent in treating TB that it is foolish to omit it until there is microbiological proof that it is ineffective (even though isoniazid resistance so commonly occurs with rifampicin resistance).
For treatment of RR- and MDT-TB, WHO treatment guidelines are as follows: "a regimen with at least five effective TB medicines during the intensive phase is recommended, including pyrazinamide and four core second-line TB medicines – one chosen from Group A, one from Group B, and at least two from Group C3 (conditional recommendation, very low certainty in the evidence). If the minimum number of effective TB medicines cannot be composed as given above, an agent from Group D2 and other agents from Group D3 may be added to bring the total to five. It is recommended that the regimen be further strengthened with high-dose isoniazid and/or ethambutol (conditional recommendation, very low certainty in the evidence)." Medicines recommended are the following:

Group A: Fluoroquinolones (levofloxacin,moxifloxicin), linezolid, bedaquiline
Group B: clofazimine, cycloserine/terizidone
Group C: Other core second-line agents (ethambutol, delamanid, pyrazinamide, imipenem-cilastatin/meropenem, amikacin/streptomycin, ethionamide/prothionamide, p-aminosalicylic acid)For patients with RR-TB or MDR-TB, "not previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents was excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9–12 months may be used instead of the longer regimens (conditional recommendation, very low certainty in the evidence)."In general, resistance to one drug within a class means resistance to all drugs within that class, but a notable exception is rifabutin: Rifampicin-resistance does not always mean rifabutin-resistance, and the laboratory should be asked to test for it. It is possible to use only one drug within each drug class. If it is difficult finding five drugs to treat then the clinician can request that high-level INH-resistance be looked for. If the strain has only low-level INH-resistance (resistance at 0.2 mg/L INH, but sensitive at 1.0 mg/L INH), then high dose INH can be used as part of the regimen. When counting drugs, PZA and interferon count as zero; that is to say, when adding PZA to a four-drug regimen, another drug must be chosen to make five. It is not possible to use more than one injectable (STM, capreomycin or amikacin), because the toxic effect of these drugs is additive: If possible, the aminoglycoside should be given daily for a minimum of three months (and perhaps thrice weekly thereafter). Ciprofloxacin should not be used in the treatment of tuberculosis if other fluoroquinolones are available. As of 2008, Cochrane reports that trials of other fluoroquinolones are ongoing.There is no intermittent regimen validated for use in MDR-TB, but clinical experience is that giving injectable drugs for five days a week (because there is no-one available to give the drug at weekends) does not seem to result in inferior results. Directly observed therapy helps to improve outcomes in MDR-TB and should be considered an integral part of the treatment of MDR-TB.Response to treatment must be obtained by repeated sputum cultures (monthly if possible). Treatment for MDR-TB must be given for a minimum of 18 months and cannot be stopped until the patient has been culture-negative for a minimum of nine months. It is not unusual for patients with MDR-TB to be on treatment for two years or more.Patients with MDR-TB should be isolated in negative-pressure rooms, if possible. Patients with MDR-TB should not be accommodated on the same ward as immunosuppressed patients (HIV-infected patients, or patients on immunosuppressive drugs). Careful monitoring of compliance with treatment is crucial to the management of MDR-TB (and some physicians insist on hospitalisation if only for this reason). Some physicians will insist that these patients remain isolated until their sputum is smear-negative, or even culture-negative (which may take many months, or even years). Keeping these patients in hospital for weeks (or months) on end may be a practical or physical impossibility, and the final decision depends on the clinical judgement of the physician treating that patient. The attending physician should make full use of therapeutic drug monitoring (in particular, of the aminoglycosides) both to monitor compliance and to avoid toxic effects.
Some supplements may be useful as adjuncts in the treatment of tuberculosis, but, for the purposes of counting drugs for MDR-TB, they count as zero (if four drugs are already in the regimen, it may be beneficial to add arginine or vitamin D or both, but another drug will be needed to make five). Supplements are:
arginine (peanuts are a good source),
vitamin D,Dzherelo,V5 Immunitor.The drugs listed below have been used in desperation, and it is uncertain as to whether they are effective at all. They are used when it is not possible to find five drugs from the list above.
imipenem,co-amoxiclav,clofazimine,prochlorperazine,metronidazole.On 28 December 2012, the U.S. Food and Drug Administration (FDA) approved bedaquiline (marketed as Sirturo by Johnson & Johnson) to treat multidrug-resistant tuberculosis, the first new treatment in 40 years. Sirturo is to be used in a combination therapy for patients who have failed standard treatment and have no other options. Sirturo is an adenosine triphosphate synthase (ATP synthase) inhibitor.The following drugs are experimental compounds that are not commercially available, but may be obtained from the manufacturer as part of a clinical trial or on a compassionate basis. Their efficacy and safety are unknown:
pretomanid (manufactured by Novartis, developed in partnership with TB Alliance), and
delamanid.
In cases of extremely resistant disease, surgery to remove infection portions of the lung is, in general, the final option. The center with the largest experience in this is the National Jewish Medical and Research Center in Denver, Colorado. In 17 years of experience, they have performed 180 operations; of these, 98 were lobectomies and 82 were pneumonectomies. There is a 3.3% operative mortality, with an additional 6.8% dying following the operation; 12% experienced significant morbidity (in particular, extreme breathlessness). Of 91 patients who were culture-positive before surgery, only 4 were culture-positive after surgery.The resurgence of tuberculosis in the United States, the advent of HIV-related tuberculosis, and the development of strains of TB resistant to the first-line therapies developed in recent decades—serve to reinforce the thesis that Mycobacterium tuberculosis, the causative organism, makes its own preferential option for the poor. The simple truth is that almost all tuberculosis deaths result from a lack of access to existing effective therapy.Treatment success rates remain unacceptably low globally with variation between regions. 2016 data published by the WHO reported treatment success rates of multidrug-resistant TB globally. For those started on treatment for multidrug-resistant TB 56% successfully completed treatment, either treatment course completion or eradication of disease; 15% of those died while in treatment; 15% were lost to follow-up; 8% had treatment failure and there was no data on the remaining 6%. Treatment success rate was highest in the World Health Organization Mediterranean region at 65%. Treatment success rates were lower than 50% in the Ukraine, Mozambique, Indonesia and India. Areas with poor TB surveillance infrastructure had higher rates of loss to follow-up of treatment.57 countries reported outcomes for patients started on extreme-drug resistant Tuberculosis, this included 9258 patients. 39% completed treatment successfully, 26% of patients died and treatment failed for 18%. 84% of the extreme Drug resistant Cohort was made up of only three countries; India, Russian Federation and Ukraine. Shorter treatment regimes for MDR-TB have been found to be beneficial having higher treatment success rates.

Epidemiology
Cases of MDR tuberculosis have been reported in every country surveyed. MDR-TB most commonly develops in the course of TB treatment, and is most commonly due to doctors giving inappropriate treatment, or patients missing doses or failing to complete their treatment. Because MDR tuberculosis is an airborne pathogen, persons with active, pulmonary tuberculosis caused by a multidrug-resistant strain can transmit the disease if they are alive and coughing. TB strains are often less fit and less transmissible, and outbreaks occur more readily in people with weakened immune systems (e.g., patients with HIV). Outbreaks among non immunocompromised healthy people do occur, but are less common.As of 2013, 3.7% of new tuberculosis cases have MDR-TB. Levels are much higher in those previously treated for tuberculosis - about 20%. WHO estimates that there were about 0.5 million new MDR-TB cases in the world in 2011. About 60% of these cases occurred in Brazil, China, India, the Russian Federation and South Africa alone. In Moldova, the crumbling health system has led to the rise of MDR-TB. In 2013, the Mexico–United States border was noted to be "a very hot region for drug resistant TB", though the number of cases remained small.It has been known for many years that INH-resistant TB is less virulent in guinea pigs, and the epidemiological evidence is that MDR strains of TB do not dominate naturally. A study in Los Angeles, California, found that only 6% of cases of MDR-TB were clustered. Likewise, the appearance of high rates of MDR-TB in New York City in the early 1990s was associated with the explosion of AIDS in that area. In New York City, a report issued by city health authorities states that fully 80 percent of all MDR-TB cases could be traced back to prisons and homeless shelters. When patients have MDR-TB, they require longer periods of treatment—about two years of multidrug regimen. Several of the less powerful second-line drugs, which are required to treat MDR-TB, are also more toxic, with side effects such as nausea, abdominal pain, and even psychosis. The Partners in Health team had treated patients in Peru who were sick with strains that were resistant to ten and even twelve drugs. Most such patients require adjuvant surgery for any hope of a cure.

Somalia
MDR-TB is widespread in Somalia, where 8.7% of newly discovered TB cases are resistant to Rifampicin and Isoniazid, in patients which were treated previously the share was 47%.Refugees from Somalia brought an until then unknown variant of MDR tuberculosis with them to Europe. A few number of cases in four different countries were considered by the European Centre for Disease Prevention and Control to pose no risk to the native population.

Russian prisons
One of the so-called "hot-spots" of drug-resistant tuberculosis is within the Russian prison system. Infectious disease researchers Nachega & Chaisson report that 10% of the one million prisoners within the system have active TB. One of their studies found that 75% of newly diagnosed inmates with TB are resistant to at least one drug; 40% of new cases are multidrug-resistant. In 1997, TB accounted for almost half of all Russian prison deaths, and as Bobrik et al. point out in their public health study, the 90% reduction in TB incidence contributed to a consequential fall in the prisoner death rate in the years following 1997. Baussano et al. articulate that concerning statistics like these are especially worrisome because spikes in TB incidence in prisons are linked to corresponding outbreaks in surrounding communities. Additionally, rising rates of incarceration, especially in Central Asian and Eastern European countries like Russia, have been correlated with higher TB rates in civilian populations. Even as the DOTS program is expanded throughout Russian prisons, researchers such as Shin et al. have noted that wide-scale interventions have not had their desired effect, especially with regard to the spread of drug-resistant strains of TB.

Contributing factors
There are several elements of the Russian prison system that enable the spread of MDR-TB and heighten its severity. Overcrowding in prisons is especially conducive to the spread of tuberculosis; an inmate in a prison hospital has (on average) 3 meters of personal space, and an inmate in a correctional colony has 2 meters. Specialized hospitals and treatment facilities within the prison system, known as TB colonies, are intended to isolate infected prisoners to prevent transmission; however, as Ruddy et al. demonstrate, there are not enough of these colonies to sufficiently protect staff and other inmates. Additionally, many cells lack adequate ventilation, which increases likelihood of transmission. Bobrik et al. have also noted food shortages within prisons, which deprive inmates of the nutrition necessary for healthy functioning.Comorbidity of HIV within prison populations has also been shown to worsen health outcomes. Nachega & Chaisson articulate that while HIV-infected prisoners are not more susceptible MDR-TB infection, they are more likely to progress to serious clinical illness if infected. According to Stern, HIV infection is 75 times more prevalent in Russian prison populations than in the civilian population. Therefore, prison inmates are both more likely to become infected with MDR-TB initially and to experience severe symptoms because of previous exposure to HIV.
Shin et al. emphasize another factor in MDR-TB prevalence in Russian prisons: alcohol and substance use. Ruddy et al. showed that risk for MDR-TB is three times higher among recreational drug users than non-users. Shin et al.s study demonstrated that alcohol usage was linked to poorer outcomes in MDR-TB treatment; they also noted that a majority of subjects within their study (many of whom regularly used alcohol) were nevertheless cured by their aggressive treatment regimen.Non-compliance with treatment plans is often cited as a contributor to MDR-TB transmission and mortality. Indeed, of the 80 newly released TB-infected inmates in Fry et al.s study, 73.8% did not report visiting a community dispensary for further treatment. Ruddy et al. cite release from facilities as one of the main causes of interruption in prisoners TB treatment, in addition to non-compliance within the prison and upon reintegration into civilian life. Fry et al.s study also listed side effects of TB treatment medications (especially in HIV positive individuals), financial worries, housing insecurities, family problems, and fear of arrest as factors that prevented some prisoners from properly adhering to TB treatment. They also note that some researchers have argued that the short-term gains TB-positive prisoners receive, such as better food or work exclusion, may dis-incentivize becoming cured. In their World Health Organization article, Gelmanova et al. posit that non-adherence to TB treatment indirectly contributes to bacterial resistance. Although ineffective or inconsistent treatment does not "create" resistant strains, mutations within the high bacterial load in non-adherent prisoners can cause resistance.
Nachega & Chaisson argue that inadequate TB control programs are the strongest driver of MDR-TB incidence. They note that prevalence of MDR-TB is 2.5 times higher in areas of poorly controlled TB. Russian-based therapy (i.e., not DOTS) has been criticized by Kimerling et al. as "inadequate" in properly controlling TB incidence and transmission. Bobrik et al. note that treatment for MDR-TB is equally inconsistent; the second-line drugs used to treat the prisoners lack specific treatment guidelines, infrastructure, training, or follow-up protocols for prisoners reentering civilian life.

Policy impacts
As Ruddy et al. note in their scholarly article, Russias recent penal reforms will greatly reduce the number of inmates inside prison facilities and thus increase the number of ex-convicts integrated into civilian populations. Because the incidence of MDR-TB is strongly predicted by past imprisonment, the health of Russian society will be greatly impacted by this change. Formerly incarcerated Russians will re-enter civilian life and remain within that sphere; as they live as civilians, they will infect others with the contagions they were exposed to in prison. Researcher Vivian Stern argues that the risk of transmission from prison populations to the general public calls for an integration of prison healthcare and national health services to better control both TB and MDR-TB. While second-line drugs necessary for treating MDR-TB are arguably more expensive than a typical regimen of DOTS therapy, infectious disease specialist Paul Farmer posits that the outcome of leaving infected prisoners untreated could cause a massive outbreak of MDR-TB in civilian populations, thereby inflicting a heavy toll on society. Additionally, as MDR-TB spreads, the threat of the emergence of totally-drug-resistant TB becomes increasingly apparent.

See also
2007 tuberculosis scare
Drug resistance
MRSA
Vancomycin-resistant enterococcus (VRE)
Totally drug-resistant tuberculosis (TDR-TB)
Medicines Patent Pool

References
NotesFarmer, Paul (1999). Infections and inequalities : the modern plagues. Berkeley, California, United States: University of California Press </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Marcus Gunn phenomenon and explain in detail? [/INST] Marcus Gunn phenomenon is an autosomal dominant condition with incomplete penetrance, in which nursing infants will have rhythmic upward jerking of their upper eyelid </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Cystic hygroma and explain in detail? [/INST] A cystic hygroma is an abnormal growth that usually appears on a babys neck or head. It consists of one or more cysts and tends to grow larger over time. The disorder usually develops while the fetus is still in the uterus, but can also appear after birth.Also known as cystic lymphangioma and macrocystic lymphatic malformation, the growth is often a congenital lymphatic lesion of many small cavities (multiloculated) that can arise anywhere, but is classically found in the left posterior triangle of the neck and armpits. The malformation contains large cyst-like cavities containing lymph, a watery fluid that circulates throughout the lymphatic system. Microscopically, cystic hygroma consists of multiple locules filled with lymph. Deep locules are quite big, but they decrease in size towards the surface.
Cystic hygromas are benign, but can be disfiguring. It is a condition which usually affects children; very rarely it can be present in adulthood.Currently, the medical field prefers to use the term lymphatic malformation, because the term cystic hygroma means water tumor. Lymphatic malformation is more commonly used now because it is a sponge-like collection of abnormal growth that contains clear lymphatic fluid. The fluid collects within the cysts or channels, usually in the soft tissue. Cystic hygromas occur when the lymphatic vessels that make up the lymphatic system are not formed properly. The two types of lymphatic malformations are macrocystic  (large cysts) and microcystic (small cysts) lymphatic malformations. A person may have only one kind of the malformation or can have a mixture of both macro- and microcysts.
Cystic hygroma can be associated with a nuchal lymphangioma or a fetal hydrops. Additionally, it can be associated with Down syndrome, Turner syndrome, or Noonan syndrome. If it is diagnosed in the third trimester, then chances of association with Down syndrome are increased, but if diagnosed in the second trimester, then it is associated with Turner syndrome.
A lethal version of this condition exists, known as Cowchock–Wapner–Kurtz syndrome, that, in addition to cystic hygroma, includes cleft palate and lymphedema, a condition of localized edema and tissue swelling caused by a compromised lymphatic system.

Signs and symptoms
Cystic hygromas are increasingly diagnosed by prenatal ultrasonography. A common sign is a neck growth. It may be found at birth, or discovered later in an infant after an upper respiratory tract infection. Cystic hygromas can grow very large and may affect breathing and swallowing. Some symptoms may include a mass or lump in the mouth, neck, cheek, or tongue. It feels like a large, fluid-filled sac. In addition, cystic hygromas can be found in other body parts, such as the arms, chest, legs, groin, and buttocks. Cystic hygromas are also often seen in Turners syndrome, although a patient who does not have the syndrome can present with this condition.

Diagnosis
Lymphatic malformations may be detected in the human fetus by ultrasound if they are of sufficient size. Detection of a cystic malformation may prompt further investigation, such as amniocentesis, to evaluate for genetic abnormalities in the fetus </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Light chain deposition disease and explain in detail? [/INST] Light chain deposition disease (LCDD) is a rare blood cell disease which is characterized by deposition of fragments of infection-fighting immunoglobulins,  called light chains (LCs), in the body. LCs are normally cleared by the kidneys, but in LCDD, these light chain deposits damage organs and cause disease. The kidneys are almost always affected and this often leads to kidney failure.  About half of people with light chain deposition disease also have a plasma cell dyscrasia, a spectrum of diseases that includes multiple myeloma, Waldenströms macroglobulinemia, and the monoclonal gammopathy of undetermined significance premalignant stages of these two diseases.  Unlike in AL amyloidosis, in which light chains are laid down in characteristic amyloid deposits, in LCDD, light chains are deposited in non-amyloid granules.

Signs and symptoms
The kidney is the organ most frequently affected.  Proteinuria, the presence of protein in the urine, is characteristic. More than 90% of people with LCDD develop kidney failure, often with rapid progression of disease.Light chains may be deposited in many other organs and may or may not result in any symptoms. Other than the kidneys, liver and heart are the most commonly involved organs.  Deposition of light chains in the liver may lead to hepatomegaly, an enlarged liver, or rarely portal hypertension or liver failure </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Hemangioendothelioma and explain in detail? [/INST] Hemangioendotheliomas are a family of vascular neoplasms of intermediate malignancy.

Signs and symptoms
They have been described as masses that fall between a hemangioma and angiosarcoma.  They are vascular tumors that commonly present with an enlarging mass and most commonly involve the lungs, liver, and musculoskeletal system, although many other body sites have been reported, including the head and neck, intestines, lymph nodes, pleura, retroperitoneum, heel, stomach.

Cause
Possibly Bartonella spp bacteraemia

Diagnosis
Classification
Hemangioendotheliomas may be classified as:

Epithelioid hemangioendothelioma is an uncommon vascular tumor of intermediate malignancy that was first described by Steven Billings, Andrew Folpe, and Sharon Weiss in 2003. These tumors are so named because their histologic appearance resembles a proliferation of epithelioid cells, with polygonal shape and eosinophilic cytoplasm.
Composite hemangioendothelioma is a low-grade angiosarcoma typically occurring in adults, although it has been described in infancy.: 601
Spindle-cell hemangioendothelioma) is a vascular tumor that was first described in 1986 by Sharon Weiss, M.D., and commonly presents in a child or young adult who develops blue nodules of firm consistency on a distal extremity.: 599  These tumors were reclassified by Dr. Weiss in 1996 as "spindle cell hemangioma", rather than hemangioendothelioma, due to the excellent prognosis observed in a group of 78 patients.
Retiform hemangioendothelioma (also known as a "Hobnail hemangioendothelioma") is a low-grade angiosarcoma, first described in 1994, presenting as a slow-growing exophytic mass, dermal plaque, or subcutaneous nodule.: 601
Kaposiform hemangioendothelioma (also known as "Infantile kaposiform hemangioendothelioma") is an uncommon vascular tumor, first described by Niedt, Greco, et al. (Hemangioma with Kaposis sarcoma-like features: report of two cases.(Niedt GW, Greco MA, Wieczorek R, Blanc WA, Knowles DM 2nd. that affects infants and young children, with rare cases having also been reported in adults. Pediatr Pathol. 1989;9(5):567-75.): 596 : 1782
Endovascular papillary angioendothelioma, also known as "Dabska tumor",  "papillary intralymphatic angioendothelioma" (PILA), "Dabska-type hemangioendothelioma", "hobnail hemangioendothelioma", and "malignant endovascular papillary angioendothelioma", is a rare low-grade angiosarcoma: 601  of lymphatic channels. Approximately 30 such tumors have been described in the medical literature. Although included in the World Health Organization tumor classification, there is uncertainty as to whether EPA is a distinct entity or a heterogenous group of tumours. The lesion usually presents as a slow-growing tumor of the skin and subcutaneous tissues of the head, neck, or extremity, of infants or young children.: 601  However, EPA has involved the testicle, deep muscle tissue as a neoplastic transformation of a larger existing benign cavernous hemangioma, bone and spleen, and has been found in adults. Some reports indicate a good prognosis but metastasis is occasionally seen.
Infantile hemangioendothelioma is a rare benign vascular tumour arising from mesenchymal tissue and is usually located in the liver. It often presents in infancy with cardiac failure because of extensive arteriovenous shunting within the lesion. It is the third most common liver tumor in children, the most common benign vascular tumor of the liver in infancy, and the most common symptomatic liver tumor during the first 6 months of life. These hemangioendotheliomas have 2 growth phases: an initial rapid growth phase, which is followed by a period of spontaneous involution (usually within the first 12 to 18 months of life). Detection of the hemangioendothelioma within the first 6 months of life is attributed to the initial rapid growth during this time; however, the tumor has been detected with fetal ultrasonography. Histopathologically, there are 2 types of hepatic hemangioendotheliomas:
Type I: Hemagioendotheliomas of this type have multiple vascular channels that are formed by an immature endothelial lining with stromal separation from bile ductules.
Type II: These hemangioendotheliomas have an appearance that is more disorganized and hypercellular, and there are no bile ductules.In children, distinguishing between a primary malignant liver tumor (hepatoblastoma) and a benign primary hepatic lesion (hemangioendothelioma) is crucial. The absence of urinary catecholamines supports the diagnosis of hemangioendothelioma. In patients with hemangioendotheliomas, elevations in α1-fetoprotein levels are milder than those found in patients with hepatoblastomas </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Acrocraniofacial dysostosis and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Splenic lymphoma with villous lymphocytes and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Drug-induced purpura and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Calculus (dental) and explain in detail? [/INST] In dentistry, calculus or tartar is a form of hardened dental plaque. It is caused by precipitation of minerals from saliva and gingival crevicular fluid (GCF) in plaque on the teeth. This process of precipitation kills the bacterial cells within dental plaque, but the rough and hardened surface that is formed provides an ideal surface for further plaque formation. This leads to calculus buildup, which compromises the health of the gingiva (gums). Calculus can form both along the gumline, where it is referred to as supragingival ("above the gum"), and within the narrow sulcus that exists between the teeth and the gingiva, where it is referred to as subgingival ("below the gum").
Calculus formation is associated with a number of clinical manifestations, including bad breath, receding gums and chronically inflamed gingiva. Brushing and flossing can remove plaque from which calculus forms; however, once formed, calculus is too hard (firmly attached) to be removed with a toothbrush. Calculus buildup can be removed with ultrasonic tools or dental hand instruments (such as a periodontal scaler).

Etymology
The word comes from Latin calculus "small stone", from calx "limestone, lime", probably related to Greek χάλιξ chalix "small stone, pebble, rubble", which many trace to a Proto-Indo-European root for "split, break up". Calculus was a term used for various kinds of stones. This spun off many modern words, including "calculate" (use stones for mathematical purposes), and "calculus", which came to be used, in the 18th century, for accidental or incidental mineral buildups in human and animal bodies, like kidney stones and minerals on teeth.Tartar, on the other hand, originates in Greek as well (tartaron), but as the term for the white encrustation inside casks, aka potassium bitartrate commonly known as cream of tartar. This came to be a term used for calcium phosphate on teeth in the early 19th century.

Calculus composition
Calculus is composed of both inorganic (mineral) and organic (cellular and extracellular matrix) components. The mineral proportion of calculus ranges from approximately 40–60%, depending on its location in the dentition, and consists primarily of calcium phosphate crystals organized into four principal mineral phases, listed here in order of decreasing ratio of phosphate to calcium:

whitlockite, Ca9(Mg,Fe)(PO4)6(PO3OH)
hydroxyapatite, Ca5(PO4)3OH
octacalcium phosphate, Ca8H2(PO4)6 · 5 H2O
and brushite, CaHPO4 · 2 H2OThe organic component of calculus is approximately 85% cellular and 15% extracellular matrix. Cell density within dental plaque and calculus is very high, consisting of an estimated 200,000,000 cells per milligram. The cells within calculus are primarily bacterial, but also include at least one species of archaea (Methanobrevibacter oralis) and several species of yeast (e.g., Candida albicans). The organic extracellular matrix in calculus consists primarily of proteins and lipids (fatty acids, triglycerides, glycolipids, and phospholipids), as well as extracellular DNA. Trace amounts of host, dietary, and environmental microdebris are also found within calculus, including salivary proteins, plant DNA, milk proteins, starch granules, textile fibers, and smoke particles.

Calculus formation
The processes of calculus formation from dental plaque are not well understood. Supragingival calculus formation is most abundant on the buccal (cheek) surfaces of the maxillary (upper jaw) molars and on the lingual (tongue) surfaces of the mandibular (lower jaw) incisors. These areas experience high salivary flow because of their proximity to the parotid and sublingual salivary glands. Subgingival calculus forms below the gumline and is typically darkened in color by the presence of black-pigmented bacteria, whose cells are coated in a layer of iron obtained from heme during gingival bleeding. Dental calculus typically forms in incremental layers that are easily visible using both electron microscopy and light microscopy. These layers form during periodic calcification events of the dental plaque, but the timing and triggers of these events are poorly understood. The formation of calculus varies widely among individuals and at different locations within the mouth. Many variables have been identified that influence the formation of dental calculus, including age, gender, ethnic background, diet, location in the oral cavity, oral hygiene, bacterial plaque composition, host genetics, access to professional dental care, physical disabilities, systemic diseases, tobacco use, and drugs and medications.

Clinical significance
Plaque accumulation causes the gingiva to become irritated and inflamed, and this is referred to as gingivitis.  When the gingiva become so irritated that there is a loss of the connective tissue fibers that attach the gums to the teeth and bone that surrounds the tooth, this is known as periodontitis.  Dental plaque is not the sole cause of periodontitis; however it is many times referred to as a primary aetiology.  Plaque that remains in the oral cavity long enough will eventually calcify and become calculus.  Calculus is detrimental to gingival health because it serves as a trap for increased plaque formation and retention; thus, calculus, along with other factors that cause a localized build-up of plaque, is referred to as a secondary aetiology of periodontitis.
When plaque is supragingival, the bacterial content contains a great proportion of aerobic bacteria and yeast, or those bacteria which utilize and can survive in an environment containing oxygen.  Subgingival plaque contains a higher proportion of anaerobic bacteria, or those bacteria which cannot exist in an environment containing oxygen. Several anaerobic plaque bacteria, such as Porphyromonas gingivalis, secrete antigenic proteins that trigger a strong inflammatory response in the periodontium, the specialized tissues that surround and support the teeth. Prolonged inflammation of the periodontium leads to bone loss and weakening of the gingival fibers that attach the teeth to the gums, two major hallmarks of periodontitis.  Supragingival calculus formation is nearly ubiquitous in humans, but to differing degrees. Almost all individuals with periodontitis exhibit considerable subgingival calculus deposits. Dental plaque bacteria have been linked to cardiovascular disease and mothers giving birth to pre-term low weight infants, but there is no conclusive evidence yet that periodontitis is a significant risk factor for either of these two conditions.

Prevention
Toothpaste with pyrophosphates or zinc citrate has been shown to produce a statistically significant reduction in plaque accumulation, but the effect of zinc citrate is so modest that its clinical importance is questionable. Some calculus may form even without plaque deposits, by direct mineralisation of the pellicle.

Calculus in other animals
Calculus formation in other animals is less well studied than in humans, but it is known to form in a wide range of species. Domestic pets, such as dogs and cats, frequently accumulate large calculus deposits. Animals with highly abrasive diets, such as ruminants and equids, rarely form thick deposits and instead tend to form thin calculus deposits that often have a metallic or opalescent sheen. In animals, calculus should not be confused with crown cementum, a layer of calcified dental tissue that encases the tooth root underneath the gingival margin and is gradually lost through periodontal disease.

Archaeological significance
Dental calculus has been shown to contain well preserved microparticles, DNA and protein in archaeological samples. The information these molecules contain can reveal information about the oral microbiome of the host and the presence of pathogens. It is also possible to identify dietary sources as well as study dietary shifts and occasionally evidence of craft activities.

Sub-gingival calculus formation and chemical dissolution
Sub-gingival calculus is composed almost entirely of two components: fossilized anaerobic bacteria whose biological composition has been replaced by calcium phosphate salts, and calcium phosphate salts that have joined the fossilized bacteria in calculus formations.  The initial attachment mechanism and the development of mature calculus formations are based on electrical charge. Unlike calcium phosphate, the primary component of teeth, calcium phosphate salts exist as electrically unstable ions. The following minerals are detectable in calculus by X-ray diffraction: brushite (CaHPO4 · 2 H2O), octacalcium phosphate (Ca8H2(PO4)6 · 5 H2O), magnesium-containing whitlockite (Ca9(Mg,Fe)(PO4)6(PO3OH)), and carbonate-containing hydroxyapatite (approximately Ca5(PO4)3OH but containing some carbonate).The reason fossilized bacteria are initially attracted to one part of the subgingival tooth surface over another is not fully understood; once the first layer is attached, ionized calculus components are naturally attracted to the same places due to electrical charge. The fossilized bacteria pile on top of one another, in a rather haphazard manner. All the while, free-floating ionic components fill in the gaps left by the fossilized bacteria. The resultant hardened structure can be compared to concrete; with the fossilized bacteria playing the role of aggregate, and the smaller calcium phosphate salts being the cement.  The once purely electrical association of fossilized bacteria then becomes mechanical, with the introduction of free-floating calcium phosphate salts.  The "hardened" calculus formations are at the heart of periodontal disease and treatment.

Removal of calculus after formation
The College of Registered Dental Hygienists of Alberta defines a dental hygienist as "a health care professional whose work focuses on the oral health of an individual or community." These dental professionals aim to improve oral health by educating patients on the prevention and management of oral disease. Dental hygienists can be found performing oral health services in various settings, including private dental offices, schools, and other community settings, such as long-term care facilities. As mentioned above in the clinical significance section, plaque and calculus deposits are a major etiological factor in the development and progression of oral disease. An important part of the scope of practice of a dental hygienist is the removal of plaque and calculus deposits. This is achieved through the use of specifically designed instruments for debridement of tooth surfaces. Treatment with these types of instruments is necessary as calculus deposits cannot be removed by brushing or flossing alone. To effectively manage disease or maintain oral health, thorough removal of calculus deposits should be completed at frequent intervals. The recommended frequency of dental hygiene treatment can be made by a registered professional, and is dependent on individual patient needs. Factors that are taken into consideration include an individuals overall health status, tobacco use, amount of calculus present, and adherence to a professionally recommended home care routine.Hand instruments are specially designed tools used by dental professionals to remove plaque and calculus deposits that have formed on the teeth. These tools include scalers, curettes, jaquettes, hoes, files and chisels. Each type of tool is designed to be used in specific areas of the mouth. Some commonly used instruments include sickle scalers which are designed with a pointed tip and are mainly used supragingivally. Curettes are mainly used to remove subgingival calculus, smooth root surfaces and to clean out periodontal pockets. Curettes can be divided into two subgroups: universals and area specific instruments. Universal curettes can be used in multiple areas, while area specific instruments are designed for select tooth surfaces. Gracey curettes are a popular type of area specific curettes. Due to their design, area specific curettes allow for better adaptation to the root surface and can be slightly more effective than universals. Hoes, chisels, and files are less widely used than scalers and curettes. These are beneficial when removing large amounts of calculus or tenacious calculus that cannot be removed with a curette or scaler alone. Chisels and hoes are used to remove bands of calculus, whereas files are used to crush burnished or tenacious calculus.For hand instrumentation to be effective and efficient, it is important for clinicians to ensure that the instruments being used are sharp. It is also important for the clinician to understand the design of the hand instruments to be able to adapt them properly.Ultrasonic scalers, also known as power scalers, are effective in removing calculus, stain, and plaque. These scalers are also useful for root planing, curettage, and surgical debridement. Not only is tenacious calculus and stain removed more effectively with ultrasonic scalers than with hand instrumentation alone, it is evident that the most satisfactory clinical results are when ultrasonics are used in adjunct to hand instrumentation. There are two types of ultrasonic scalers; piezoelectric and magnetostrictive. Oscillating material in both of these handpieces cause the tip of the scaler to vibrate at high speeds, between 18,000 and 50,000 Hz. The tip of each scaler uses a different vibration pattern for removal of calculus. The magnetostrictive power scaler vibration is elliptical, activating all sides of the tip, whereas the piezoelectric vibration is linear and is more active on the two sides of the tip.Special tips for ultrasonic scalers are designed to address different areas of the mouth and varying amounts of calculus buildup. Larger tips are used for heavy subgingival or supragingival calculus deposits, whereas thinner tips are designed more for definitive subgingival debridement. As the high frequency vibrations loosen calculus and plaque, heat is generated at the tip </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Endogenous depression and explain in detail? [/INST] Endogenous depression (melancholia) is an atypical sub-class of major depressive disorder (clinical depression). It could be caused by genetic and biological factors. Endogenous depression occurs due to the presence of an internal (cognitive, biological) stressor instead of an external (social, environmental) stressor. Endogenous depression includes patients with treatment-resistant, non-psychotic, major depressive disorder, characterized by abnormal behavior of the endogenous opioid system but not the monoaminergic system. Symptoms vary in severity, type, and frequency and can be attributed to cognitive, social, biological, or environmental factors that result in persistent feelings of sadness and distress. Since symptoms are due to a biological phenomenon, prevalence rates tend to be higher in older adults. Due to this fact, biological-focused treatment plans are often used in therapy to ensure the best prognosis.Endogenous depression was part of the Kraepelinian dichotomy system.

Signs and symptoms
The forefront indication that a depressive episode is manifesting is the sudden loss of energy or motivation in daily routines. When this occurs, it is not uncommon for individuals to seek medical attention with excessive worrying or anxiety that a more severe, physiological disease may be the underlying issue. However, without an actual disease present, this neurotic thinking often results in severe anxiety, sleep disturbance, and mood swings which may hinder social relationships. Individuals with endogenous depression may experience inconsistencies in symptom severity  which is often the reason for delayed treatment. If left untreated, symptoms may progress to a major depressive episode.

Risk factors
Endogenous depression occurs as the results of an internal stressor—commonly cognitive or biological—and not an external factor. Potential risk factors include these cognitive or biological factors. Patients with endogenous depression often are more likely to have a positive family history of disorders and fewer psychosocial and environmental factors that cause their symptoms. A family history of depression and perceived poor intimate relationships are internal risk factors associated with this type of depression </s>