<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Myotonic dystrophy and can you explain it in depth? [/INST] Myotonic dystrophy (DM) is a type of muscular dystrophy, a group of genetic disorders that cause progressive muscle loss and weakness. In DM, muscles are often unable to relax after contraction. Other manifestations may include cataracts, intellectual disability and heart conduction problems. In men, there may be early balding and an inability to have children. While myotonic dystrophy can occur at any age, onset is typically in the 20s and 30s.Myotonic dystrophy is caused by a genetic mutation in one of two genes. Mutation of the DMPK gene causes myotonic dystrophy type 1 (DM1). Mutation of CNBP gene causes type 2 (DM2). DM is typically inherited from a persons parents, following an autosomal dominant inheritance pattern, and it generally worsens with each generation. A type of DM1 may be apparent at birth. DM2 is generally milder. Diagnosis is confirmed by genetic testing.There is no cure. Treatments may include braces or wheelchairs, pacemakers and non-invasive positive pressure ventilation. The medications mexiletine or carbamazepine can help relax muscles. Pain, if it occurs, may be treated with tricyclic antidepressants and nonsteroidal anti-inflammatory drugs (NSAIDs).Myotonic dystrophy affects more than 1 in 8,000 people worldwide. It is the most common form of muscular dystrophy that begins in adulthood. It was first described in 1909, with the underlying cause of type 1 determined in 1992.

Signs and symptoms
DM causes muscle weakness, early onset of cataracts, and myotonia, which is delayed relaxation of muscles after contraction. Cataracts can be either a cortical cataract with a blue dot appearance, or a posterior subcapsular cataract. Other organs affected include the heart, lungs, gastrointestinal tract, skin, and brain. Insulin resistance can also occur. Signs and symptoms vary considerably by severity, unusual phenotype, and form (DM1/DM2). DM1 and DM2 differ in regards to the muscles they affect, age of onset, severity of disease, and extramuscular manifestations.

DM1
DM1 usually begins in the muscles of the hands, feet, neck, or face. One manifestation of facial weakness is drooping of the eyelid (ptosis). It slowly progresses to involve other muscle groups, including the heart. Myotonia tends to be more prominent in DM1 compared to DM2. Other DM1 manifestations include problems with executive function (e.g., organization, concentration, word-finding) and hypersomnia. Abnormalities in the electrical activity of the heart are common in DM1, manifesting as arrhythmias or conduction blocks. Sometimes, dilated cardiomyopathy occurs. Symptoms onset any time from birth to adulthood. The earlier the disease onset, the greater the variety of possible signs and symptoms. Thus, various diagnostic classifications based on the age of onset/severity of the disease have been proposed, although DM1 manifestations likely lie on a continuum.

Congenital DM1
When DM1 onsets at birth, it is called congenital DM1. Manifestations that can be present at birth include hypotonia, respiratory failure, feeding difficulty, and club foot (talipes equinovarus), any of which tend to resolve over several years. During childhood, intellectual impairment, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorders (ASD) can result. Gastrointestinal issues can result, which can be severe, manifestations including diarrhea, constipation, and fecal incontinence. The symptoms of adult DM often manifest during adolescence. Infantile DM1 can be distinguished as another disease category, or it can be grouped with congenital DM1 or childhood-onset DM1.

Childhood-onset DM1
Childhood-onset DM1 is defined as onset of symptoms between ages 1 and 10 years. Manifestations include the same intellectual and gastrointestinal symptoms seen in congenital DM1.

DM2
DM2 is generally milder than DM1, with generally fewer DM2 people requiring assistive devices than DM1 people.
DM2 preferentially affects muscles closer to or on the torso, including the neck flexors, hip flexors, and hip extensors. Muscle pain is prominent in DM2. Heart issues, while still potentially fatal, are less common and severe in DM2 than DM1. Symptoms onset in early to late adulthood. Severe congenital onset, which can occur in DM1, has not been observed in DM2.

Genetics
Myotonic dystrophy (DM) is a genetic condition that is inherited in an autosomal dominant pattern, meaning each child of an affected individual has a 50% chance of inheriting the disease. The mutation involves satellite DNA, which is tandemly repeated sequences of DNA that do not code for a protein. The repeats implicated in myotonic dystrophy are either 3 or 4 nucleotides in length, classified as microsatellites. Disease results from an abnormally increased number of these microsatellites, termed microsatellite expansion.

DM1
The microsatellite expansion responsible for DM1 is of cytosine-thymine-guanine (CTG) triplet repeats, termed trinucleotide repeat expansion and classifying DM1 as a one of several trinucleotide repeat disorders. This expansion occurs at the end of the DMPK gene, in the 3 untranslated region. DMPK is located on the long arm of chromosome 19. DMPK codes for myotonic dystrophy protein kinase, a protein expressed predominantly in skeletal muscle.Between 5 and 37 repeats is considered normal; between 38 and 49 repeats is considered pre-mutation, and although not producing symptoms, children can have further repeat expansion and symptomatic disease; greater than 50 repeats almost invariably is symptomatic, with some noted exceptions. Longer repeats are usually associated with earlier onset and more severe disease.DMPK alleles with greater than 37 repeats are unstable and additional trinucleotide repeats may be inserted during cell division in mitosis and meiosis. Consequently, the children of individuals with premutations or mutations inherit DMPK alleles which are longer than their parents and therefore are more likely to be affected or display an earlier onset and greater severity of the condition, a phenomenon known as anticipation. Repeat expansion is generally considered to be a consequence of the incorporation of additional bases as a result of strand slippage during either DNA replication or DNA repair synthesis.  Misalignments occurring during homologous recombinational repair, double-strand break repair or during other DNA repair processes likely contribute to trinucleotide repeat expansions in DM1. Paternal transmission of the congenital form is uncommon (13%), possibly due to selection pressures against sperm with expanded repeats, but juvenile or adult-onset is equally transmitted from either parent. Anticipation tends to be less severe than in cases of maternal inheritance.The RNA from the expanded trinucleotide repeat region forms intranucleoplasmic hairpin loops due to the extensive hydrogen bonding between C-G base pairs, and it has been demonstrated that these sequester the splicing regulator MBNL1 to form distinctive foci.A severe form of DM1, congenital myotonic dystrophy, may appear in newborns of mothers who have DM. Congenital myotonic dystrophy can also be inherited via the paternal gene, although it is said to be relatively rare. Congenital means that the condition is present from birth.

DM2
The microsatellite expansion responsible for DM2 is of cytosine-cytosine-thymine-guanine (CCTG) repeats, classifying it as a tetranucleotide repeat disorder. This expansion occurs in the first intron CNBP gene on chromosome 3.The repeat expansion for DM2 is much larger than for DM1, ranging from 75 to over 11,000 repeats. Like DM1, the size of the microsatellite repeat array lengthens from generation to generation. Unlike DM1, anticipation does not result, as the degree of repeat expansion beyond 75 repeats does not affect the age of onset or disease severity.The repeat expansion produces an RNA transcript that binds to RNA-binding proteins such as MBNL1, as in DM1. Also, repeat expansion likely reduces expression of CNBP, loss of which causes muscle toxicity.

Pathophysiology
Molecular
Mutations of DM1 and DM2 cause production of RNA that sequesters RNA-binding proteins, causing dysregulated RNA splicing. This dysregulated RNA splicing is particularly toxic to skeletal, cardiac, and smooth muscle. One example in DM1 involves the chloride channel ClC-1. Mutated DMPK RNA binds to MBNL1, causing ClC-1 pre-mRNA to be spliced into the fetal form instead of the adult form. Functional loss of the chloride channel causes myotonia.

Histology
In DM1, there can be increased central nuclei, angular fibers, fiber atrophy, and pyknotic clumps. There can be selective atrophy of type 1 muscle fibers. Muscle fibers show signs of degeneration and regeneration. There is modest fibrosis of the endomysium.In DM2, there can be variation in the sizes of muscle fibers, although often there are no abnormalities. There is selective atrophy of type 2 muscle fibers. Again, there are central nuclei and nuclear clumps.

Diagnosis
The diagnosis of DM1 and DM2 can be difficult due to the large number of neuromuscular disorders, most of which are very rare. One study found that diagnosis is made an average of seven years after symptom onset for DM1, and fourteen years for DM2.As a result, people with multiple symptoms that may be explained by a complex disorder such as DM1 or DM2 will generally be referred by their primary care physician to a neurologist for diagnosis. Depending on the presentation of symptoms, people may be referred to a number of medical specialists including cardiologists, ophthalmologists, endocrinologists, and rheumatologists. In addition, the clinical presentation is obscured by the degree of severity or the presence of unusual phenotypes.
Though there is presently no cure for DM and management is currently symptom-based, a precise diagnosis is still necessary to anticipate multiple other problems that may develop over time (e.g. cataracts). An accurate diagnosis is important to assist with appropriate medical monitoring and management of symptoms. In addition, genetic counseling should be made available to all people because of the high risk of transmission. Potentially serious anesthetic risks are important to note, so the presence of this disorder should be brought to the attention of all medical providers.

Classification
There are two main types of myotonic dystrophy. Type 1 (DM1), also known as Steinert disease, has a severe congenital form and a milder childhood-onset form as well as an adult-onset form. This disease is most often in the facial muscles, levator palpebrae superioris, temporalis, sternocleidomastoids, distal muscles of the forearm, hand intrinsic muscles, and ankle dorsiflexors. Type 2 (DM2), also known as proximal myotonic myopathy (PROMM), is rarer and generally manifests with milder signs and symptoms than DM1.Other forms of myotonic dystrophy not associated with DM1 or DM2 genetic mutations have been described. One case which was proposed as a candidate for the "DM3" label, was later characterized as an unusual form of inclusion body myopathy associated with Pagets disease and frontotemporal dementia.

Genetic testing
Genetic tests, including prenatal testing, are available for both confirmed forms. Molecular testing is considered the gold standard of diagnosis.

Prenatal testing
Testing at pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a DMPK mutation. This can be done at 10–12 weeks gestation by a procedure called chorionic villus sampling (CVS) that involves removing a tiny piece of the placenta and analyzing DNA from its cells. It can also be done by amniocentesis after 14 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it and those who are interested in learning more should check with their doctor or genetic counselor.
There is also another procedure called preimplantation diagnosis that allows a couple to have a child that is unaffected by the genetic condition in their family. This procedure is experimental and not widely available. Those interested in learning more about this procedure should check with their doctor or genetic counselor.

Predictive testing
It is possible to test someone who is at risk for developing DM1 before they are showing symptoms to see whether they inherited an expanded trinucleotide repeat. This is called predictive testing. Predictive testing cannot determine the age of onset that someone will begin to have symptoms or the course of the disease. If the child is not having symptoms, the testing is not possible with an exception of emancipated minors as a policy.

Auxiliary testing
Electrodiagnostic testing (EMG and NCS) can detect the electrical signs of myotonia before myotonia becomes noticeable to the affected individual.Muscle biopsy can reveal damage of the muscle, but findings are generally nonspecific and do not greatly aid in diagnosis.

Management
There is currently no cure for or treatment specific to myotonic dystrophy. Management is focused on the complications of the disease, particularly those related to the lungs and heart, which are life-threatening. Complications relating to the cardiopulmonary system account for 70% of deaths due to DM1. Compromised lung function can, in turn, contribute to life-threatening complications during anesthesia and pregnancy.Lung complications are the leading cause of death in DM1, warranting lung function monitoring with pulmonary function tests every 6 months. Central sleep apnea or obstructive sleep apnea may cause excessive daytime sleepiness, and these individuals should undergo a sleep study. Non-invasive ventilation may be offered if there is an abnormality. Otherwise, there is evidence for the use of modafinil as a central nervous system stimulant, although a Cochrane review has described the evidence thus far as inconclusive.Cardiac complications are the second leading cause of death in DM1, and commonly no symptoms are present prior to adverse events. All affected individuals are advised to have an annual or biennial ECG. Pacemaker insertion may be required for individuals with cardiac conduction abnormalities. Improving the quality of life which can be measured using specific questionnaires is also a main objective of the medical care.

Physical activity
There is a lack of high-quality evidence to determine the effectiveness and the safety of physical activities for people who have myotonic dystrophy. Further research is required to determine if combined strength and aerobic training at moderate intensity is safe for people who have neuromuscular diseases, however the combination of aerobic and strength exercises may increase muscle strength. Aerobic exercise via stationary bicycle with an ergometer may be safe and effective in improving fitness in people with DM1. Cardiovascular impairments and myotonic sensitivities to exercise and temperature necessitate close monitoring of people and educating people in self-monitoring during exercise via the Borg scale, heart rate monitors, and other physical exertion measurements.

Orthotics
Muscular weakness of dorsiflexors (dorsiflexion) hinders the ability to clear the floor during the swing phase of gait and people may adopt a steppage gait pattern or ankle-foot-orthotics may be indicated. Factors such as hand function, skin integrity, and comfort must be assessed prior to prescription. Neck braces can also be prescribed for neck muscle weakness.

Mobility aids and adaptive equipment
Upper and lower limb weakness, visual impairments and myotonia may lead to the need for mobility aids and functional adaptive equipment such as buttonhooks and handled sponges for optimal hand function. If assistive devices and home adaptations are needed, physical therapists may refer on to occupational therapist(s) for further assessment.

Prognosis
Life expectancy in non-congenital late-onset or adult onset DM1 is in the early 50s, with pulmonary complications being the leading cause of death, followed by cardiac complications. DM2 life expectancy has yet to be studied.

Epidemiology
The prevalence of DM1 ranges from 5 to 20 per 100,000 (1:20,000–1:5000). Up to 48 per 100,000 (1:2100) of individuals tested positive for the mutation of DM1 in New York, although not all of these individuals would have become symptomatic. Again in New York, premutations for DM1 were found in 191 per 100,000 (1:525). DM2 prevalence is not known, but genetic studies estimate it to be as high as 1:1830. DM affects males and females approximately equally. About 30,000 people in the United States are affected </s>


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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Toxic and nutritional optic neuropathy and can you explain it in depth? [/INST] Toxic and nutritional optic neuropathy is a group of medical disorders defined by visual impairment due to optic nerve damage secondary to a toxic substance and/or nutritional deficiency.  The causes of these disorders are various, but they are linked by shared signs and symptoms, which this article will describe.  In several of these disorders, both toxic and nutritional factors play a role, acting synergistically.

Signs and symptoms
Vision loss in toxic and nutritional optic neuropathy is bilateral, symmetric, painless, gradual, and progressive.  Dyschromatopsia, a change in color vision, is often the first symptom.  Some patients notice that certain colors, particularly red, are less bright or vivid; others have a general loss of color perception.  Loss of visual acuity may start with a blur or haze at the point of fixation, followed by a progressive decline.  The degree of vision loss can extend to total blindness, but a loss beyond 20/400 is rare, except in the case of methanol ingestion.  Peripheral vision is usually spared since the pattern of loss typically involves a central or cecocentral scotoma, a visual field defect at or surrounding the point of fixation.  This pattern can be revealed via visual field testing.
Upon examination, the pupils usually demonstrate a normal response to light and near stimulation.  In those who are practically blind, the pupils will be dilated with a weak or absent response to light.  The optic disc may appear normal, swollen, or hyperemic in early stages.  With hyperemia, disc hemorrhages may also be present.  Continued damage to the optic nerve results in the development of optic atrophy, classically seen as temporal pallor of the optic disc.

Cause
Toxic optic neuropathy
There are several causes of toxic optic neuropathy. Among these are: ingestion of methanol (wood alcohol), ethylene glycol (automotive antifreeze), disulfiram (used to treat chronic alcoholism), halogenated hydroquinolones (amebicidal medications), ethambutol and isoniazid (tuberculosis treatment), and antibiotics such as linezolid and chloramphenicol as well as chloroquine and the related hydroxychloroquine (for lupus and rheumatoid arthritis) where it is known as chloroquine retinopathy.  Tobacco is also a major cause of toxic optic neuropathy.

Nutritional optic neuropathy
The predominant cause of nutritional optic neuropathy is thought to be deficiency of B-complex vitamins, particularly thiamine (vitamin B1), cyanocobalamin (vitamin B12) and recently copper.  Deficiency of pyridoxine (vitamin B6), niacin (vitamin B3), riboflavin (vitamin B2), and/or folic acid also seems to play a role.  Those individuals who consume excessive amounts of alcohol and use tobacco are at greater risk because they tend to be malnourished.  Those with pernicious anemia are also at risk due to an impaired ability to absorb vitamin B12 from the intestinal tract.

Pathophysiology
All of the above risk factors impact mitochondrial oxidative phosphorylation.  Thus, the toxic and nutritional optic neuropathies are actually acquired mitochondrial optic neuropathies.  The clinical picture that they produce is akin to that of the congenital mitochondrial optic neuropathies, e.g., Lebers hereditary optic neuropathy and Kjers optic neuropathy.

Diagnosis
The diagnosis of toxic or nutritional optic neuropathy is usually established by a detailed medical history and careful eye examination.  If the medical history clearly points to a cause, neuroimaging to rule out a compressive or infiltrative lesion is optional.  However, if the medical history is atypical or does not clearly point to a cause, neuroimaging is required to rule out other causes and confirm the diagnosis.  In most cases of suspected toxic or nutritional optic neuropathy that require neuroimaging, an MRI scan is obtained.  Further testing, guided by the medical history and physical examination, can be performed to elucidate a specific toxin or nutritional deficiency as a cause of the optic neuropathy.  Examples include blood testing for methanol levels or vitamin B12 levels.

Treatment
Treatment of toxic and nutritional optic neuropathy is dictated by the cause of the disorder.

Toxic optic neuropathy is treated by identification and removal of the offending agent.  Depending upon the individual affected, the nature of the agent, total exposure prior to removal, and degree of vision loss at the time of diagnosis, the prognosis is variable.
Nutritional optic neuropathy is treated with improved nutrition.  A well-balanced diet with plenty of protein and green leafy vegetables, vitamin supplementation (thiamine, vitamin B12, folic acid, multivitamins), and reduction of smoking and/or drinking are the mainstay of treatment.  Again, prognosis is variable and dependent upon the affected individual, treatment compliance, and degree of vision loss at diagnosis.In both toxic and nutritional neuropathy, vision generally recovers to normal over several days to weeks, though it may take months for full restoration and there is always the risk of permanent vision loss.  Visual acuity usually recovers before color vision.

Epidemiology
In industrialized nations, toxic and nutritional optic neuropathy is relatively uncommon and is primarily associated with specific medications, occupational exposures, or tobacco and alcohol use disorder.  However, in developing nations, nutritional optic neuropathy is much more common, especially in regions afflicted by famine.  All genders and all races are equally affected, and all ages are susceptible.

References
Further reading
Glaser, JS (1999). "Nutritional and toxic optic neuropathies".  In Glaser, JS (ed.). Neuro-ophthalmology (3rd ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 181–6.
Lessell, S (2000). "Nutritional deficiency and toxic optic neuropathies".  In Albert, DM; Jakobiec, FA (eds.). Principles and Practice of Ophthalmology (2nd ed.). Philadelphia: W.B </s>


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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Syphilis and can you explain it in depth? [/INST] Syphilis (/ˈsɪfɪlɪs/) is a sexually transmitted infection caused by the bacterium Treponema pallidum subspecies pallidum. The signs and symptoms of syphilis vary depending in which of the four stages it presents (primary, secondary, latent, and tertiary). The primary stage classically presents with a single chancre (a firm, painless, non-itchy skin ulceration usually between 1 cm and 2 cm in diameter) though there may be multiple sores. In secondary syphilis, a diffuse rash occurs, which frequently involves the palms of the hands and soles of the feet. There may also be sores in the mouth or vagina. In latent syphilis, which can last for years, there are few or no symptoms. In tertiary syphilis, there are gummas (soft, non-cancerous growths), neurological problems, or heart symptoms. Syphilis has been known as "the great imitator" as it may cause symptoms similar to many other diseases.Syphilis is most commonly spread through sexual activity. It may also be transmitted from mother to baby during pregnancy or at birth, resulting in congenital syphilis. Other diseases caused by Treponema bacteria include yaws (T. pallidum subspecies pertenue), pinta (T. carateum), and nonvenereal endemic syphilis (T. pallidum subspecies endemicum). These three diseases are not typically sexually transmitted. Diagnosis is usually made by using blood tests; the bacteria can also be detected using dark field microscopy. The Centers for Disease Control and Prevention (U.S.) recommend all pregnant women be tested.The risk of sexual transmission of syphilis can be reduced by using a latex or polyurethane condom. Syphilis can be effectively treated with antibiotics. The preferred antibiotic for most cases is benzathine benzylpenicillin injected into a muscle. In those who have a severe penicillin allergy, doxycycline or tetracycline may be used. In those with neurosyphilis, intravenous benzylpenicillin or ceftriaxone is recommended. During treatment people may develop fever, headache, and muscle pains, a reaction known as Jarisch–Herxheimer.In 2015, about 45.4 million people had syphilis infections, of which six million were new cases. During 2015, it caused about 107,000 deaths, down from 202,000 in 1990. After decreasing dramatically with the availability of penicillin in the 1940s, rates of infection have increased since the turn of the millennium in many countries, often in combination with human immunodeficiency virus (HIV). This is believed to be partly due to increased promiscuity, prostitution, decreasing use of condoms and unsafe sexual practices among men who have sex with men.

Signs and symptoms
Syphilis can present in one of four different stages: primary, secondary, latent, and tertiary, and may also occur congenitally. It was referred to as "the great imitator" by Sir William Osler due to its varied presentations.

Primary
Primary syphilis is typically acquired by direct sexual contact with the infectious lesions of another person. Approximately 2–6 weeks after contact (with a range of 10–90 days) a skin lesion, called a chancre, appears at the site and this contains infectious spirochetes. This is classically (40% of the time) a single, firm, painless, non-itchy skin ulceration with a clean base and sharp borders approximately 0.3–3.0 cm in size. The lesion may take on almost any form. In the classic form, it evolves from a macule to a papule and finally to an erosion or ulcer. Occasionally, multiple lesions may be present (~40%), with multiple lesions being more common when coinfected with HIV. Lesions may be painful or tender (30%), and they may occur in places other than the genitals (2–7%). The most common location in women is the cervix (44%), the penis in heterosexual men (99%), and anally and rectally in men who have sex with men (34%). Lymph node enlargement frequently (80%) occurs around the area of infection, occurring seven to 10 days after chancre formation. The lesion may persist for three to six weeks if left untreated.

Secondary
Secondary syphilis occurs approximately four to ten weeks after the primary infection. While secondary disease is known for the many different ways it can manifest, symptoms most commonly involve the skin, mucous membranes, and lymph nodes. There may be a symmetrical, reddish-pink, non-itchy rash on the trunk and extremities, including the palms and soles. The rash may become maculopapular or pustular. It may form flat, broad, whitish, wart-like lesions on mucous membranes, known as condyloma latum. All of these lesions harbor bacteria and are infectious. Other symptoms may include fever, sore throat, malaise, weight loss, hair loss, and headache. Rare manifestations include liver inflammation, kidney disease, joint inflammation, periostitis, inflammation of the optic nerve, uveitis, and interstitial keratitis. The acute symptoms usually resolve after three to six weeks; about 25% of people may present with a recurrence of secondary symptoms. Many people who present with secondary syphilis (40–85% of women, 20–65% of men) do not report previously having had the classical chancre of primary syphilis.

Latent
Latent syphilis is defined as having serologic proof of infection without symptoms of disease. It develops after secondary syphilis and is divided into early latent and late latent stages. Early latent syphilis is defined by the World Health Organization as less than 2 years after original infection. Early latent syphilis is infectious as up to 25% of people can develop a recurrent secondary infection (during which spirochetes are actively replicating and are infectious). Two years after the original infection the person will enter late latent syphilis and is not as infectious as the early phase. The latent phase of syphilis can last many years after which, without treatment, approximately 15-40% of people can develop tertiary syphilis.

Tertiary
Tertiary syphilis may occur approximately 3 to 15 years after the initial infection, and may be divided into three different forms: gummatous syphilis (15%), late neurosyphilis (6.5%), and cardiovascular syphilis (10%). Without treatment, a third of infected people develop tertiary disease. People with tertiary syphilis are not infectious.Gummatous syphilis or late benign syphilis usually occurs 1 to 46 years after the initial infection, with an average of 15 years. This stage is characterized by the formation of chronic gummas, which are soft, tumor-like balls of inflammation which may vary considerably in size. They typically affect the skin, bone, and liver, but can occur anywhere.Cardiovascular syphilis usually occurs 10–30 years after the initial infection. The most common complication is syphilitic aortitis, which may result in aortic aneurysm formation.Neurosyphilis refers to an infection involving the central nervous system. Involvement of the central nervous system in syphilis (either asymptomatic or symptomatic) can occur at any stage of the infection. It may occur early, being either asymptomatic or in the form of syphilitic meningitis, or late as meningovascular syphilis, general paresis, or tabes dorsalis.Meningovascular syphilis involves inflammation of the small and medium arteries of the central nervous system. It can present between 1–10 years after the initial infection. Meningovascular syphilis is characterized by stroke, cranial nerve palsies and spinal cord inflammation. Late symptomatic neurosyphilis can develop decades after the original infection and includes 2 types; general paresis and tabes dorsalis. General paresis presents with dementia, personality changes, delusions, seizures, psychosis and depression. Tabes dorsalis is characterized by gait instability, sharp pains in the trunk and limbs, impaired positional sensation of the limbs as well as having a positive Rombergs sign. Both tabes dorsalis and general paresis may present with Argyll Robertson pupil which are pupils that constrict when the person focuses on near objects (accommodation reflex) but do not constrict when exposed to bright light (pupillary reflex).

Congenital
Congenital syphilis is that which is transmitted during pregnancy or during birth. Two-thirds of syphilitic infants are born without symptoms. Common symptoms that develop over the first couple of years of life include enlargement of the liver and spleen (70%), rash (70%), fever (40%), neurosyphilis (20%), and lung inflammation (20%). If untreated, late congenital syphilis may occur in 40%, including saddle nose deformation, Higouménakis sign, saber shin, or Cluttons joints among others. Infection during pregnancy is also associated with miscarriage. The three main dental defects in congenital syphilis are Hutchinsons incisors (screwdriver shaped incisors), Moons molars or bud molars, and Fourniers molars or mulberry molars (molars with abnormal occlusal anatomy resembling a mulberry).

Cause
Bacteriology
Treponema pallidum subspecies pallidum is a spiral-shaped, Gram-negative, highly mobile bacterium. Three other human diseases are caused by related Treponema pallidum subspecies, including yaws (subspecies pertenue), pinta (subspecies carateum) and bejel (subspecies endemicum). Unlike subspecies pallidum, they do not cause neurological disease. Humans are the only known natural reservoir for subspecies pallidum. It is unable to survive more than a few days without a host. This is due to its small genome (1.14Mbp) failing to encode the metabolic pathways necessary to make most of its macronutrients. It has a slow doubling time of greater than 30 hours. The bacterium is known for its ability to evade the immune system and its invasiveness.

Transmission
Syphilis is transmitted primarily by sexual contact or during pregnancy from a mother to her baby; the spirochete is able to pass through intact mucous membranes or compromised skin. It is thus transmissible by kissing near a lesion, as well as oral, vaginal, and anal sex. Approximately 30% to 60% of those exposed to primary or secondary syphilis will get the disease. Its infectivity is exemplified by the fact that an individual inoculated with only 57 organisms has a 50% chance of being infected. Most new cases in the United States (60%) occur in men who have sex with men; and in this population 20% of syphilis cases were due to oral sex alone. Syphilis can be transmitted by blood products, but the risk is low due to screening of donated blood in many countries. The risk of transmission from sharing needles appears to be limited.It is not generally possible to contract syphilis through toilet seats, daily activities, hot tubs, or sharing eating utensils or clothing. This is mainly because the bacteria die very quickly outside of the body, making transmission by objects extremely difficult.

Diagnosis
Syphilis is difficult to diagnose clinically during early infection. Confirmation is either via blood tests or direct visual inspection using dark field microscopy. Blood tests are more commonly used, as they are easier to perform. Diagnostic tests are unable to distinguish between the stages of the disease.

Blood tests
Blood tests are divided into nontreponemal and treponemal tests.Nontreponemal tests are used initially, and include venereal disease research laboratory (VDRL) and rapid plasma reagin (RPR) tests. False positives on the nontreponemal tests can occur with some viral infections, such as varicella (chickenpox) and measles. False positives can also occur with lymphoma, tuberculosis, malaria, endocarditis, connective tissue disease, and pregnancy.Because of the possibility of false positives with nontreponemal tests, confirmation is required with a treponemal test, such as treponemal pallidum particle agglutination (TPHA) or fluorescent treponemal antibody absorption test (FTA-Abs). Treponemal antibody tests usually become positive two to five weeks after the initial infection. Neurosyphilis is diagnosed by finding high numbers of leukocytes (predominately lymphocytes) and high protein levels in the cerebrospinal fluid in the setting of a known syphilis infection.

Direct testing
Dark field microscopy of serous fluid from a chancre may be used to make an immediate diagnosis. Hospitals do not always have equipment or experienced staff members, and testing must be done within 10 minutes of acquiring the sample. Two other tests can be carried out on a sample from the chancre: direct fluorescent antibody (DFA) and polymerase chain reaction (PCR) tests. DFA uses antibodies tagged with fluorescein, which attach to specific syphilis proteins, while PCR uses techniques to detect the presence of specific syphilis genes. These tests are not as time-sensitive, as they do not require living bacteria to make the diagnosis.

Prevention
Vaccine
As of 2018, there is no vaccine effective for prevention. Several vaccines based on treponemal proteins reduce lesion development in an animal model but research continues.

Sex
Condom use reduces the likelihood of transmission during sex, but does not eliminate the risk. The Centers for Disease Control and Prevention (CDC) states, "Correct and consistent use of latex condoms can reduce the risk of syphilis only when the infected area or site of potential exposure is protected. However, a syphilis sore outside of the area covered by a latex condom can still allow transmission, so caution should be exercised even when using a condom."Abstinence from intimate physical contact with an infected person is effective at reducing the transmission of syphilis. The CDC states, "The surest way to avoid transmission of sexually transmitted diseases, including syphilis, is to abstain from sexual contact or to be in a long-term mutually monogamous relationship with a partner who has been tested and is known to be uninfected."

Congenital disease
Congenital syphilis in the newborn can be prevented by screening mothers during early pregnancy and treating those who are infected. The United States Preventive Services Task Force (USPSTF) strongly recommends universal screening of all pregnant women, while the World Health Organization (WHO) recommends all women be tested at their first antenatal visit and again in the third trimester. If they are positive, it is recommended their partners also be treated. Congenital syphilis is still common in the developing world, as many women do not receive antenatal care at all, and the antenatal care others receive does not include screening. It still occasionally occurs in the developed world, as those most likely to acquire syphilis are least likely to receive care during pregnancy. Several measures to increase access to testing appear effective at reducing rates of congenital syphilis in low- to middle-income countries. Point-of-care testing to detect syphilis appeared to be reliable although more research is needed to assess its effectiveness and into improving outcomes in mothers and babies.

Screening
The CDC recommends that sexually active men who have sex with men be tested at least yearly. The USPSTF also recommends screening among those at high risk.Syphilis is a notifiable disease in many countries, including Canada, the European Union, and the United States. This means health care providers are required to notify public health authorities, which will then ideally provide partner notification to the persons partners. Physicians may also encourage patients to send their partners to seek care. Several strategies have been found to improve follow-up for STI testing, including email and text messaging of reminders for appointments.

Treatment
As a form of chemotherapy, elemental mercury was frequently used to treat syphilis in Europe very early on in the epidemic, and in this respect was rather effective.  Mercury is highly anti-microbial, and in the early stages of infection was sometimes sufficient in halting development of the disease when applied to cankers or other wounds.  Once the bacterium gained a strong foothold, however, the amounts and forms of mercury necessary to control its development exceeded the human ability to endure this extremely toxic metal, and the treatment became worse and more lethal than the disease.  Medically directed mercury poisoning also became widespread, and thousands died in desperate attempts to rid themselves of the excruciating, disfiguring, and humiliating illness.

Early infections
The first-line treatment for uncomplicated syphilis (primary or secondary stages) remains a single dose of intramuscular benzathine benzylpenicillin. Doxycycline and tetracycline are alternative choices for those allergic to penicillin; due to the risk of birth defects, these are not recommended for pregnant women. Resistance to macrolides, rifampicin, and clindamycin is often present. Ceftriaxone, a third-generation cephalosporin antibiotic, may be as effective as penicillin-based treatment. It is recommended that a treated person avoid sex until the sores are healed.

Late infections
For neurosyphilis, due to the poor penetration of benzathine penicillin into the central nervous system, those affected are given large doses of intravenous penicillin G for a minimum of 10 days. If a person is allergic to penicillin, ceftriaxone may be used or penicillin desensitization attempted. Other late presentations may be treated with once-weekly intramuscular benzathine penicillin for three weeks. Treatment at this stage solely limits further progression of the disease and has a limited effect on damage which has already occurred. Serologic cure can be measured when the non-treponemal titers decline by a factor of 4 or more in 6–12 months in early syphilis or 12–24 months in late syphilis.

Jarisch–Herxheimer reaction
One of the potential side effects of treatment is the Jarisch–Herxheimer reaction. It frequently starts within one hour and lasts for 24 hours, with symptoms of fever, muscle pains, headache, and a fast heart rate. It is caused by cytokines released by the immune system in response to lipoproteins released from rupturing syphilis bacteria.

Pregnancy
Penicillin is an effective treatment for syphilis in pregnancy but there is no agreement on which dose or route of delivery is most effective.

Epidemiology
In 2012, about 0.5% of adults were infected with syphilis, with 6 million new cases. In 1999, it is believed to have infected 12 million additional people, with greater than 90% of cases in the developing world. It affects between 700,000 and 1.6 million pregnancies a year, resulting in spontaneous abortions, stillbirths, and congenital syphilis. During 2015, it caused about 107,000 deaths, down from 202,000 in 1990. In sub-Saharan Africa, syphilis contributes to approximately 20% of perinatal deaths. Rates are proportionally higher among intravenous drug users, those who are infected with HIV, and men who have sex with men. In the United States about 55,400 people are newly infected each year. In the United States as of 2020, rates of syphilis have increased by more than threefold; in 2018 approximately 86% of all cases of syphilis in the United States were in men. African Americans accounted for almost half of all cases in 2010. As of 2014, syphilis infections continue to increase in the United States.Syphilis was very common in Europe during the 18th and 19th centuries. Flaubert found it universal among nineteenth-century Egyptian prostitutes. In the developed world during the early 20th century, infections declined rapidly with the widespread use of antibiotics, until the 1980s and 1990s. Since 2000, rates of syphilis have been increasing in the US, Canada, the UK, Australia and Europe, primarily among men who have sex with men. Rates of syphilis among US women have remained stable during this time, while rates among UK women have increased, but at a rate less than that of men. Increased rates among heterosexuals have occurred in China and Russia since the 1990s. This has been attributed to unsafe sexual practices, such as sexual promiscuity, prostitution, and decreasing use of barrier protection.Left untreated, it has a mortality rate of 8% to 58%, with a greater death rate among males. The symptoms of syphilis have become less severe over the 19th and 20th centuries, in part due to widespread availability of effective treatment, and partly due to virulence of the bacteria. With early treatment, few complications result. Syphilis increases the risk of HIV transmission by two to five times, and coinfection is common (30–60% in some urban centers). In 2015, Cuba became the first country to eliminate mother-to-child transmission of syphilis.

History
The origin of syphilis is disputed. Syphilis was present in the Americas before European contact, and it may have been carried from the Americas to Europe by the returning crewmen from Christopher Columbuss voyage to the Americas, or it may have existed in Europe previously but gone unrecognized until shortly after Columbuss return. These are the Columbian and pre-Columbian hypotheses, respectively. The Columbian hypothesis is better supported by the evidence and findings from phylogenetic science suggest that it is, in fact, a New World disease.The timing of the arrival of syphilis in Europe certainly supports the above theory, Columbus having journeyed in 1492. The first written records of an outbreak of syphilis in Europe occurred in 1494 or 1495 in Naples, Italy, during a French invasion (Italian War of 1494–98). Since it was claimed to have been spread by French troops, it was initially called the "French disease" by the people of Naples. The disease reached London in 1497 and was recorded at St Batholomews Hospital as infected 10 out of the 20 patients. In 1530, the pastoral name "syphilis" (the name of a character) was first used by the Italian physician and poet Girolamo Fracastoro as the title of his Latin poem in dactylic hexameter Syphilis sive morbus gallicus (Syphilis or The French Disease) describing the ravages of the disease in Italy. In Great Britain it was also called the "Great Pox".In the 16th through 19th centuries, syphilis was one of the largest public health burdens in prevalence, symptoms, and disability,: 208–209  although records of its true prevalence were generally not kept because of the fearsome and sordid status of sexually transmitted infections in those centuries.: 208–209  According to a 2020 study, more than 20% of individuals in the age range 15–34 years in late 18th century London were treated for syphilis. At the time the causative agent was unknown but it was well known that it was spread sexually and also often from mother to child. Its association with sex, especially sexual promiscuity and prostitution, made it an object of fear and revulsion and a taboo. The magnitude of its morbidity and mortality in those centuries reflected that, unlike today, there was no adequate understanding of its pathogenesis and no truly effective treatments. Its damage was caused not so much by great sickness or death early in the course of the disease but rather by its gruesome effects decades after infection as it progressed to neurosyphilis with tabes dorsalis. Mercury compounds and isolation were commonly used, with treatments often worse than the disease.There is some evidence to suggest that syphilis was  a common childhood skin disease in the Old World, and did not originate in the New World.  According to this hypothesis, syphilis was a mostly benign infection like chicken pox which for thousands of years had been common among the young who transmitted the disease among themselves—and as adults, they gained immunity and could not be reinfected.  Once living conditions in Europe began to change and certain social classes began to practice greater hygiene, syphilis was driven out of the age group in which it was harmless.  It then began to appear in adults who were unable to fend off the infection because they had never been exposed as children, and they readily spread it via sexual contact to other adults who also had limited or no resistance, causing deformity and death where before it had been only been a temporary childhood ailment.  This transition is reported to have coincided temporally with the return of the Columbus expedition from the New World.  The most compelling evidence for its validity is the presence of syphilitic-like damage to bones in a number of adult skeletons found in the British city of Hull who were buried over a century before Columbus made his journey to the Americas.More recent analysis of that research, however, concluded in 2012 that syphilis almost certainly had a New World origin.The causative organism, Treponema pallidum, was first identified by Fritz Schaudinn and Erich Hoffmann, in 1905. The first effective treatment for syphilis was arsphenamine, discovered by Sahachiro Hata in 1909, during a survey of hundreds of newly synthesized organic arsenical compounds led by Paul Ehrlich. It was manufactured and marketed from 1910 under the trade name Salvarsan by Hoechst AG. This organoarsenic compound was the first modern chemotherapeutic agent.
During the 20th century, as both microbiology and pharmacology advanced greatly, syphilis, like many other infectious diseases, became more of a manageable burden than a scary and disfiguring mystery, at least in developed countries among those people who could afford to pay for timely diagnosis and treatment. Penicillin was discovered in 1928, and effectiveness of treatment with penicillin was confirmed in trials in 1943, at which time it became the main treatment.Many famous historical figures, including Franz Schubert, Arthur Schopenhauer, Édouard Manet, Charles Baudelaire, and Guy de Maupassant are believed to have had the disease. Friedrich Nietzsche was long believed to have gone mad as a result of tertiary syphilis, but that diagnosis has recently come into question.

Arts and literature
The earliest known depiction of an individual with syphilis is Albrecht Dürers Syphilitic Man, a woodcut believed to represent a Landsknecht, a Northern European mercenary. The myth of the femme fatale or "poison women" of the 19th century is believed to be partly derived from the devastation of syphilis, with classic examples in literature including John Keats "La Belle Dame sans Merci".The Flemish artist Stradanus designed a print called Preparation and Use of Guayaco for Treating Syphilis, a scene of a wealthy man receiving treatment for syphilis with the tropical wood guaiacum sometime around 1590.

Tuskegee and Guatemala studies
The "Tuskegee Study of Untreated Syphilis in the Negro Male"  was an infamous, unethical and racist clinical study conducted between 1932 and 1972 by the U.S. Public Health Service. Whereas the purpose of this study was to observe the natural history of untreated syphilis; the African-American men in the study were told they were receiving free treatment for "bad blood" from the United States government.The Public Health Service started working on this study in 1932 in collaboration with Tuskegee University, a historically black college in Alabama. Researchers enrolled 600 poor, African-American sharecroppers from Macon County, Alabama in the study. Of these men, 399 had contracted syphilis before the study began, and 201 did not have the disease. Medical care, hot meals and free burial insurance were given to those who participated. The men were told that the study would last six months, but in the end it continued for 40 years. After funding for treatment was lost, the study was continued without informing the men that they were only being studied and would not be treated. Facing insufficient participation, the Macon County Health Department nevertheless wrote to subjects to offer them a "last chance" to get a special "treatment", which was not a treatment at all, but a spinal tap administered exclusively for diagnostic purposes. None of the men infected were ever told that they had the disease, and none were treated with penicillin even after the antibiotic had been proven to successfully treat syphilis. According to the Centers for Disease Control, the men were told they were being treated for "bad blood"—a colloquialism describing various conditions such as fatigue, anemia and syphilis—which was a leading cause of death among southern African-American men.The 40-year study became a textbook example of poor medical ethics because researchers had knowingly withheld treatment with penicillin and because the subjects had been misled concerning the purposes of the study. The revelation in 1972 of these study failures by a whistleblower, Peter Buxtun, led to major changes in U.S. law and regulation on the protection of participants in clinical studies. Now studies require informed consent, communication of diagnosis, and accurate reporting of test results.

Similar experiments were carried out in Guatemala from 1946 to 1948. It was done during the administration of American President Harry S. Truman and Guatemalan President Juan José Arévalo with the cooperation of some Guatemalan health ministries and officials. Doctors infected soldiers, prostitutes, prisoners and mental patients with syphilis and other sexually transmitted infections, without the informed consent of the subjects, and treated most subjects with antibiotics. The experiment resulted in at least 83 deaths. In October 2010, the U.S. formally apologized to Guatemala for the ethical violations that took place. Secretary of State Hillary Clinton and Health and Human Services Secretary Kathleen Sebelius stated "Although these events occurred more than 64 years ago, we are outraged that such reprehensible research could have occurred under the guise of public health. We deeply regret that it happened, and we apologize to all the individuals who were affected by such abhorrent research practices." The experiments were led by physician John Charles Cutler who also participated in the late stages of the Tuskegee syphilis experiment.

Names
It was first called grande verole or the "great pox" by the French. Other historical names have included "button scurvy", sibbens, frenga and dichuchwa, among others. Since it was a disgraceful disease, the disease was known in several countries by the name of their neighbouring country. The English, the Germans, and the Italians called it "the French disease", while the French referred to it as the "Neapolitan disease". The Dutch called it the "Spanish/Castilian disease". To the Turks it was known as the "Christian disease", whilst in India, the Hindus and Muslims named the disease after each other.

References
Further reading
Ghanem KG, Ram S, Rice PA (February 2020). "The Modern Epidemic of Syphilis". N. Engl. J. Med. 382 (9): 845–54. doi:10.1056/NEJMra1901593. PMID 32101666. S2CID 211537893.
Ropper AH (October 2019). "Neurosyphilis". N. Engl. J. Med. 381 (14): 1358–63. doi:10.1056/NEJMra1906228 </s>


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LG most commonly affects middle aged people, but has occasionally been observed in young people. Males are found to be affected twice as often as females.

Causes
Lymphomatoid granulomatosis involves malignant B cells and reactive, non-malignant T cells and is almost always associated with infection of the malignant B cells by the Epstein-Barr virus; it is therefore considered to be a form of the Epstein-Barr virus-associated lymphoproliferative diseases. The disease is believed to be induced by a combination of Epstein Barr virus infection and immunosuppression through immunosuppressive drugs (with case reports of methotrexate and azathioprine), infections such as HIV or chronic viral hepatitis or endogenous T cell defects.

Pathophysiology
The onset of the disease results in proliferation of EBV-infected malignant B-cells and a cytotoxic T-cell response which in turn leads to organ infiltration and dysfunction of the affected organs. The disease typically always relapse after successful treatment due to inability of the immune system and current viral drugs to eliminate an EBV-infection </s>


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Acute interstitial pneumonitis is often categorized as both an interstitial lung disease and a form of acute respiratory distress syndrome (ARDS) but it is distinguished from the chronic forms of interstitial pneumonia such as idiopathic pulmonary fibrosis.

Symptoms and signs
The most common symptoms of acute interstitial pneumonitis are highly productive cough with expectoration of thick mucus, fever, and difficulties breathing. These often occur over a period of one to two weeks before medical attention is sought. The presence of fluid means the person experiences a feeling similar to drowning. Difficulties breathing can quickly progress to an inability to breathe without support (respiratory failure).Acute interstitial pneumonitis typically progresses rapidly, with hospitalization and mechanical ventilation often required only days to weeks after initial symptoms of cough, fever, and difficulties breathing develop.

Diagnosis
Rapid progression from initial symptoms to respiratory failure is a key feature. An X-ray that shows ARDS is necessary for diagnosis (fluid in the small air sacs (alveoli) in both lungs). In addition, a biopsy of the lung that shows organizing diffuse alveolar damage is required for diagnosis. This type of alveolar damage can be attributed to nonconcentrated and nonlocalized alveoli damage, marked alveolar septal edema with inflammatory cell infiltration, fibroblast proliferation, occasional hyaline membranes, and thickening of the alveolar walls. The septa are lined with atypical, hyperplastic type II pneumocytes, thus leading to the collapse of airspaces </s>


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Genes
Although genetic deficiencies are currently considered rare, variations in these genes may predispose to common obesity. Many candidate genes are highly expressed in the central nervous system.Several additional loci have been identified </s>


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