<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 Naegleriasis and can you explain it in depth? [/INST] Naegleriasis (also known as primary amoebic meningoencephalitis; PAM) is an almost invariably fatal infection of the brain by the free-living unicellular eukaryote Naegleria fowleri. Symptoms are meningitis-like and include headache, fever, nausea, vomiting, a stiff neck, confusion, hallucinations and seizures. Symptoms progress rapidly over around five days, and death usually results within one to two weeks of symptoms.N. fowleri is typically found in warm bodies of fresh water, such as ponds, lakes, rivers and hot springs. It is also found in an amoeboid or temporary flagellate stage in soil, poorly maintained municipal water supplies, water heaters, near warm-water discharges of industrial plants and in poorly chlorinated or unchlorinated swimming pools. There is no evidence of it living in salt water. As the disease is rare, it is often not considered during diagnosis.Although infection occurs very rarely, it almost inevitably results in death. Of the 450 or so naegleriasis cases in the past 60 years, only seven have survived, for a case fatality rate of 98.5%.

Signs and symptoms
Onset of symptoms begins one to nine days following exposure (with an average of five). Initial symptoms include changes in taste and smell, headache, fever, nausea, vomiting, back pain, and a stiff neck. Secondary symptoms are also meningitis-like including confusion, hallucinations, lack of attention, ataxia, cramp and seizures. After the start of symptoms, the disease progresses rapidly over three to seven days, with death usually occurring anywhere from seven to fourteen days later, although it can take longer. In 2013, a man in Taiwan died 25 days after being infected by Naegleria fowleri.It affects healthy children or young adults who have recently been exposed to bodies of fresh water. Some people have presented with a clinical triad of edematous brain lesions, immune suppression and fever. Scientists speculate that lower age groups are at a higher risk of contracting the disease because adolescents have a more underdeveloped and porous cribriform plate, through which the amoeba travels to reach the brain.

Cause
N. fowleri invades the central nervous system via the nose, specifically through the olfactory mucosa of the nasal tissues. This usually occurs as the result of the introduction of water that has been contaminated with N. fowleri into the nose during activities such as swimming, bathing or nasal irrigation.The amoeba follows the olfactory nerve fibers through the cribriform plate of the ethmoid bone into the skull. There, it migrates to the olfactory bulbs and subsequently other regions of the brain, where it feeds on the nerve tissue. The organism then begins to consume cells of the brain, piecemeal through trogocytosis, by means of an amoebostome, a unique actin-rich sucking apparatus extended from its cell surface. It then becomes pathogenic, causing primary amoebic meningoencephalitis (PAM or PAME).Primary amoebic meningoencephalitis presents symptoms similar to those of bacterial and viral meningitis. Upon abrupt disease onset, a plethora of problems arise. Endogenous cytokines, which release in response to pathogens, affect the hypothalamus thermoregulatory neurons and cause a rise in body temperature. Additionally, cytokines may act on the vascular organ of the lamina terminalis, leading to the synthesis of prostaglandin (PG) E2 which acts on the hypothalamus, resulting in an increase in body temperature. Also, the release of cytokines and exogenous exotoxins coupled with an increase in intracranial pressure stimulate nociceptors in the meninges creating pain sensations.
The release of cytotoxic molecules in the central nervous system results in extensive tissue damage and necrosis, such as damage to the olfactory nerve through lysis of nerve cells and demyelination. Specifically, the olfactory nerve and bulbs become necrotic and hemorrhagic. Spinal flexion leads to nuchal rigidity, or stiff neck, due to the stretching of the inflamed meninges. The increase in intracranial pressure stimulates the area postrema to create nausea sensations which may lead to brain herniation and damage to the reticular formation. Ultimately, the increase in cerebrospinal fluid from inflammation of the meninges increases intracranial pressure and leads to the destruction of the central nervous system. Although the exact pathophysiology behind the seizures caused by PAM is unknown, scientists speculate that the seizures arise from altered meningeal permeability caused by increased intracranial pressure.

Pathogenesis
Naegleria fowleri propagates in warm, stagnant bodies of fresh water (typically during the summer months), and enters the central nervous system after insufflation of infected water by attaching itself to the olfactory nerve. It then migrates through the cribriform plate and into the olfactory bulbs of the forebrain, where it multiplies itself greatly by feeding on nerve tissue.

Diagnosis
N. fowleri can be grown in several kinds of liquid axenic media or on non-nutrient agar plates coated with bacteria. Escherichia coli can be used to overlay the non-nutrient agar plate and a drop of cerebrospinal fluid sediment is added to it. Plates are then incubated at 37 °C and checked daily for clearing of the agar in thin tracks, which indicate the trophozoites have fed on the bacteria.Detection in water is performed by centrifuging a water sample with E. coli added, then applying the pellet to a non-nutrient agar plate. After several days, the plate is microscopically inspected and Naegleria cysts are identified by their morphology. Final confirmation of the species identity can be performed by various molecular or biochemical methods.Confirmation of Naegleria presence can be done by a so-called flagellation test, where the organism is exposed to a hypotonic environment (distilled water). Naegleria, in contrast to other amoebae, differentiates within two hours into the flagellate state. Pathogenicity can be further confirmed by exposure to high temperature (42 °C): Naegleria fowleri is able to grow at this temperature, but the nonpathogenic Naegleria gruberi is not.

Prevention
Michael Beach, a recreational waterborne illness specialist for the Centers for Disease Control and Prevention, stated in remarks to the Associated Press that wearing of nose clips to prevent insufflation of contaminated water would be effective protection against contracting PAM, noting that "Youd have to have water going way up in your nose to begin with".Advice stated in the press release from Taiwans Centers for Disease Control recommended people prevent fresh water from entering the nostrils and avoid putting their heads down into fresh water or stirring mud in the water with feet. When starting to suffer from fever, headache, nausea, or vomiting subsequent to any kind of exposure to fresh water, even in the belief that no fresh water has traveled through the nostrils, people with such conditions should be carried to hospital quickly and make sure doctors are well-informed about the history of exposure to fresh water.

Treatment
On the basis of the laboratory evidence and case reports, heroic doses of amphotericin B have been the traditional mainstay of PAM treatment since the first reported survivor in the United States in 1982.Treatment has often also used combination therapy with multiple other antimicrobials in addition to amphotericin, such as fluconazole, miconazole, rifampicin and azithromycin. They have shown limited success only when administered early in the course of an infection. Fluconazole is commonly used as it has been shown to have synergistic effects against naegleria when used with amphotericin in-vitro.While the use of rifampicin has been common, including in all four North American cases of survival, its continued use has been questioned. It only has variable activity in-vitro and it has strong effects on the therapeutic levels of other antimicrobials used by inducing cytochrome p450 pathways.In 2013, two successfully treated cases in the United States utilized the medication miltefosine. As of 2015, there was no data on how well miltefosine is able to reach the central nervous system. As of 2015 the U.S. CDC offered miltefosine to doctors for the treatment of free-living amoebas including naegleria. In one of the cases, a 12-year-old female, was given miltefosine and targeted temperature management to manage cerebral edema that is secondary to the infection. She survived with no neurological damage. The targeted temperature management commingled with early diagnosis and the miltefosine medication has been attributed with her survival. On the other hand, the other survivor, an 8-year-old male, was diagnosed several days after symptoms appeared and was not treated with targeted temperature management; however, he was administered the miltefosine. He suffered what is likely permanent neurological damage.In 2016, a 16-year-old boy also survived PAM. He was treated with the same protocols of the 12-year-old girl in 2013. He recovered making a near complete neurological recovery; however, he has stated that learning has been more difficult for him since contracting the disease.In 2018, a 10-year-old girl in the Spanish city of Toledo became the first person to have PAM in Spain, and was successfully treated using intravenous and intrathecal amphotericin B.

Prognosis
Since its first description in the 1960s, only seven people worldwide have been reported to have survived PAM out of 450 cases diagnosed, implying a fatality rate of about 98.5%. The survivors include four in the United States, one in Mexico and one in Spain. One of the US survivors had brain damage that is likely permanent, but there are two documented surviving cases in the United States who made a full recovery with no neurological damage; they were both treated with the same protocols.

Epidemiology
The disease is rare and highly lethal: there had only been 300 cases as of 2008. Drug treatment research at Aga Khan University in Pakistan has shown that in-vitro drug susceptibility tests with some FDA approved drugs used for non-infectious diseases (digoxin and procyclidine were shown to be most effective of the drugs studied) have proved to kill Naegleria fowleri with an amoebicidal rate greater than 95%. The same source has also proposed a device for drug delivery via the transcranial route to the brain.In the US, the most common states with cases reported of PAM from N. fowleri are the southern states, with Texas and Florida having the highest prevalence. The most commonly affected age group is 5–14-year olds (those who play in water). The number of cases of infection could increase due to climate change, which was posited as the reason for three cases in Minnesota in 2010, 2012, and 2015.As of 2013, the numbers of reported cases were expected to increase simply because of better-informed diagnoses being made both in ongoing cases and in autopsy findings.

History
In 1899, Franz Schardinger first discovered and documented an amoeba he called Amoeba gruberi that could transform into a flagellate. The genus Naegleria was established by Alexis Alexeieff in 1912, who grouped the flagellate amoeba. He coined the term Naegleria after Kurt Nägler, who researched amoebae. It was not until 1965 that doctors Malcolm Fowler and Rodney F. Carter in Adelaide, Australia, reported the first four human cases of amoebic meningoencephalitis. These cases involved four Australian children, one in 1961 and the rest in 1965, all of whom had succumbed to the illness. Their work on amebo-flagellates has provided an example of how a protozoan can effectively live both freely in the environment, and in a human host.In 1966, Fowler termed the infection resulting from N. fowleri primary amoebic meningoencephalitis (PAM) to distinguish this central nervous system (CNS) invasion from other secondary invasions made by other amoebae such as Entamoeba histolytica. A retrospective study determined the first documented case of PAM possibly occurred in Britain in 1909. In 1966, four cases were reported in the US </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 Ptosis (breasts) and can you explain it in depth? [/INST] Ptosis or sagging of the female breast is a natural consequence of aging. The rate at which a womans breasts drop and the degree of ptosis depends on many factors. The key factors influencing breast ptosis over a womans lifetime are cigarette smoking, her number of pregnancies, higher body mass index, larger bra cup size, and significant weight change.
Post-menopausal women or people with collagen deficiencies (such as Ehlers-Danlos) may experience increased ptosis due to a loss of skin elasticity. Many women and medical professionals mistakenly believe that breastfeeding increases sagging. It is also commonly believed that the breast itself offers insufficient support and that wearing a bra prevents sagging, which has not been found to be true.Plastic surgeons categorize the degree of ptosis by evaluating the position of the nipple relative to the infra-mammary fold, the point at which the underside of the breasts attach to the chest wall. In the most advanced stage, the nipples are below the fold and point toward the ground.

Signs and symptoms
A womans breasts change in size, volume, and position on her chest throughout her life. In young women with large breasts, sagging may occur early in life due to the effects of gravity. It may be primarily caused by the volume and weight of the breasts which are disproportionate to her body size.

Impact of pregnancy
During pregnancy, the ovaries and the placenta produce estrogen and progesterone. These hormones stimulate the 15 to 20 lobes of the milk-secreting glands in the breasts to develop. Women who experience multiple pregnancies repeatedly stretch the skin envelope during engorgement while lactating. As a womans breasts change in size during repeated pregnancies, the size of her breasts change as her mammary glands are engorged with milk and as she gains and loses weight with each pregnancy. In addition, when milk production stops (usually as a child is weaned), the voluminous mammary glands diminish in volume, but they still add bulk and firmness to the breast.  A 2010 review found that weight gain during pregnancy and breastfeeding were not significant risk factors for ptosis.

Middle-aged women
In middle-aged women, breast ptosis is caused by a combination of factors. If a woman has been pregnant, postpartum hormonal changes will cause her depleted milk glands to atrophy. Breast tissue and suspensory ligaments may also be stretched if the woman is overweight or loses and gains weight. When these factors are at play, the breast prolapses, or falls forward. When a woman with sagging breasts stands, the underside or inferior skin of the breast folds over the infra-mammary fold and lies against the chest wall. The nipple-areola complex tends to move lower on the breast relative to the inframammary crease. The nipple of the breast may also tend to point downward.

Post-menopausal women
In post-menopausal women, breast atrophy is aggravated by the inelasticity of over-stretched, aged skin. This is due in part to the reduction in estrogen, which affects all body tissues, including breast tissue. The loss of estrogen reduces breast size and fullness. Estrogen is also essential to maintaining a fibrous protein called collagen, which makes up much of the breasts connective tissue.

Ptosis scale
Plastic surgeons describe the degree of breast sagging using a ptosis scale like the modified Regnault ptosis scale below:
Grade I: Mild ptosis—The nipple is at the level of the infra-mammary fold and above most of the lower breast tissue.
Grade II: Moderate ptosis—The nipple is located below the infra-mammary fold but higher than most of the breast tissue hangs.
Grade III: Advanced ptosis—The nipple is below the inframammary fold and at the level of maximum breast projection.
Pseudoptosis—The nipple is located either at or above the infra-mammary fold, while the lower half of the breast sags below the fold. This is most often seen when a woman stops nursing, as her milk glands atrophy, causing her breast tissue to sag.
Parenchymal Maldistribution—The lower breast tissue is lacking fullness, the inframammary fold is very high, and the nipple and areola are relatively close to the fold. This is usually a developmental deformity.

Causes
University of Kentucky plastic surgeon Brian Rinker encountered many women in his practice who attributed their sagging breasts to breastfeeding, which was also the usual belief among medical practitioners. He decided to find out if this was true, and between 1998 and 2006 he and other researchers interviewed 132 women who were seeking breast augmentation or breast lifts. They studied the womens medical history, body mass index (BMI), their number of pregnancies, their breast cup size before pregnancy, and smoking status. The study results were presented at a conference of the American Society of Plastic Surgeons.According to Rinkers research, there are several key factors. A history of cigarette smoking "breaks down a protein in the skin called elastin, which gives youthful skin its elastic appearance and supports the breast." The number of pregnancies was strongly correlated with ptosis, with the effects increasing with each pregnancy. As most women age, breasts naturally yield to gravity and tend to sag and fold over the inframammary crease, the lower attachment point to the chest wall. This is more true for larger-breasted women. The fourth reason was significant weight gain or loss (greater than 50 pounds (23 kg)). Other significant factors were higher body mass index and larger bra cup size.In Rinkers study, 55% of respondents reported an adverse change in breast shape after pregnancy. Many women mistakenly attribute the changes and their sagging breasts to breastfeeding, and as a result some are reluctant to nurse their infants. Research shows that breastfeeding is not the factor that many thought it was. Rinker concluded that "Expectant mothers should be reassured that breastfeeding does not appear to have an adverse effect upon breast appearance." Also discounted as causes affecting ptosis are weight gain during pregnancy and lack of participation in regular upper body exercise.

Effect of vigorous exercise
When running, breasts may move three-dimensionally: vertically, horizontally and laterally, in an overall figure-8 motion. Unrestrained movement of large breasts may contribute to sagging over time. Motion studies have revealed that when a woman runs, more than 50% of the breasts total movement is vertical, 22% is side-to-side, and 27% is in-and-out. A 2007 study found that encapsulation-type sports bras, in which each cup is separately molded, are more effective than compression-type bras, which press the breasts close to the body, at reducing total breast motion during exercise. Encapsulation bras reduce motion in two of the three planes, while compression bras reduce motion in only one plane. Previously, it was commonly believed that a woman with small to medium-size breasts benefited most from a compression-type sports bra, and women with larger breasts need an encapsulation-type sports bra.

Mechanism
Anatomically, a females breasts do not contain any muscle but are composed of soft, glandular tissue. Breasts are composed of mammary glands, milk ducts, adipose tissue (fat tissue) and Coopers ligaments.
Mammary glands remain relatively constant throughout life. Fat tissue surrounds the mammary glands, and its volume will normally vary throughout life. Although the exact mechanisms that determine breast shape and size are largely unknown, the amount and distribution of fat tissue and, to a lesser extent, mammary tissue, cause variations in breast size, shape and volume. Some experts believe Coopers ligaments, which are connective tissue with the breast, provide some support within breasts, but theres no agreement on whether they provide support or simply divide breast tissue into compartments.

Treatment
Bras
Since breasts are an external organ and do not contain muscle, exercise cannot improve their shape. They are not protected from external forces and are subject to gravity. Many women mistakenly believe that breasts cannot anatomically support themselves and that wearing a brassiere will prevent their breasts from sagging later in life. Researchers, bra manufacturers, and health professionals cannot find any evidence to support the idea that wearing a bra for any amount of time slows breast ptosis. Bra manufacturers are careful to claim that bras only affect the shape of breasts while they are being worn.In fact, there is some evidence that bra use reduces the development of Coopers ligaments, connective tissue that supports breast shape. That atrophy from bra wearing may therefore lead to more breast sag in the long run, much as the connective tissue in a limb weakens while its in a cast and must be re-strengthened afterward. Studies have actually documented that, after an initial period of adjustment, women experienced a significant increase in comfort and breast firmness from going without bras.

Surgery
Some women with ptosis choose to undergo plastic surgery to make their breasts less ptotic. Plastic surgeons offer several procedures for lifting sagging breasts. Surgery to correct the size, contour, and elevation of sagging breasts is called mastopexy </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 Micrognathism 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 Common variable immunodeficiency and can you explain it in depth? [/INST] Common variable immunodeficiency (CVID) is an immune disorder characterized by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM and IgA. Symptoms generally include high susceptibility to foreign invaders, chronic lung disease, and inflammation and infection of the gastrointestinal tract. CVID affects males and females equally. The condition can be found in children or teens but is generally not diagnosed or recognized until adulthood. The average age of diagnosis is between 20 and 50. However, symptoms vary greatly between people. "Variable" refers to the heterogeneous clinical manifestations of this disorder, which include recurrent bacterial infections, increased risk for autoimmune disease and lymphoma, as well as gastrointestinal disease. CVID is a lifelong disease.

Signs and symptoms
The symptoms of CVID vary between those affected. Its main features are hypogammaglobulinemia and recurrent infections. Hypogammaglobulinemia manifests as a significant decrease in the levels of IgG antibodies, usually alongside IgA antibodies; IgM antibody levels are also decreased in about half of those affected. Infections are a direct result of the low antibody levels in the circulation, which do not adequately protect them against pathogens. The microorganisms that most frequently cause infections in CVID are bacteria Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus. Pathogens less often isolated from those affected include Neisseria meningitidis, Pseudomonas aeruginosa, and Giardia lamblia. Infections mostly affect the respiratory tract (nose, sinuses, bronchi, lungs) and the ears; they can also occur at other sites, such as the eyes, skin, and gastrointestinal tract. These infections respond to antibiotics but can recur upon discontinuation of antibiotics. Bronchiectasis can develop when severe recurrent pulmonary infections are left untreated.
In addition to infections, people with CVID can develop complications. These include:

Autoimmune manifestations, e.g. pernicious anemia, autoimmune haemolytic anemia (AHA), idiopathic thrombocytopenic purpura (ITP), psoriasis, vitiligo, rheumatoid arthritis, primary hypothyroidism, atrophic gastritis. Autoimmunity is the main complication in people with CVID, appearing in some form in up to 50% of individuals;
Malignancies, particularly non-Hodgkins lymphoma and gastric carcinoma;
Enteropathy, which manifests with a blunting of intestinal villi and inflammation, and is usually accompanied by symptoms such as abdominal cramps, diarrhea, constipation, and in some cases malabsorption and weight loss. Symptoms of CVID enteropathy are similar to those of celiac disease, but do not respond to a gluten-free diet. Infectious causes must be excluded before a diagnosis of enteropathy can be made, as people with CVID are more susceptible to intestinal infections, e.g. by Giardia lamblia;
Lymphocytic infiltration of tissues, which can cause enlargement of lymph nodes (lymphadenopathy), of the spleen (plenomegaly) and of the liver (hepatomegaly), as well as the formation of granulomas.  In the lung this is known as granulomatous–lymphocytic interstitial lung disease.Anxiety and depression can occur as a result of dealing with the other symptoms.CVID patients generally complain of severe fatigue.As with any antibody deficiency, the most common types of infections and illnesses involve the ears, sinuses, nose, and lungs. Common infections include:

Pneumonia
Ear infections
Sinusitis
Chronic coughing (lasting from a few weeks to many months)
Gastrointestinal infectionsGastrovascular infections or inflammation are very common for those with CVID. Signs of a gastrovascular infection include abdominal pain, nausea, bloating, vomiting, diarrhea, and weight loss. Many individuals with CVID have an impaired ability to absorb nutrients, including vitamins, proteins, minerals, fats, and sugar within the digestive tract.Due to changes in development in B cells, some individuals with CVID have accumulations of lymphocytes in lymphoid tissues. This can cause mild to severely swollen lymph nodes or inflammation of the spleen. In addition, a certain percentage of individuals with CVID are more susceptible to developing certain forms of cancer, more so than those without the condition. The two most common cancers in common variable immunodeficiency patients include lymphoma and certain stomach cancers. The risk for these given cancers is almost fifty times greater in common variable immunodeficiency patients than those without.
People with common variable immunodeficiency have trouble fighting off infections due to the lack of antibodies produced which normally resist invading microbes. Due to impaired antibody development vaccines are not effective. Recurring bacterial infections are generally found in the upper and lower areas of the respiratory tract. Many who have a recurring lung infection, report developing, chronic lung diseases, and potentially life-threatening complications later in life.

Causes
The cause of CVID is poorly understood. A likely cause are Deletions in genes that encode cell surface proteins and cytokine receptors, such as CD19, CD20, CD21, and CD80. Additionally, the disease is defined by T cell defects, namely reduced proliferative capacity. The condition is hard to diagnose, taking on average 6–7 years after onset. CVID is a primary immunodeficiency. The underlying causes of CVID are largely obscure. Genetic mutations can be identified as the cause of disease in about 10% of people, while familial inheritance accounts for 10–25% of cases. Rather than arising from a single genetic mutation, CVID seems to result from variety of mutations that all contribute to a failure in antibody production.
Mutations in the genes encoding ICOS, TACI, CD19, CD20, CD21, CD80 and BAFFR have been identified as causative of CVID. Susceptibility to CVID may also be linked to the major histocompatibility complex (MHC) of the genome, particularly to DR-DQ haplotypes. A mutation in the NFKB2 gene has recently been shown to cause CVID-like symptoms in a murine model. The frequency of this NFKB2 mutation in the CVID population is, however, yet to be established.

Diagnosis
According to a European registry study, the mean age at onset of symptoms was 26.3 years old. As per the criteria laid out by ESID (European Society for Immunodeficiencies) and PAGID (Pan-American Group for Immunodeficiency), CVID is diagnosed if:
the person presents with a marked decrease of serum IgG levels (<4.5 g/L) and a marked decrease below the lower limit of normal for age in at least one of the isotypes IgM or IgA;
the person is four years of age or older;
the person lacks antibody immune response to protein antigens or immunization.Diagnosis is chiefly by exclusion, i.e. alternative causes of hypogammaglobulinemia, such as X-linked agammaglobulinemia, must be excluded before a diagnosis of CVID can be made.
Diagnosis is difficult because of the diversity of phenotypes seen in people with CVID. For example, serum immunoglobulin levels in people with CVID vary greatly. Generally, people can be grouped as follows: no immunoglobulin production, immunoglobulin (Ig) M production only, or both normal IgM and IgG production. Additionally, B cell numbers are also highly variable. 12% of people have no detectable B cells, 12% have reduced B cells, and 54% are within the normal range. In general, people with CVID display higher frequencies of naive B cells and lower frequencies of class-switched memory B cells. Frequencies of other B cell populations, such as IgD memory B cells, transitional B cells, and CD21 B cells, are also affected, and are associated with specific disease features. Although CVID is often thought of as a serum immunoglobulin and B cell-mediated disease, T cells can display abnormal behavior. Affected individuals typically present with low frequencies of CD4+, a T-cell marker, and decreased circulation of regulatory T cells and iNKT cell. Notably, approximately 10% of people display CD4+ T cell counts lower than 200 cells/mm3; this particular phenotype of CVID has been named LOCID (Late Onset Combined Immunodeficiency), and has a poorer prognosis than classical CVID.

Types
The following types of CVID have been identified, and correspond to mutations in different gene segments.

Treatment
Treatment options are limited, and usually include lifelong immunoglobulin replacement therapy. This therapy is thought to help reduce bacterial infections. This treatment alone is not wholly effective, and many people still experience other symptoms such as lung disease and noninfectious inflammatory symptoms.  This treatment replenishes Ig subtypes that the person lacks and is given at frequent intervals for life, and is thought to help reduce bacterial infections and boost immune function. Before therapy begins, plasma donations are tested for known blood-borne pathogens, then pooled and processed to obtain concentrated IgG samples. Infusions can be administered in three different forms: intravenously (IVIg), subcutaneously (SCIg), and intramuscularly (IMIg).
The administration of intravenous immunoglobulins requires the insertion of a cannula or needle in a vein, usually in the arms or hands. Because highly concentrated product is used, IVIg infusions take place every 3 to 4 weeks. Subcutaneous infusions slowly release the Ig serum underneath the skin, again through a needle, and takes place every week. Intramuscular infusions are no longer widely used, as they can be painful and are more likely to cause reactions.
People often experience adverse side effects to immunoglobulin infusions, including:

swelling at the insertion site (common in SCIG)
chills
headache
nausea (common in IVIG)
fatigue (common in IVIG)
muscle aches and pain, or joint pain
fever (common in IVIG and rare in SCIG)
hives (rare)
thrombotic events (rare)
aseptic meningitis (rare, more common in people with SLE)
anaphylactic shock (very rare)In addition to Ig replacement therapy, treatment may also involve immune suppressants, to control autoimmune symptoms of the disease, and high dose steroids like corticosteroids. In some cases, antibiotics are used to fight chronic lung disease resulting from CVID. The outlook for people varies greatly depending on their level of lung and other organ damage prior to diagnosis and treatment.

Epidemiology
CVID has an estimated prevalence of about 1:50,000 in Caucasians. The disease seems to be less prevalent amongst Asians and African-Americans. Males and females are equally affected; however, among children, boys predominate. A recent study of people in Europe with primary immunodeficiencies found that 30% had CVID, as opposed to a different immunodeficiency. 10–25% of people inherited the disease, typically through autosomal-dominant inheritance. Given the rarity of the disease, it is not yet possible to generalize on disease prevalence among ethnic and racial groups. CVID shortens the life-span; but no study currently has a median age recorded. One study suggests the median age of death for men and women is 42 and 44 years old, respectively, but most patients involved in the study are still alive. Those people with accompanying disorders had the worst prognosis (50% survival 33 years after diagnosis) and those people with only CVID-caused frequent infections had the longest survival rates, with another study stating a life expectancy almost equalling that of the general UK population. Additionally, people with CVID with one or more noninfectious complications have an 11 times higher risk of death as compared to people with only infections.

History
Immunodeficiencies comprise many diseases and are genetic defects affecting the immune system. There are roughly 150 immunodeficiencies spanning over 120 genetic defects.Charles Janeway Sr. is generally credited with the first description of a case of CVID in 1953. The case involved a 39-year-old who had recurrent infections, bronchiectasis, and meningitis. CVID has since emerged as the predominant class of primary antibody deficiencies. It is thought to affect between 1 in 25,000 to 1 in 50,000 people worldwide. Though described in 1953, there was no standard definition for CVID until the 1990s, which caused widespread confusion during diagnosis. During the 1990s, the European Society for Immunodeficiency (ESID) and Pan-American Group for Immunodeficiency (PAGID) developed diagnostic criteria, including minimum age of diagnosis and the need to exclude other conditions, to describe the disease. These criteria were published in 1999 and since that time, some aspects, like increasing the minimum age, have been changed.

Research
Current research is aimed at studying large cohorts of people with CVID in an attempt to better understand age of onset, as well as mechanism, genetic factors, and progression of the disease.Funding for research in the US is provided by the National Institutes of Health. Key research in the UK was previously funded by the Primary Immunodeficiency Association (PiA) until its closure in January 2012, and funding is raised through the annual Jeans for Genes campaign. Current efforts are aimed at studying the following:
Causes of complications </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 Ocular hypertension and can you explain it in depth? [/INST] Ocular hypertension is the presence of elevated fluid pressure inside the eye (intraocular pressure), usually with no optic nerve damage or visual field loss.For most individuals, the normal range of intraocular pressure is between 10 mmHg and 21 mmHg </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 Dracunculiasis and can you explain it in depth? [/INST] Dracunculiasis, also called Guinea-worm disease, is a parasitic infection by the Guinea worm, Dracunculus medinensis. A person becomes infected by drinking water containing water fleas infected with guinea worm larvae. The worms penetrate the digestive tract and escape into the body. Around a year later, the adult worm migrates to an exit site – usually a lower limb – and induces an intensely painful blister on the skin. The blister eventually bursts to form an intensely painful open wound, from which the worm slowly crawls over several weeks. The wound remains painful throughout the worms emergence, disabling the infected person for the three to ten weeks it takes the worm to emerge. During this time, the open wound can become infected with bacteria, leading to death in around 1% of cases.There is no medication to treat dracunculiasis. Instead, the mainstay of treatment is the careful wrapping of the emerging worm around a small stick to encourage its exit. Each day, a few more centimeters of the worm emerge, and the stick is turned to maintain gentle tension. With too much tension, the worm can break and die in the wound, causing severe pain and swelling at the ulcer site. Dracunculiasis is a disease of extreme poverty, occurring in places with poor access to clean drinking water. Prevention efforts center on filtering drinking water to remove water fleas, as well as public education campaigns to discourage people from soaking their emerging worms in sources of drinking water.
Humans have had dracunculiasis since at least 1,000 BCE, and accounts consistent with dracunculiasis appear in surviving documents from physicians of antiquity. In the 19th and early 20th centuries, dracunculiasis was widespread across much of Africa and South Asia, affecting as many as 48 million people per year. The effort to eradicate dracunculiasis began in the 1980s following the successful eradication of smallpox. By 1995, every country with endemic dracunculiasis had established a national eradication program. In the ensuing years, dracunculiasis cases have dropped precipitously, and 15 previously endemic countries have been certified to have eradicated dracunculiasis, leaving the disease endemic in just four countries: Chad, Ethiopia, Mali, and South Sudan. A record low 15 cases of dracunculiasis were reported worldwide in 2021. If the eradication program succeeds, dracunculiasis will become the second human disease ever eradicated.

Signs and symptoms
The first signs of dracunculiasis occur around a year after infection, as the full-grown female worm prepares to leave the infected persons body. As the worm migrates to its exit site – typically the lower leg, though they can emerge anywhere on the body – some people have allergic reactions, including hives, fever, dizziness, nausea, vomiting, and diarrhea. Upon reaching its destination, the worm forms a fluid-filled blister under the skin. Over 1–3 days, the blister grows larger, begins to cause severe burning pain, and eventually bursts leaving a small open wound. The wound remains intensely painful as the worm slowly emerges over several weeks to months.In an attempt to alleviate the excruciating burning pain, the host will nearly always attempt to submerge the affected body part in water. When this occurs and the worm is exposed to water, it spews a white substance into the water containing thousands of larvae. As the worm emerges, the open blister often becomes infected with bacteria, resulting in redness and swelling, the formation of abscesses, or in severe cases gangrene, sepsis or lockjaw. When the secondary infection is near a joint (typically the ankle), the damage to the joint can result in stiffness, arthritis, or contractures.Infected people commonly harbor multiple worms – with an average 1.8 worms per person; up to 40 at a time – which will emerge from separate blisters at the same time. 90% of worms emerge from the legs or feet. However, worms can emerge from anywhere on the body.

Cause
Dracunculiasis is caused by infection with the roundworm Dracunculus medinensis. D. medinensis larvae reside within small aquatic crustaceans called copepods or water fleas. When humans drink the water, they can unintentionally ingest infected copepods. During digestion the copepods die, releasing the D. medinensis larvae. The larvae exit the digestive tract by penetrating the stomach and intestine, taking refuge in the abdomen or retroperitoneal space. Over the next two to three months the larvae develop into adult male and female worms. The male remains small at 4 cm (1.6 in) long and 0.4 mm (0.016 in) wide; the female is comparatively large, often over 100 cm (39 in) long and 1.5 mm (0.059 in) wide. Once the worms reach their adult size they mate, and the male dies. Over the ensuing months, the female migrates to connective tissue or along bones, and continues to develop.About a year after the initial infection, the female migrates to the skin, forms an ulcer, and emerges. When the wound touches freshwater, the female spews a milky-white substance containing hundreds of thousands of larvae into the water. Over the next several days as the female emerges from the wound, she can continue to discharge larvae into surrounding water. The larvae are eaten by copepods, and after two to three weeks of development, they are infectious to humans again.

Diagnosis
Dracunculiasis is diagnosed by visual examination – the thin white worm emerging from the blister is unique to this disease. Dead worms sometimes calcify and can be seen in the subcutaneous tissue by X-ray.

Treatment
There is no medicine to kill D. medinensis or prevent it from causing disease once within the body. Instead, treatment focuses on slowly and carefully removing the worm from the wound over days to weeks. Once the blister bursts and the worm begins to emerge, the wound is soaked in a bucket of water, allowing the worm to empty itself of larvae away from a source of drinking water. As the first part of the worm emerges, it is typically wrapped around a piece of gauze or a stick to maintain steady tension on the worm, encouraging its exit. Each day, several centimeters of the worm emerge from the blister, and the stick is wound to maintain tension. This is repeated daily until the full worm emerges, typically within a month. If too much pressure is applied at any point, the worm can break and die, leading to severe swelling and pain at the site of the ulcer.Treatment for dracunculiasis also tends to include regular wound care to avoid infection of the open ulcer while the worm is leaving. The U.S. Centers for Disease Control and Prevention (CDC) recommends cleaning the wound before the worm emerges. Once the worm begins to exit the body, the CDC recommends daily wound care: cleaning the wound, applying antibiotic ointment, and replacing the bandage with fresh gauze. Painkillers like aspirin or ibuprofen can help ease the pain of the worms exit.

Outcomes
Dracunculiasis is a debilitating disease, causing substantial disability in around half of those infected. People with worms emerging can be disabled for the three to ten weeks it takes the worms to fully emerge. When worms emerge near joints, the inflammation around a dead worm, or infection of the open wound can result in permanent stiffness, pain, or destruction of the joint. Some people with dracunculiasis have continuing pain for 12 to 18 months after the worm has emerged. Around 1% of dracunculiasis cases result in death from secondary infections of the wound.When dracunculiasis was widespread, it would often affect entire villages at once. Outbreaks occurring during planting and harvesting seasons severely impair a communitys agricultural operations – earning dracunculiasis the moniker "empty granary disease" in some places. Communities affected by dracunculiasis also see reduced school attendance as children of affected parents must take over farm or household duties, and affected children may be physically prevented from walking to school for weeks.Infection does not create immunity, so people can repeatedly experience dracunculiasis throughout their lives.

Prevention
There is no vaccine for dracunculiasis, and once infected with D. medinensis there is no way to prevent the disease from running its full course. Consequently, nearly all effort to reduce the burden of dracunculiasis focuses on preventing the transmission of D. medinensis from person to person. This is primarily accomplished by filtering drinking water to physically remove copepods. Nylon filters, finely woven cloth, or specialized filter straws are all effective means of copepod removal. Sources of drinking water can be treated with the larvicide temephos, which kills copepods. Where possible, open sources of drinking water are replaced by deep wells that can serve as new sources of clean water. Public education campaigns inform people in affected areas how dracunculiasis spreads and encourage those with the disease to avoid soaking their wounds in bodies of water that are used for drinking.

Epidemiology
Dracunculiasis is nearly eradicated, with just 15 cases reported worldwide in 2021. This is down from 27 cases in 2020, and dramatically less than the estimated 3.5 million annual cases in 20 countries in 1986 – the year the World Health Assembly called for dracunculiasis eradication. Dracunculiasis remains endemic in just four countries: Chad, Ethiopia, Mali, and South Sudan.Dracunculiasis is a disease of extreme poverty, occurring in places where there is poor access to clean drinking water. Cases tend to be split roughly equally between males and females, and can occur in all age groups. Within a given place, dracunculiasis risk is linked to occupation; people who farm or fetch drinking water are most likely to be infected.Cases of dracunculiasis have a seasonal cycle, though the timing varies by location. Along the Sahara deserts southern edge, cases peak during the mid-year rainy season (May–October) when stagnant water sources are more abundant. Along the Gulf of Guinea, cases are more common during the dry season (October–March) when flowing water sources dry up.

History
Dracunculiasis has been with humans for at least 3,000 years, as the remnants of a guinea worm infection have been found in the mummy of a girl entombed in Egypt around 1,000 BCE. Diseases consistent with the effects of dracunculiasis are referenced by writers throughout antiquity. The disease of "fiery serpents" that plagues the Hebrews in the Old Testament (around 1250 BCE) is often attributed to dracunculiasis. Plutarchs Symposiacon refers to a (now lost) description of a similar disease by the 2nd century BCE writer Agatharchides concerning a "hitherto unheard of disease" in which "small worms issue from [peoples] arms and legs... insinuating themselves between the muscles [to] give rise to horrible sufferings". Many of antiquitys famous physicians also write of diseases consistent with dracunculiasis, including Galen, Rhazes, and Avicenna; though there was some disagreement as to the nature of the disease, with some attributing it to a worm, while others considered it to be a corrupted part of the body emerging. In his 1674 treatise on dracunculiasis, Georg Hieronymous Velschius first proposed that the Rod of Asclepius, a common symbol of the medical profession, depicts a recently extracted guinea worm.Carl Linnaeus included the guinea worm in his 1758 edition of Systema Naturae, naming it Gordius medinensis. In Johann Friedrich Gmelins 13th edition of Systema Naturae (1788), he renamed the worm Filaria medinensis, leaving Gordius for free-living worms. Henry Bastian authored the first detailed description of the worm itself, published in 1863. The following year, in his book Entozoa, Thomas Spencer Cobbold used the name Dracunculus medinensis, which was enshrined as the official name by the International Commission on Zoological Nomenclature in 1915. Despite longstanding knowledge that the worm was associated with water, the lifecycle of D. medinensis was the topic of protracted debate. Alexei Pavlovich Fedchenko filled a major gap with his 1870 publication describing that D. medinensis larvae can infect and develop inside Cyclops crustaceans. The next step was shown by Robert Thomson Leiper, who described in a 1907 paper that monkeys fed D. medinensis-infected Cyclops developed mature guinea worms, while monkeys directly fed D. medinensis larvae did not.In the 19th and 20th centuries, dracunculiasis was widespread across nearly all of Africa and South Asia, though we lack exact case counts from the pre-eradication era. In a 1947 article in the Journal of Parasitology, Norman R. Stoll used rough estimates of populations in endemic areas to suggest that there could be as many as 48 million cases of dracunculiasis per year. In 1976, the WHO estimated the global burden at 10 million cases per year. Ten years later, as the eradication effort was beginning, the WHO estimated 3.5 million cases per year worldwide.

Etymology
Dracunculiasis Latin name, Dracunculus medinensis ("little dragon from Medina"), derives from its one-time high incidence in the city of Medina (in modern Saudi Arabia), and its common name, Guinea worm, is due to a similar past high incidence along the Guinea coast of West Africa. It is no longer endemic in either location.

Eradication
The campaign to eradicate dracunculiasis began at the urging of the CDC in 1980. Following smallpox eradication (last case in 1977; eradication certified in 1981), dracunculiasis was considered an achievable eradication target since it was relatively uncommon and preventable with only behavioral changes. In 1981, the steering committee for the United Nations International Drinking Water Supply and Sanitation Decade (a program to improve global drinking water during the decade from 1981 to 1990) adopted the goal of eradicating dracunculiasis as part of their efforts. The following June, an international meeting termed "Workshop on Opportunities for Control of Dracunculiasis" concluded that dracunculiasis could be eradicated through public education, drinking water improvement, and larvicide treatments. In response, India began its national eradication program in 1983. In 1986, the 39th World Health Assembly issued a statement endorsing dracunculiasis eradication and calling on member states to craft eradication plans. The same year,  The Carter Center began collaborating with the government of Pakistan to initiate its national program, which then launched in 1988. By 1996, national eradication programs had been launched in every country with endemic dracunculiasis: Ghana and Nigeria in 1989; Cameroon in 1991; Togo, Burkina Faso, Senegal, and Uganda in 1992;  Benin, Mauritania, Niger, Mali, and Côte dIvoire in 1993; Sudan, Kenya, Chad, and Ethiopia in 1994; Yemen and the Central African Republic in 1995.Each national eradication program had three phases. The first phase consisted of a nationwide search to identify the extent of dracunculiasis transmission and develop national and regional plans of action. The second phase involved the training and distribution of staff and volunteers to provide public education village-by-village, surveil for cases, and deliver water filters. This continued and evolved as needed until the national burden of disease was very low. Then in a third phase, programs intensified surveillance efforts with the goal of identifying each case within 24 hours of the worm emerging and preventing the person from contaminating drinking water supplies. Most national programs offered voluntary in-patient centers, where those affected could stay and receive food and care until their worms were removed.In May 1991, the 44th World Health Assembly called for an international certification system to verify dracunculiasis eradication country-by-country. To this end, in 1995 the WHO established the International Commission for the Certification of Dracunculiasis Eradication (ICCDE). Once a country reports zero cases of dracunculiasis for a calendar year, the ICCDE considers that country to have interrupted guinea worm transmission, and is then in the "precertification phase". If the country repeats this feat with zero cases in each of the next three calendar years, the ICCDE sends a team to the country to assess the countrys disease surveillance systems and to verify the countrys reports. The ICCDE can then formally recommend the WHO Director-General certify a country as free of dracunculiasis.Since the initiation of the global eradication program, the ICCDE has certified 15 of the original endemic countries as having eradicated dracunculiasis: Pakistan in 1997; India in 2000; Senegal and Yemen in 2004; the Central African Republic and Cameroon in 2007; Benin, Mauritania, and Uganda in 2009; Burkina Faso and Togo in 2011; Côte dIvoire, Niger, and Nigeria in 2013; and Ghana in 2015.

Other animals
In addition to humans, D. medinensis can infect dogs. Infections of domestic dogs have been particularly common in Chad, where they helped reignite dracunculiasis transmission in 2010. Dogs are thought to be infected by eating a paratenic host, likely a fish or amphibian. As with humans, prevention efforts have focused on preventing infection by encouraging people in affected areas to bury fish entrails as well as to identify and tie up dogs with emerging worms so that they cannot access drinking water sources until after the worms have emerged. Domestic ferrets can be infected with D </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 Macroglossia and can you explain it in depth? [/INST] Macroglossia is the medical term for an unusually large tongue. Severe enlargement of the tongue can cause cosmetic and functional difficulties in speaking, eating, swallowing and sleeping. Macroglossia is uncommon, and usually occurs in children. There are many causes. Treatment depends upon the exact cause.

Signs and symptoms
Although it may be asymptomatic, symptoms usually are more likely to be present and more severe with larger tongue enlargements. Signs and symptoms include:

Dyspnea - difficult, noisy breathing, obstructive sleep apnea or airway obstruction
Dysphagia - difficulty swallowing and eating
Dysphonia - disrupted speech, possibly manifest as lisping
Sialorrhea - drooling
Angular cheilitis - sores at the corners of the mouth
Crenated tongue - indentations on the lateral borders of the tongue caused by pressure from teeth ("pie crust tongue")
Open bite malocclusion - a type of malocclusion of the teeth
Mandibular prognathism - enlarged mandible
Mouth breathing
Orthodontic abnormalities - including diastema and tooth spacingA tongue that constantly protrudes from the mouth is vulnerable to drying out, ulceration, infection or even necrosis.

Causes
Macroglossia may be caused by a wide variety of congenital and acquired conditions. Isolated macroglossia has no determinable cause. The most common causes of tongue enlargement are vascular malformations (e.g. lymphangioma or hemangioma) and muscular hypertrophy (e.g. Beckwith–Wiedemann syndrome or hemihyperplasia). Enlargement due to lymphangioma gives the tongue a pebbly appearance with multiple superficial dilated lymphatic channels. Enlargement due to hemihyperplasia is unilateral. In edentulous persons, a lack of teeth leaves more room for the tongue to expand into laterally, which can create problems with wearing dentures and may cause pseudomacroglossia.Amyloidosis is an accumulation of insoluble proteins in tissues that impedes normal function. This can be a cause of macroglossia if amyloid is deposited in the tissues of the tongue, which gives it a nodular appearance. Beckwith–Wiedemann syndrome is a rare hereditary condition, which may include other defects such as omphalocele, visceromegaly, gigantism or neonatal hypoglycemia.
The tongue may show a diffuse, smooth generalized enlargement. The face may show maxillary hypoplasia causing relative mandibular prognathism. Apparent macroglossia can also occur in Down syndrome. The tongue has a papillary, fissured surface. Macroglossia may be a sign of hypothyroid disorders.
Other causes include mucopolysaccharidosis, neurofibromatosis, multiple endocrine neoplasia type 2B, myxedema, acromegaly, angioedema, tumors (e.g. carcinoma), Glycogen storage disease type 2, Simpson–Golabi–Behmel syndrome, Triploid syndrome, trisomy 4p, fucosidosis, alpha-mannosidosis, Klippel–Trénaunay syndrome, cardiofaciocutaneous syndrome, Ras pathway disorders, transient neonatal diabetes, and lingual thyroid.

Diagnosis
Macroglossia is usually diagnosed clinically. Sleep endoscopy and imaging may be used for assessment of obstructive sleep apnea. The initial evaluation of all patients with macroglossia may involve abdominal ultrasound and molecular studies for Beckwith–Wiedemann syndrome.

Classification
The ICD-10 lists macroglossia under "other congenital malformations of the digestive system". Definitions of macroglossia have been proposed, including "a tongue that protrudes beyond the teeth during [the] resting posture" and "if there is an impression of a tooth on the lingual border when the patients slightly open their mouths". Others have suggested there is no objective definition of what constitutes macroglossia. Some propose a distinction between true macroglossia, when histologic abnormalities correlate with the clinical findings of tongue enlargement, and relative macroglossia, where histology does not provide a pathologic explanation for the enlargement </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 Methemoglobinemia and can you explain it in depth? [/INST] Methemoglobinemia, or methaemoglobinaemia, is a condition of elevated methemoglobin in the blood. Symptoms may include headache, dizziness, shortness of breath, nausea, poor muscle coordination, and blue-colored skin (cyanosis). Complications may include seizures and heart arrhythmias.Methemoglobinemia can be due to certain medications, chemicals, or food or it can be inherited from a persons parents. Substances involved may include benzocaine, nitrates, or dapsone. The underlying mechanism involves some of the iron in hemoglobin being converted from the ferrous [Fe2+] to the ferric [Fe3+] form. The diagnosis is often suspected based on symptoms and a low blood oxygen that does not improve with oxygen therapy. Diagnosis is confirmed by a blood gas.Treatment is generally with oxygen therapy and methylene blue. Other treatments may include vitamin C, exchange transfusion, and hyperbaric oxygen therapy. Outcomes are generally good with treatment. Methemoglobinemia is relatively uncommon, with most cases being acquired rather than genetic.

Signs and symptoms
Signs and symptoms of methemoglobinemia (methemoglobin level above 10%) include shortness of breath, cyanosis, mental status changes (~50%), headache, fatigue, exercise intolerance, dizziness, and loss of consciousness.People with severe methemoglobinemia (methemoglobin level above 50%) may exhibit seizures, coma, and death (level above 70%). Healthy people may not have many symptoms with methemoglobin levels below 15%. However, people with co-morbidities such as anemia, cardiovascular disease, lung disease, sepsis, or who have abnormal hemoglobin species (e.g. carboxyhemoglobin, sulfhemoglobinemia or sickle hemoglobin) may experience moderate to severe symptoms at much lower levels (as low as 5–8%).

Cause
Acquired
Methemoglobinemia may be acquired.  Classical drug causes of methemoglobinaemia include various antibiotics (trimethoprim, sulfonamides, and dapsone), local anesthetics (especially articaine, benzocaine, prilocaine, and lidocaine), and aniline dyes, metoclopramide, rasburicase, umbellulone, chlorates, bromates, and nitrites.  Nitrates are suspected to cause methemoglobinemia.In otherwise healthy individuals, the protective enzyme systems normally present in red blood cells rapidly reduce the methemoglobin back to hemoglobin and hence maintain methemoglobin levels at less than one percent of the total hemoglobin concentration. Exposure to exogenous oxidizing drugs and their metabolites (such as benzocaine, dapsone, and nitrates) may lead to an increase of up to a thousandfold of the methemoglobin formation rate, overwhelming the protective enzyme systems and acutely increasing methemoglobin levels.Infants under 6 months of age have lower levels of a key methemoglobin reduction enzyme (NADH-cytochrome b5 reductase) in their red blood cells. This results in a major risk of methemoglobinemia caused by nitrates ingested in drinking water, dehydration (usually caused by gastroenteritis with diarrhea), sepsis, or topical anesthetics containing benzocaine or prilocaine resulting in blue baby syndrome. Nitrates used in agricultural fertilizers may leak into the ground and may contaminate well water. The current EPA standard of 10 ppm nitrate-nitrogen for drinking water is specifically set to protect infants. Benzocaine applied to the gums or throat (as commonly used in baby teething gels, or sore throat lozenges) can cause methemoglobinemia.

Genetic
Due to a deficiency of the enzyme diaphorase I (cytochrome b5 reductase), methemoglobin levels rise and the blood of met-Hb patients has reduced oxygen-carrying capacity. Instead of being red in color, the arterial blood of met-Hb patients is brown. This results in the skin of white patients gaining a bluish hue. Hereditary met-Hb is caused by a recessive gene. If only one parent has this gene, offspring will have normal-hued skin, but if both parents carry the gene, there is a chance the offspring will have blue-hued skin.Another cause of congenital methemoglobinemia is seen in patients with abnormal hemoglobin variants such as hemoglobin M (HbM), or hemoglobin H (HbH), which are not amenable to reduction despite intact enzyme systems.Methemoglobinemia can also arise in patients with pyruvate kinase deficiency due to impaired production of NADH  – the essential cofactor for diaphorase I. Similarly, patients with glucose-6-phosphate dehydrogenase deficiency may have impaired production of another co-factor, NADPH.

Pathophysiology
The affinity for oxygen of ferric iron is impaired. The binding of oxygen to methemoglobin results in an increased affinity for oxygen in the remaining heme sites that are in ferrous state within the same tetrameric hemoglobin unit.  This leads to an overall reduced ability of the red blood cell to release oxygen to tissues, with the associated oxygen–hemoglobin dissociation curve therefore shifted to the left. When methemoglobin concentration is elevated in red blood cells, tissue hypoxia may occur.Normally, methemoglobin levels are <1%, as measured by the CO-oximetry test. Elevated levels of methemoglobin in the blood are caused when the mechanisms that defend against oxidative stress within the red blood cell are overwhelmed and the oxygen carrying ferrous ion (Fe2+) of the heme group of the hemoglobin molecule is oxidized to the ferric state (Fe3+). This converts hemoglobin to methemoglobin, resulting in a reduced ability to release oxygen to tissues and thereby hypoxia. This can give the blood a bluish or chocolate-brown color. Spontaneously formed methemoglobin is normally reduced (regenerating normal hemoglobin) by protective enzyme systems, e.g., NADH methemoglobin reductase (cytochrome-b5 reductase) (major pathway), NADPH methemoglobin reductase (minor pathway) and to a lesser extent the ascorbic acid and glutathione enzyme systems. Disruptions with these enzyme systems lead to methemoglobinemia. Hypoxia occurs due to the decreased oxygen-binding capacity of methemoglobin, as well as the increased oxygen-binding affinity of other subunits in the same hemoglobin molecule, which prevents them from releasing oxygen at normal tissue oxygen levels.

Diagnosis
The diagnosis of methemoglobinemia is made with the typical symptoms, a suggestive history, low oxygen saturation on pulse oximetry measurements (SpO2) and these symptoms (cyanosis and hypoxia) failing to improve on oxygen treatment. The definitive test would be obtaining either CO-oximeter or a methemoglobin level on an arterial blood gas test.
Arterial blood with an elevated methemoglobin level has a characteristic chocolate-brown color as compared to normal bright red oxygen-containing arterial blood; the color can be compared with reference charts.The SaO2 calculation in the arterial blood gas analysis is falsely normal, as it is calculated under the premise of hemoglobin either being oxyhemoglobin or deoxyhemoglobin. However, co-oximetry can distinguish the methemoglobin concentration and percentage of hemoblobin.
At the same time, the SpO2 concentration as measured by pulse ox is false high, because methemoglobin absorbs the pulse ox light at the 2 wavelengths it uses to calculate the ratio of oxyhemoglobin and deoxyhemoglobin. For example with a methemoglobin level of 30-35%, this ratio of light absorbance is 1.0, which translates into a false high SpO2 of 85%.

Differential diagnosis
Other conditions that can cause bluish skin include argyria, sulfhemoglobinemia, heart failure,  Amiodarone-induced bluish skin pigmentation and acrodermatitis enteropathica.

Treatment
Methemoglobinemia can be treated with supplemental oxygen and methylene blue. Methylene blue is given as a 1% solution (10 mg/ml) 1 to 2 mg/kg administered intravenously slowly over five minutes. Although the response is usually rapid, the dose may be repeated in one hour if the level of methemoglobin is still high one hour after the initial infusion. Methylene blue inhibits monoamine oxidase, and serotonin toxicity can occur if taken with an SSRI (selective serotonin reuptake inhibitor) medicine.Methylene blue restores the iron in hemoglobin to its normal (reduced) oxygen-carrying state. This is achieved by providing an artificial electron acceptor (such as methylene blue or flavin) for NADPH methemoglobin reductase (RBCs usually dont have one; the presence of methylene blue allows the enzyme to function at 5× normal levels). The NADPH is generated via the hexose monophosphate shunt.
Genetically induced chronic low-level methemoglobinemia may be treated with oral methylene blue daily. Also, vitamin C can occasionally reduce cyanosis associated with chronic methemoglobinemia, and may be helpful in settings in which methylene blue is unavailable or contraindicated (e.g., in an individual with G6PD deficiency). Diaphorase (cytochrome b5 reductase) normally contributes only a small percentage of the red blood cells reducing capacity, but can be pharmacologically activated by exogenous cofactors (such as methylene blue) to five times its normal level of activity.

Epidemiology
Methemoglobinemia mostly affects infants under 6 months of age (particularly those under 4 months) due to low hepatic production of methemoglobin reductase. The most at-risk populations are those with water sources high in nitrates, such as wells and other water that is not monitored or treated by a water treatment facility </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 Familial hypercholesterolemia and can you explain it in depth? [/INST] Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL cholesterol), in the blood and early cardiovascular disease. The most common mutations diminish the number of functional LDL receptors in the liver. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH (such as dietary modification and statin tablets). Nevertheless, treatment (including higher statin doses) is usually effective.
FH is classified as a type 2 familial dyslipidemia. There are five types of familial dyslipidemia (not including subtypes), and each are classified from both the altered lipid profile and by the genetic abnormality. For example, high LDL (often due to LDL receptor defect) is type 2. Others include defects in chylomicron metabolism, triglyceride metabolism, and metabolism of other cholesterol-containing particles, such as VLDL and IDL.
About 1 in 100 to 200 people have mutations in the LDLR gene that encodes the LDL receptor protein, which normally removes LDL from the circulation, or apolipoprotein B (ApoB), which is the part of LDL that binds with the receptor; mutations in other genes are rare. People who have one abnormal copy (are heterozygous) of the LDLR gene may develop cardiovascular disease prematurely at the age of 30 to 40. Having two abnormal copies (being homozygous) may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, inherited in an autosomal dominant pattern, occurring in 1:250 people in most countries; homozygous FH is much rarer, occurring in 1 in 300,000 people.Heterozygous FH is normally treated with statins, bile acid sequestrants, or other lipid-lowering agents that lower cholesterol levels. New cases are generally offered genetic counseling. Homozygous FH often does not respond to medical therapy and may require other treatments, including LDL apheresis (removal of LDL in a method similar to dialysis) and occasionally liver transplantation.

Signs and symptoms
Physical signs
High cholesterol levels normally do not cause any symptoms. Yellow deposits of cholesterol-rich fat may be seen in various places on the body such as around the eyelids (known as xanthelasma palpebrarum), the outer margin of the iris (known as arcus senilis corneae), and in the tendons of the hands, elbows, knees and feet, particularly the Achilles tendon (known as a tendon xanthoma).

Cardiovascular disease
Accelerated deposition of cholesterol in the walls of arteries leads to atherosclerosis, the underlying cause of cardiovascular disease. The most common problem in FH is the development of coronary artery disease (atherosclerosis of the coronary arteries that supply the heart) at a much younger age than would be expected in the general population. This may lead to angina pectoris (chest pain or tightness on exertion) or heart attacks. Less commonly, arteries of the brain are affected; this may lead to transient ischemic attacks (brief episodes of weakness on one side of the body or inability to talk) or occasionally stroke. Peripheral artery occlusive disease (obstruction of the arteries of the legs) occurs mainly in people with FH who smoke; this can cause pain in the calf muscles during walking that resolves with rest (intermittent claudication) and problems due to a decreased blood supply to the feet (such as gangrene).
Atherosclerosis risk is increased further with age and in those who smoke, have diabetes, high blood pressure and a family history of cardiovascular disease.

Diagnosis
Approximately 85% of individuals with this disorder have not been diagnosed and consequently are not receiving lipid-lowering treatments. Physical examination findings can help a physician make the diagnosis of FH. Tendon xanthomas are seen in 20-40% of individuals with FH and are pathognomonic for the condition. A xanthelasma or corneal arcus may also be seen. These common signs are supportive of the diagnosis, but are non-specific findings.

Lipid measurements
Cholesterol levels may be determined as part of health screening for health insurance or occupational health, when the external physical signs such as xanthelasma, xanthoma, arcus are noticed, symptoms of cardiovascular disease develop, or a family member has been found to have FH. A pattern compatible with hyperlipoproteinemia type IIa on the Fredrickson classification is typically found: raised level of total cholesterol, markedly raised level of low-density lipoprotein (LDL), normal level of high-density lipoprotein (HDL), and normal level of triglycerides. Total cholesterol levels of 350–550 mg/dL are typical of heterozygous FH while total cholesterol levels of 650–1000 mg/dL are typical of homozygous FH. The LDL is typically above the 75th percentile, that is, 75% of the healthy population would have a lower LDL level. Cholesterol levels can be drastically higher in people with FH who are also obese.

Mutation analysis
On the basis of the isolated high LDL and clinical criteria (which differ by country), genetic testing for LDL receptor mutations and ApoB mutations can be performed. Mutations are detected in between 50 and 80% of cases; those without a mutation often have higher triglyceride levels and may in fact have other causes for their high cholesterol, such as combined hyperlipidemia due to metabolic syndrome.

Differential diagnosis
FH needs to be distinguished from familial combined hyperlipidemia and polygenic hypercholesterolemia. Lipid levels and the presence of xanthomata can confirm the diagnosis. Sitosterolemia and cerebrotendineous xanthomatosis are two rare conditions that can also present with premature atherosclerosis and xanthomas. The latter condition can also involve neurological or psychiatric manifestations, cataracts, diarrhea and skeletal abnormalities.

Genetics
The most common genetic defects in FH are LDLR mutations (prevalence 1 in 250, depending on the population), ApoB mutations (prevalence 1 in 1000), PCSK9 mutations (less than 1 in 2500) and LDLRAP1. The related disease sitosterolemia, which has many similarities with FH and also features cholesterol accumulation in tissues, is due to ABCG5 and ABCG8 mutations.

LDL receptor
The LDL receptor gene is located on the short arm of chromosome 19 (19p13.1-13.3). It comprises 18 exons and spans 45 kb, and the protein gene product contains 839 amino acids in mature form. A single abnormal copy (heterozygote) of FH causes cardiovascular disease by the age of 50 in about 40% of cases. Having two abnormal copies (homozygote) causes accelerated atherosclerosis in childhood, including its complications. The plasma LDL levels are inversely related to the activity of LDL receptor (LDLR). Homozygotes have LDLR activity of less than 2%, while heterozygotes have defective LDL processing with receptor activity being 2–25%, depending on the nature of the mutation. Over 1000 different mutations are known.There are five major classes of FH due to LDLR mutations:
Class I: LDLR is not synthesized at all.
Class II: LDLR is not properly transported from the endoplasmic reticulum to the Golgi apparatus for expression on the cell surface.
Class III: LDLR does not properly bind LDL on the cell surface because of a defect in either apolipoprotein B100 (R3500Q) or in LDL-R.
Class IV: LDLR bound to LDL does not properly cluster in clathrin-coated pits for receptor-mediated endocytosis (pathway step 2).
Class V: LDLR is not recycled back to the cell surface (pathway step 5).

Apolipoprotein B
Apolipoprotein B, in its ApoB100 form, is the main apolipoprotein, or protein part of the lipoprotein particle. Its gene is located on the second chromosome (2p24-p23) and is 46.2 kb long. FH is often associated with the mutation of R3500Q, which causes replacement of arginine by glutamine at position 3500. The mutation is located on a part of the protein that normally binds with the LDL receptor, and binding is reduced as a result of the mutation. Like LDLR, the number of abnormal copies determines the severity of the hypercholesterolemia.

PCSK9
Mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene were linked to autosomal dominant (i.e. requiring only one abnormal copy) FH in a 2003 report. The gene is located on the first chromosome (1p34.1-p32) and encodes a 666 amino acid protein that is expressed in the liver. It has been suggested that PCSK9 causes FH mainly by reducing the number of LDL receptors on liver cells.

LDLRAP1
Abnormalities in the ARH gene, also known as LDLRAP1, were first reported in a family in 1973. In contrast to the other causes, two abnormal copies of the gene are required for FH to develop (autosomal recessive). The mutations in the protein tend to cause the production of a shortened protein. Its real function is unclear, but it seems to play a role in the relation between the LDL receptor and clathrin-coated pits. People with autosomal recessive hypercholesterolemia tend to have more severe disease than LDLR-heterozygotes but less severe than LDLR-homozygotes.

Pathophysiology
LDL cholesterol normally circulates in the body for 2.5 days, and subsequently the apolipoprotein B portion of LDL cholesterol binds to the LDL receptor on the liver cells, triggering its uptake and digestion. This process results in the removal of LDL from the circulatory system. Synthesis of cholesterol by the liver is suppressed in the HMG-CoA reductase pathway. In FH, LDL receptor function is reduced or absent, and LDL circulates for an average duration of 4.5 days, resulting in significantly increased level of LDL cholesterol in the blood with normal levels of other lipoproteins. In mutations of ApoB, reduced binding of LDL particles to the receptor causes the increased level of LDL cholesterol. It is not known how the mutation causes LDL receptor dysfunction in mutations of PCSK9 and ARH.Although atherosclerosis occurs to a certain degree in all people, people with FH may develop accelerated atherosclerosis due to the excess level of LDL. The degree of atherosclerosis approximately depends on the number of LDL receptors still expressed and the functionality of these receptors. In many heterozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In the more serious homozygous forms, the receptor is not expressed at all.Some studies of FH cohorts suggest that additional risk factors are generally at play when a person develops atherosclerosis. In addition to the classic risk factors such as smoking, high blood pressure, and diabetes, genetic studies have shown that a common abnormality in the prothrombin gene (G20210A) increases the risk of cardiovascular events in people with FH. Several studies found that a high level of lipoprotein(a) was an additional risk factor for ischemic heart disease. The risk was also found to be higher in people with a specific genotype of the angiotensin-converting enzyme (ACE).

Screening
Cholesterol screening and genetic testing among family members of people with known FH is cost-effective. Other strategies such as universal screening at the age of 16 were suggested in 2001. The latter approach may however be less cost-effective in the short term. Screening at an age lower than 16 was thought likely to lead to an unacceptably high rate of false positives.A 2007 meta-analysis found that "the proposed strategy of screening children and parents for familial hypercholesterolaemia could have considerable impact in preventing the medical consequences of this disorder in two generations simultaneously." "The use of total cholesterol alone may best discriminate between people with and without FH between the ages of 1 to 9 years."Screening of toddlers has been suggested, and results of a trial on 10,000 one-year-olds were published in 2016. Work was needed to find whether screening was cost-effective, and acceptable to families. Genetic counseling can help assist in genetic testing following a positive cholesterol screen for FH.

Treatment
Heterozygous FH
FH is usually treated with statins. Statins act by inhibiting the enzyme hydroxymethylglutaryl CoA reductase (HMG-CoA-reductase) in the liver. In response, the liver produces more LDL receptors, which remove circulating LDL from the blood. Statins effectively lower cholesterol and LDL levels, although sometimes add-on therapy with other drugs is required, such as bile acid sequestrants (cholestyramine or colestipol), nicotinic acid preparations or fibrates. Control of other risk factors for cardiovascular disease is required, as risk remains somewhat elevated even when cholesterol levels are controlled. Professional guidelines recommend that the decision to treat a person with FH with statins should not be based on the usual risk prediction tools (such as those derived from the Framingham Heart Study), as they are likely to underestimate the risk of cardiovascular disease; unlike the rest of the population, FH have had high levels of cholesterol since birth, probably increasing their relative risk. Prior to the introduction of the statins, clofibrate (an older fibrate that often caused gallstones), probucol (especially in large xanthomas) and thyroxine were used to reduce LDL cholesterol levels.
More controversial is the addition of ezetimibe, which inhibits cholesterol absorption in the gut. While it reduces LDL cholesterol, it does not appear to improve a marker of atherosclerosis called the intima-media thickness. Whether this means that ezetimibe is of no overall benefit in FH is unknown.There are no interventional studies that directly show mortality benefit of cholesterol lowering in FH. Rather, evidence of benefit is derived from a number of trials conducted in people who have polygenic hypercholesterolemia (in which heredity plays a smaller role). Still, a 1999 observational study of a large British registry showed that mortality in people with FH had started to improve in the early 1990s when statins were introduced.A cohort study suggested that treatment of FH with statins leads to a 48% reduction in death from coronary heart disease to a point where people are no more likely to die of coronary heart disease than the general population. However, if the person already had coronary heart disease the reduction was 25%. The results emphasize the importance of early identification of FH and treatment with statins.Alirocumab and evolocumab, both monoclonal antibodies against PCSK9, are specifically indicated as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia, who require additional lowering of LDL cholesterol.More recently Inclisiran has been approved for the treatment of HeFH

Homozygous FH
Homozygous FH is harder to treat. The LDL (Low Density Lipoprotein) receptors are minimally functional, if at all. Only high doses of statins, often in combination with other medications, are modestly effective in improving lipid levels. If medical therapy is not successful at reducing cholesterol levels, LDL apheresis may be used; this filters LDL from the bloodstream in a process reminiscent of dialysis. Very severe cases may be considered for a liver transplant; this provides a liver with normally functional LDL receptors, and leads to rapid improvement of the cholesterol levels, but at the risk of complications from any solid organ transplant (such as rejection, infections, or side-effects of the medication required to suppress rejection). Other surgical techniques include partial ileal bypass surgery, in which part of the small bowel is bypassed to decrease the absorption of nutrients and hence cholesterol, and portacaval shunt surgery, in which the portal vein is connected to the vena cava to allow blood with nutrients from the intestine to bypass the liver.Lomitapide, an inhibitor of the microsomal triglyceride transfer protein, was approved by the US FDA in December 2012 as an orphan drug for the treatment of homozygous familial hypercholesterolemia. In January 2013, The US FDA also approved mipomersen, which inhibits the action of the gene apolipoprotein B, for the treatment of homozygous familial hypercholesterolemia. Gene therapy is a possible future alternative.Evinacumab, a monoclonal antibody inhibiting angiopoietin-like protein 3, was approved in 2021 for adjunct therapy.

Children
Given that FH is present from birth and atherosclerotic changes may begin early in life, it is sometimes necessary to treat adolescents or even teenagers with agents that were originally developed for adults. Due to safety concerns, many physicians prefer to use bile acid sequestrants and fenofibrate as these are licensed in children. Nevertheless, statins seem safe and effective, and in older children may be used as in adults.An expert panel in 2006 advised on early combination therapy with LDL apheresis, statins, and cholesterol absorption inhibitors in children with homozygous FH at the highest risk.

Epidemiology
The global prevalence of FH is approximately 10 million people. In most populations studied, heterozygous FH occurs in about 1:250 people, but not all develop symptoms </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 Chignon 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 Stepmother and can you explain it in depth? [/INST] A stepmother, stepmum or stepmom is a non-biological female parent married to ones preexisting parent.
A stepmother-in-law is a stepmother of ones spouse. Children from her spouses previous unions are known as her stepchildren.

Culture
Stepparents (mainly stepmothers) may also face some societal challenges due to the stigma surrounding the "evil stepmother" character. Morello notes that the introduction of the "evil stepmother" character in the past is problematic to stepparents today, as it has created a stigma towards stepmothers. The presence of this stigma can have a negative impact on stepmothers self-esteem.

Fiction
In fiction, stepmothers are often portrayed as being wicked and evil. The character of the wicked stepmother features heavily in fairy tales; the most famous examples are Cinderella, Snow White and Hansel and Gretel. Stepdaughters are her most common victim, and then stepdaughter/stepson pairs, but stepsons also are victims as in The Juniper Tree—sometimes, as in East of the Sun and West of the Moon, because he refused to marry his stepsister as she wished, or, indeed, they may make their stepdaughters-in-law their victims, as in The Boys with the Golden Stars. In some fairy tales, such as Giambattista Basiles La Gatta Cennerentola or the Danish Green Knight, the stepmother wins the marriage by ingratiating herself with the stepdaughter, and once she obtains it, becomes cruel.In some fairy tales, the stepdaughters escape by marrying does not free her from her stepmother. After the birth of the stepdaughters first child, the stepmother may attempt to murder the new mother and replace her with her own daughter—thus making her the stepmother to the next generation. Such a replacement occurs in The Wonderful Birch, Brother and Sister, and The Three Little Men in the Wood; only by foiling the stepmothers plot (and usually executing her), is the story brought to a happy ending. In the Korean Folktale Janghwa Hongryeon jeon, the stepmother kills her own stepdaughters.

In many stories with evil stepmothers, the hostility between the stepmother and the stepchild is underscored by having the child succeed through aid from the dead mother. This motif occurs from Norse mythology, where Svipdagr rouses his mother Gróa from the grave so as to learn from her how to accomplish a task his stepmother set, to fairy tales such as the Brothers Grimm version of Cinderella, where Aschenputtel receives her clothing from a tree growing on her mothers grave, the Russian Vasilissa the Beautiful, where Vasilissa is aided by a doll her mother gave, and her mothers blessing, and the Malay Bawang Putih Bawang Merah, where the heroines mother comes back as fish to protect her.

The notion of the word stepmother being descriptive of an intrinsically unkind parent is suggested by peculiar wording in John Gambles "An Irish Wake" (1826). He writes of a woman soon to die, who instructs her successor to "be kind to my children." Gamble writes that the injunction was forgotten and that she "proved a very step-mother."
Fairy tales can have variants where one tale has an evil mother and the other an evil stepmother: in The Six Swans by the Brothers Grimm and also in The Wild Swans by Hans Christian Andersen, the heroine is persecuted by her husbands mother and in another one by her stepmother, and in The Twelve Wild Ducks, by his stepmother. Sometimes this appears to be a deliberate switch: The Brothers Grimm, having put in their first editions versions of Snow White and Hansel and Gretel where the villain was the biological mother, altered it to a stepmother in later editions, perhaps to mitigate the storys violence. Another reason for the change from a villainous mother to a villainous stepmother may have been the belief that mothers were sacred, as well as the belief that people would not believe that a mother could harbor such ill-will and animosity toward their child. The Icelandic fairy tale The Horse Gullfaxi and the Sword Gunnfoder features a good stepmother, who indeed aids the prince like a fairy godmother, but this figure is very rare in fairy tales.
The stepmother may be identified with other evils the characters meet. For instance, both the stepmother and the witch in Hansel and Gretel are deeply concerned with food, the stepmother to avoid hunger, the witch with her house built of food and her desire to eat the children, and when the children kill the witch and return home, their stepmother has mysteriously died.This hostility from the stepmother and tenderness from the true mother has been interpreted in varying ways. A psychological interpretation, by Bruno Bettelheim, describes it as "splitting" the actual mother in an ideal mother and a false mother that contains what the child dislikes in the actual mother. However, historically, many women died in childbirth, their husbands remarried, and the new stepmothers competed with the children of the first marriage for resources; the tales can be interpreted as factual conflicts from history. In some fairy tales, such as The Juniper Tree, the stepmothers hostility is overtly the desire to secure the inheritance of her children.Stepmothers also make many appearances in Chinese tales of family. Wicked stepmothers are common. In Classic of Filial Piety, Guo Jujing told the story of Min Ziqian, who had lost his mother at a young age. His stepmother had two more sons and saw to it that they were warmly dressed in winter but neglected her stepson. When her husband discovered this, he decided to divorce her. His son interceded, on the ground that she neglected only him, but when they had no mother, all three sons would be neglected. His father relented, and the stepmother henceforth took care of all three children. For this, he was held up as a model of filial piety.
Conversely, the exemplary stepmother prefers the stepson to her own child, in recognition that his seniority makes him superior. The "righteous stepmother of Qi", faced with her son and stepson having been found by a murdered man, and both having confessed to shield the other, argues for her sons execution because her husband had ordered her to look after her stepson, and her son is the junior brother; the king pardoned them both for her devotion to duty.The ubiquity of the wicked stepmother has made it a frequent theme of revisionist fairy tale fantasy. This can range from Tanith Lees Red as Blood, where the stepmother queen is desperately trying to protect the land from her evil stepdaughters magic, to Diana Wynne Joness Howls Moving Castle, where, although it is known that stepmothers are evil, the actual stepmother is guilty of nothing more than some carelessness, to Erma Bombecks retelling where Cinderella is lazy and a liar. More subtly, Piers Anthony depicted the Princess Threnody as being cursed by her stepmother in Crewel Lye: A Caustic Yarn: if she ever entered Castle Roogna, it would fall down. But Threnody explains that her presence at the castle caused her father to dote on her and neglect his duties to the destruction of the kingdom; her stepmother had merely made her destructive potential literal, and forced her to confront what she was doing.The character of the evil stepmother can also be found in the genre of young adult fiction or young adult social problem novels. In Lisa Heathfields Paper Butterflies. the protagonist June suffers horrific abuse at the hands of her stepmother, a fact that she conceals from her father.
Despite many examples of evil or cruel stepmothers, loving stepmothers also exist in fiction. In Kevin and Kell, Kell is portrayed as loving her stepdaughter Lindesfarne, whom her husband Kevin had adopted during his previous marriage. Likewise, Lindesfarne considers Kell her mother, and has a considerably more favorable view of her than Angelique, Kevins ex-wife and her adoptive mother, due to feeling neglected by Angelique during her childhood. The Disney film Enchanted also makes references to the "evil stepmother" belief, as the villainess is a stepmother, but her wickedness comes from her selfishness and power hungriness rather than the simple fact she is a stepmother. When a little girl tells the heroine Giselle that all stepmothers are evil, Giselle reminds her that she personally knows some wonderful women who were good stepmothers, and the fact a woman is a stepmother does not suddenly change her personality </s>