<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 exudative vitreoretinopathy and can you explain it in depth? [/INST] Familial exudative vitreoretinopathy (FEVR, pronounced as fever) is a genetic disorder affecting the growth and development of blood vessels in the retina of the eye. This disease can lead to visual impairment and sometimes complete blindness in one or both eyes. FEVR is characterized by incomplete vascularization of the peripheral retina. This can lead to the growth of new blood vessels which are prone to leakage and hemorrhage and can cause retinal folds, tears, and detachments. Treatment involves laser photocoagulation of the avascular portions of the retina to reduce new blood vessel growth and risk of complications including leakage of retinal blood vessels and retinal detachments.

Information
Pathophysiology
FEVR is caused by genetic defects involving the regulation of blood vessel growth in developing eyes. As a result, there is poor blood vessel growth to the periphery of the retina. The lack of blood supply to the peripheral retina triggers the release of molecules that stimulate blood vessel growth, such as vascular endothelial growth factor (VEGF). However, this new blood vessel growth, also known as neovascularization, can lead to further complications such as the leakage and hemorrhage of retinal blood vessels, retinal tears, and detachments.Genetics
There have been several gene mutations associated with FEVR. These genes code for proteins involved in the WNT signaling pathway, which is involved in the development of the human eye and regulation of blood vessel growth. Depending on the genes involved, FEVR can follow an autosomal dominant, autosomal recessive, or X-linked inheritance pattern. There is varying penetrance and expressivity depending on the genes involved </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 Stiff skin syndrome and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Möbius syndrome and can you explain it in depth? [/INST] Möbius syndrome is a rare congenital neurological disorder which is characterized by facial paralysis and the inability to move the eyes from side to side. Most people with Möbius syndrome are born with complete facial paralysis and cannot close their eyes or form facial expressions. Limb and chest wall abnormalities sometimes occur with the syndrome. People with Möbius syndrome have normal intelligence, although their lack of facial expression is sometimes incorrectly taken to be due to dullness or unfriendliness. It is named for Paul Julius Möbius, a German neurologist who first described the syndrome in 1888. In 1994, the "Moebius Syndrome Foundation" was founded, and later that year the first "Moebius Syndrome Foundation Conference" was held in Los Angeles. A charity for Möbius syndrome was set up and registered in the UK in 1999 by Linda Anderson from Tyne and Wear, whose son had been born with the condition in 1980. She campaigned for many years, held conferences and gave medical speeches in America before she had to step away from the charity because of ill health.

Signs and symptoms
People with Möbius syndrome are born with facial paralysis and the inability to move their eyes laterally. Often, their upper lip is retracted due to muscle shrinkage. Occasionally, the cranial nerves V and VIII are affected. If cranial nerve VIII is affected, the person experiences hearing loss.Other symptoms that sometimes occur with Möbius syndrome are:
Limb abnormalities—clubbed feet, missing fingers or toes
Chest-wall abnormalities (Poland syndrome)
Crossed eyes (strabismus)
Difficulty in breathing and/or in swallowing
Corneal erosion resulting from difficulty in blinkingChildren with Möbius syndrome may have delayed speech because of paralysis of muscles that move the lips, soft palate and tongue root. However, with speech therapy, most people with Möbius syndrome can develop understandable speech. Möbius syndrome has been associated with increased occurrence of the symptoms of autism. Some children with Möbius syndrome are mistakenly labeled as intellectually disabled because of their expressionless faces, strabismus and frequent drooling.

Social and lifestyle effects
Möbius syndrome does not prevent individuals from experiencing personal and professional success. Due to the importance of facial expression and smiling in social interaction, the inability to form either can lead to individuals with Möbius being perceived as unhappy, unfriendly or uninterested in conversations. Individuals who are familiar with Möbius patients such as family or friends can recognize other signals of emotion such as body language, to the point that they sometimes report forgetting that the person has facial paralysis. Indeed, people with Möbius syndrome are often adept at compensating for a lack of expression by using body language, posture, and vocal tone to convey emotion.

Pathogenesis
Möbius syndrome results from the underdevelopment of the VI and VII cranial nerves. The VI cranial nerve controls lateral eye movement, and the VII cranial nerve controls facial expression.The causes of Möbius syndrome are poorly understood. It is thought to result from a vascular disruption (temporary loss of bloodflow) in the brain during prenatal development. There can be many reasons for vascular disruption leading to Möbius syndrome. Most cases do not appear to be genetic. However, genetic links have been found in a few families. Some maternal trauma may result in impaired or interrupted blood flow (ischemia) or lack of oxygen (hypoxia) to a developing fetus. Some cases are associated with reciprocal translocation between chromosomes or maternal illness. In the majority of cases of Möbius syndrome in which autosomal dominant inheritance is suspected, sixth and seventh cranial nerve paralysis (palsy) occurs without associated limb abnormalities.The use of drugs and a traumatic pregnancy may also be linked to the development of Möbius syndrome. The use of the drugs misoprostol or thalidomide by women during pregnancy has been linked to the development of Möbius syndrome in some cases. Misoprostol is used to induce abortions in Brazil and Argentina as well as in the United States. Misoprostol abortions are successful 90% of the time, meaning that 10% of the time the pregnancy continues. Studies show that the use of misoprostal during pregnancy increases the risk of developing Möbius syndrome by a factor of 30. While this is a dramatic increase in risk, the incidence of Möbius syndrome without misoprostal use is estimated at one in 50000 to 100000 births (making the incidence of Möbius syndrome with misoprostol use, less than one in 1000 births). The use of cocaine (which also has vascular effects) has been implicated in Möbius syndrome.Some researchers have suggested that the underlying problem of this disorder could be congenital hypoplasia or agenesis of the cranial nerve nuclei. Certain symptoms associated with Möbius syndrome may be caused by incomplete development of facial nerves, other cranial nerves, and other parts of the central nervous system.

Oral/dental concerns
Neonatal
When a child is born with Möbius syndrome, there may be difficulty in closing the mouth or swallowing. The tongue may fasciculate (quiver) or be hypotonic (low muscle tone). The tongue may be larger or smaller than average. There may be low tone of the muscles of the soft palate, pharynx, and the masticatory system. The palate may be arched excessively (a high palate), because the tongue does not form a suction that would normally shape the palate down further. The palate may have a groove (this may be partially due to intubation early on if it is for an extended period of time) or may be cleft (incompletely formed). The opening to the mouth may be small. Feeding problems may become a critical issue early on if adequate nutrition is difficult.

Primary dentition
The primary (baby) teeth generally start coming in by 6 months of age, and all 20 teeth may be in by two and a half years of age. The eruption timing varies greatly. There may be an incomplete formation of the enamel on the teeth (enamel hypoplasia) that makes the teeth more vulnerable to caries (cavities). There may be missing teeth eruptions. If the infant is not closing down properly, the lower jaws become more noticeably deficient (micrognathia or retrognathia). The front teeth may not touch when the child closes down because the back teeth have overerrupted or because of incomplete formation of the maxilla. This condition is called an anterior open bite and has facial/skeletal implications. The saliva may be thick, or the infant may have a dry mouth.

Transitional dentition
Between age 5 and 7, most children start losing their primary teeth. Occasionally, some primary teeth are slow to exfoliate (fall out), and the dentist may want to remove a primary tooth early to prevent orthodontic problems. Likewise, premature loss of primary teeth may create orthodontic problems later on. When a tooth is lost prematurely, removable or fixed spacers may be needed to prevent the shifting of teeth. Interceptive orthodontic treatment can be initiated at this stage of development to help with crowding or to help relate the upper and lower jaws. Consistent with a high palate is a narrow arch shape of the upper teeth as they line up in the mouth. This may cause the upper front teeth to flare out and become more prone to fracture if accidentally hit. Interceptive orthodontics has an important role in this situation. Appliances that expand the upper arch tend to bring the front teeth back into a more-normal position. Some appliances can even help allow the front teeth to close to normal in an open-bite situation. The mouth and lips may tend to get dry with the Möbius patient. Lack of a good oral seal (lips together) allows the gingiva (gums) to get dry and may get inflamed and irritated.

Permanent dentition
After the last primary tooth is lost, usually around the age of twelve, final orthodontic treatment can be initiated. A patient that has not been able to close or swallow well probably will have an open bite, deficient lower-jaw growth, a narrow archform with crowded teeth, and upper anterior flaring of teeth. Orthognathic (jaw) surgery may be indicated. This should be completed in most situations before the smile surgery where the gracilis muscle is grafted to the face.Genetic links to 13q12.2 and 1p22 have been suggested.

Diagnosis
Diagnosis is typically made by the physical characteristics and symptoms, patient history and a thorough clinical evaluation. There is no specific diagnostic test that confirms Möbius syndrome. Some specialised tests may be carried out to rule out other causes of facial palsy.

Treatment
There is no single course of medical treatment or cure for Möbius syndrome. Treatment is supportive and in accordance with symptoms. If they have difficulty nursing, infants may require feeding tubes or special bottles to maintain sufficient nutrition. Physical, occupational, and speech therapy can improve motor skills and coordination and can lead to better control of speaking and eating abilities. Often, frequent lubrication with eye drops is sufficient to combat dry eye that results from impaired blinking. Surgery can correct crossed eyes, protect the cornea via tarsorraphy, and improve limb and jaw deformities. Sometimes called smile surgery by the media, muscle transfers grafted from the thigh to the corners of the mouth can be performed to provide the ability to smile. Although "smile surgery" may provide the ability to smile, the procedure is complex and can take twelve hours for each side of the face. Also, the surgery cannot be considered a "cure" for Möbius syndrome, because it does not improve the ability to form other facial expressions.

Epidemiology
It is estimated that there are, on average, 2 to 20 cases of Möbius syndrome per million births </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 Chylomicron retention disease and can you explain it in depth? [/INST] Chylomicron retention disease is a disorder of fat absorption. It is associated with SAR1B. Mutations in SAR1B prevent the release of chylomicrons in the circulation which leads to nutritional and developmental problems. It is a rare autosomal recessive disorder with around 40 cases reported worldwide. Since the disease allele is recessive, parents usually do not show symptoms.Without functional chylomicrons, certain fat-soluble vitamins such as vitamin D and vitamin E cannot be absorbed. Chylomicrons have a crucial role in fat absorption and transport, thus a deficiency in chylomicron functioning reduces available levels of dietary fats and fat-soluble vitamins.

History
Chylomicron Retention Disease, also called Andersons disease, is an autosomal recessive lipid malabsorption syndrome characterized by abnormally low amounts of cholesterol in the blood. This disease most frequently is diagnosed in infants. Charlotte Anderson first published a description of the disorder in 1961, where she observed a seven month old girl who developed intestinal mucosa filled with fat droplets. In 2003, Jones and colleagues identified mutations in the SAR1B gene, which transcripts the SAR1B protein involved in COPII transport and proposed this was the molecular defect of the disorder. To present day, 17 mutations of the SAR1B gene have been discovered. This disease is rare, with only 50 cases diagnosed worldwide.

Genetics
The Sar1B GTPase is an enzyme located in epithelial cells of the gastrointestinal tract. These proteins are critical for release of chylomicrons in the body.Chylomicron retention disease is an autosomal homozygous recessive disorder arising from mutations in the gene encoding the Sar1B GTPase. The Sar1B gene is located at position 5q31.1 in the fifth chromosome and is composed of eight exons. Alternative splicing of the second exon results into two different splice isoforms for the Sar1B transcript RNA.  In CMRD, a mutation of this genomic sequence affects the Sar1B enzymes ability to interact with Guanine Exchange Factors (GEFs) and GTP-Activating Proteins (GAPs). The mutation of exon 6 of the sequence can eliminate the critical chain that is responsible for recognizing guanine. This strips the GTPase of its capability to hydrolyze GTP, its hallmark trait. This overall affects the ability of Sar1B GTPase to control chylomicron release. A third mutant allele containing a missense mutation has also been reported to cause CMRD. All three of these alleles display recessive inheritance, suggesting that they loss-of-function mutations cause the symptoms of CMRD.

Physiology
During digestion, fats, or triglycerides(TGs), are enzymatically catabolized by lipases into two fatty acids and a monoglyceride molecule. Those components are then transported across the enterocyte membrane as micelles and reformed into triglycerides once across the membrane.Once transported to the ER the triglycerides are incorporated into pre-chylomicrons which are made up of TGs, cholesterol, and phospholipids. The pre-chylomicrons are then packaged into PCTV in order to be transported to the Golgi apparatus for additional maturation prior to exocytosis into the lymphatic system.  From the lymphatic system, they enter general circulation, where they are produced in various forms that can be absorbed by bodily tissues and metabolized or stored by adipose tissue.
Before the PCTV leaves the ER, it is incorporated into a COPII coatomer of five proteins.
The PCTV undergoes a similar mechanism for budding as normal COPII transport vesicles. Though PCTV does not require COPII coatomer proteins for budding from the ER, association with the coatomer is necessary for docking and fusion with the cis-golgi network. In chylomicron retention disease, the PCTV vesicles are competent for budding from the ER membrane but are defective for fusion with the cis-golgi body.
Sar1B is a GTPase and one of the five proteins of the COPll coatomer. A mutation in the sar1B gene and subsequently the sar1B protein are the common genetic origins of chylomicron retention disorder. Without the fully functional sar1B protein, the COPll coatomer proteins engulf pre-chylomicrons exiting the ER but are unable to disassemble upon arrival at the cis-Golgi, preventing membrane fusion with this organelle.

Signs and symptoms
Physical symptoms of CMRD involving development and function of the gastrointestinal tract and nervous system typically manifest  between  infancy and adolescence. The symptoms of CmRD are similar to the physical symptoms  of malnutrition, as the disease arises due to the poor absorption of lipids and fat-soluble nutrients such as vitamin E. For this reason, the disease is likely to be under-diagnosed by physicians . Fat-soluble nutrients are essential for growth, development, and normal bodily function. Vitamin E deficiency is especially serious, as the vitamin is necessary for proper neurological function and development. Without Vitamin E, neurons cannot operate correctly and signals from the brain are weakened. This leads to reduced muscle development and reduced muscle contraction.
Symptoms that manifest in the GI tract are likely to be a consequence of both reduced absorption of fats and physiological stress imposed on enterocytes that can not shuttle fats into circulation . Additional symptoms that occur throughout the body can be attributed to the lack of sufficient lipid sources.
Chronic Malabsorptive Diarrhea- Diarrhea that results from the poor absorption of fats
Steatorrhea- Abnormal stools, often foul smelling, due to the increased presence of undigested fats
Vomiting
Vitamin E Deficiency- Low levels of Vitamin E due to the malabsorption of fats in the diet, causes poor brain, muscle, and eye development.
Cardiomyopathy- A class of disease that affects heart muscle, causing shortness of breath, tiredness, and swelling of the legs
Slowed Growth
Failure to Thrive- Insufficient weight gain, or drastic levels of weight loss in children
Hypocholesterolemia- Low blood cholesterol levels
Hepatic Steatosis (Fatty Liver)- Excessive fat buildup in the liver, a result of the abnormal lipid panels of CMRD patients
Hyporeflexia- Absent or low levels of muscle reflexes
Amyotrophy- Muscle tissue “wasting,” the loss of muscle tissue

Diagnosis
There is no medical consensus on methodology of diagnosis for CMRD itself. There are, however, protocols used to diagnose the family of genetic disorders to which CMRD belongs. Assessment of hypobetalipoproteinemia relies chiefly on blood lipid analysis following a 12-hr fasting period.  Lipids analyzed are LDL (low-density lipoproteins), triglyceride, and apolipoprotein B levels. A patient could be diagnosed with CMRD should they lack sufficient apolipoprotein B levels in the blood. Furthermore, a minimally invasive endoscopic procedure can be used to examine the bowel. A pale intestine can also be indicative of CMRD.Because patient outcomes rely on early diagnosis, it is recommended that candidates for the disorder should receive lipid panel testing prior to 6 months of age. In patients with only CMRD, lipid panels are expected to display normal triglyceride levels, but LDL and HDL levels may >50% below normal range. The test should also reveal low levels of Vitamin E and heightened levels of creatine kinase in the blood.

Prognosis
As of March 2020, only 50 cases of CMRD have been documented in the medical literature. This small number speaks to the rarity of the disease as well as the lack of thorough research and documentation. As a result, the full course of the disease, life expectancy, and mortality are also poorly documented.
Clinical manifestation of  CMRD symptoms begin during infancy and early childhood but may go undetected due to the non-specific symptoms associated with the disease. Many of these symptoms can be attributed to malnutrition and nonspecific postnatal diarrhea, confounding early diagnosis. Careful regulation of diet and nutrition are required for management of CMRD since the disease results from the poor absorption of nutrients from food.

Treatment
It is recommended that patients with CMRD follow a strict low-fat diet in addition to fat-soluble vitamin supplementation </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 Denture-related stomatitis and can you explain it in depth? [/INST] Denture-related stomatitis is a common condition where mild inflammation and redness of the oral mucous membrane occurs beneath a denture. In about 90% of cases, Candida species are involved, which are normally a harmless component of the oral microbiota in many people. Denture-related stomatitis is the most common form of oral candidiasis (a yeast infection of the mouth). It is more common in elderly people, and in those who wear a complete upper denture (a denture which replaces all the upper teeth, worn by someone with no natural teeth in their upper jaw). Denture-related stomatitis is more likely to develop when the denture is left constantly in the mouth, rather than removing it during sleep, and when the denture is not cleaned regularly.

Signs and symptoms
Despite the alternative name for this condition, "denture sore mouth", it is usually painless and asymptomatic. The appearance of the involved mucosa is erythematous (red) and edematous (swollen), sometimes
with petechial hemorrhage (pin-points of bleeding). This usually occurs beneath an upper denture. Sometimes angular cheilitis can coexist, which is inflammation of the corners of the mouth, also often associated with Candida albicans. Stomatitis rarely develops under a lower denture. The affected mucosa is often sharply defined, in the shape of the covering denture.

Causes
The major risk factor for the development of this condition is wearing an upper complete denture, particularly when it is not removed during sleep and cleaned regularly. Older dentures are more likely to be involved. Other factors include xerostomia (dry mouth), diabetes or a high carbohydrate diet. Human immunodeficiency virus (HIV) can rarely be an underlying factor.Wearing dental appliances such as dentures alters the oral microbiota. A microbial plaque composed of bacteria and/or yeasts forms on the fitting surface of the denture (the surface which rests against the palate) and on the mucosa which is covered. Over time, this plaque may be colonized by Candida species. The local environment under a denture is more acidic and less exposed to the cleansing action of saliva, which favors high Candida enzymatic activity and may cause inflammation in the mucosa. C. albicans is the most commonly isolated organism, but occasionally bacteria are implicated.There is controversy as to whether this condition represents a true infection by C. albicans or just a reaction to the various micro-organisms present underneath a denture.  It has been reported that often the surface of the denture shows positive culture for Candida but biopsies of the mucosa rarely show hyphae invading epithelium. Similarly, microbiologic swabs of the involved mucosa show a much less heavy colonization than the surface of the denture. This has led some to conclude that the defining feature of a true infection is absent in denture-related stomatitis.Poorly fitting dentures may cause pressure on the mucosa and mechanical irritation may create a similar clinical appearance, but this is uncommon. An orthodontic appliance may uncommonly produce a similar result. However, mucosal trauma is thought increase the ability of C. albicans to invade the tissues.Aside from infection and mechanical trauma, inflammatory reactions of the mucosa beneath a denture can also result from irritation or allergy (allergic contact stomatitis) caused by the materials in the denture itself (acrylic, cobalt, chromium), or in response to substances within denture adhesives. Incomplete curing of the acrylic resin (the prosthetic material) may also be an involved factor.

Diagnosis
The diagnosis is usually made based upon the clinical appearance, and swabs can be taken of the surface of the denture. Investigations to rule out possibility of diabetes may be indicated. Tissue biopsy is not usually indicated, but if taken shows histologic evidence of proliferative or degenerative responses and reduced keratinization and epithelial atrophy.

Classification
The Newton classification divides denture-related stomatitis into three types based on severity. Type one may represent an early stage of the condition, whilst type two is the most common and type three is uncommon.
Type 1 - Localized inflammation or pinpoint hyperemia
Type 2 - More diffuse erythema (redness) involving part or all of the mucosa which is covered by the denture
Type 3 - Inflammatory nodular/papillary hyperplasia usually on the central hard palate and the alveolar ridge

Treatment
The most important aspect of treatment is improving denture hygiene, i.e. removing the denture at night, cleaning and disinfecting it, and storing it overnight in an antiseptic solution. This is important as the denture is usually infected with C. albicans which will cause re-infection if it is not removed. Substances which are used include solutions of alkaline peroxides, alkaline hypochlorites (e.g. hypochlorite, which may over time corrode metal components of dental appliances), acids (e.g. benzoic acid), yeast lytic enzymes and proteolytic enzymes (e.g. alcalase protease) </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 Bipolar II disorder and can you explain it in depth? [/INST] Bipolar II disorder (BP-II) is a mood disorder on the bipolar spectrum, characterized by at least one episode of hypomania and at least one episode of major depression. Diagnosis for BP-II requires that the individual must never have experienced a full manic episode. Otherwise, one manic episode meets the criteria for bipolar I disorder (BP-I).Hypomania is a sustained state of elevated or irritable mood that is less severe than mania yet may still significantly affect the quality of life and result in permanent consequences including reckless spending, damaged relationships and poor judgment.: 1651  Unlike mania, hypomania is not associated with psychosis. The hypomanic episodes associated with BP-II must last for at least four days.Commonly, depressive episodes are more frequent and more intense than hypomanic episodes. Additionally, when compared to BP-I, type II presents more frequent depressive episodes and shorter intervals of well-being. The course of BP-II is more chronic and consists of more frequent cycling than the course of BP-I. Finally, BP-II is associated with a greater risk of suicidal thoughts and behaviors than BP-I or unipolar depression. Although BP-II is commonly perceived to be a milder form of type I, this is not the case. Types I and II present equally severe burdens.BP-II is notoriously difficult to diagnose. Patients usually seek help when they are in a depressed state, or when their hypomanic symptoms manifest themselves in unwanted effects, such as high levels of anxiety, or the seeming inability to focus on tasks. Because many of the symptoms of hypomania are often mistaken for high-functioning behavior or simply attributed to personality, patients are typically not aware of their hypomanic symptoms. In addition, many people with BP-II have periods of normal affect. As a result, when patients seek help, they are very often unable to provide their doctor with all the information needed for an accurate assessment; these individuals are often misdiagnosed with unipolar depression. BP-II is more common than BP-I, while BP-II and major depressive disorder have about the same rate of diagnosis. Of all individuals initially diagnosed with major depressive disorder, between 40% and 50% will later be diagnosed with either BP-I or BP-II. Substance use disorders (which have high co-morbidity with BP-II) and periods of mixed depression may also make it more difficult to accurately identify BP-II. Despite the difficulties, it is important that BP-II individuals be correctly assessed so that they can receive the proper treatment. Antidepressant use, in the absence of mood stabilizers, is correlated with worsening BP-II symptoms.

Causes
Multiple factors contribute to the development of bipolar spectrum disorders, although there have been very few studies conducted to examine the possible causes of BP-II specifically. While no identifiable single dysfunctions in specific neurotransmitters have been found, preliminary data has shown that calcium signal transmission, the glutamatergic system, and hormonal regulation play a role in the pathophysiology of the disease. The cause of Bipolar disorder can be attributed to misfiring neurotransmitters that overstimulate the amygdala, which in turn causes the prefrontal cortex to stop working properly. The bipolar patient becomes overwhelmed with emotional stimulation with no way of understanding it, which can trigger mania and exacerbate the effects of depression.

Signs and symptoms
Bipolar disorder is characterized by marked swings in mood, activity, and behavior. BP-II is characterized by periods of hypomania, which may occur before, after, or independently of a depressive episode.

Hypomania
Hypomania is the signature characteristic of BP-II, defined by an experience of elevated mood. A patients mood is typically cheerful, enthusiastic, euphoric, or irritable. In addition, they can present with symptoms of inflated self-esteem or grandiosity, decreased need for sleep, talkativeness or pressured speech, flight of ideas or rapid cycling of thoughts, distractibility, increased goal-directed activity, psychomotor agitation, and/or excessive involvement in activities that have a high potential for painful consequences (engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments.)Hypomania is distinct from mania. During a typical hypomanic episode, patients may present as upbeat, may show signs of poor judgment or display signs of increased energy despite lack of sleep, but do not meet the full criteria for an acute manic episode. Patients may display elevated confidence, but do not express delusional thoughts as in mania. They can experience increase in goal-directed activity and creativity, but do not reach the severity of aimlessness and disorganization. Speech may be rapid, but interruptible. Patients with hypomania never present with psychotic symptoms and do not reach the severity to require psychiatric hospitalization.For these reasons, hypomania commonly goes unnoticed. Individuals often will only seek treatment during a depressive episode, and their history of hypomania may go undiagnosed. Although hypomania may increase functioning, episodes require treatment as they may indicate increasing instability and can precipitate a depressive episode.

Depressive episodes
It is during depressive episodes that BP-II patients often seek help. Symptoms may be syndromal or subsyndromal.Depressive episodes in BP-II can present similarly to those experienced in unipolar depressive disorders. Patients characteristically experience a depressed mood and may describe themselves as feeling sad, gloomy, down in the dumps, hopeless, or for most of the day, nearly every day. In children, this can present with an irritable mood. Most patients report significant fatigue, loss of energy, or tiredness. Patients or their family members may note diminished interest in usual activities such as sex, hobbies, or daily routines. Many patients report a change in appetite along with associated weight change. Sleep disturbances may be present, and can manifest as problems falling or staying asleep, frequent awakenings, excessive sleep, or difficulties getting up in the morning. Around half of depressed patients develop changes in psychomotor activity, described as slowness in thinking, speaking, or movement. Conversely, they may also present with agitation, with inability to sit still or wringing their hands. Changes in posture, speech, facial expression, and grooming can be observed. Other signs and symptoms include changes in posture and facial expression, slowed speech, poor hygiene, unkempt appearance, feelings of guilt, shame, or helplessness, diminished ability to concentrate, nihilistic thoughts, and suicidal ideation.Many experts in the field have attempted to find reliable differences between BP-I depressive episodes and episodes of major depressive disorder, but the data is inconsistent. However, some clinicians report that patients who came in with a depressive episode, but were later diagnosed as having bipolar disorder often presented with hypersomnia, increased appetite, psychomotor retardation, and a history of antidepressant-induced hypomania. Evidence also suggests that BP-II is strongly associated with atypical depression.

Mood episodes with mixed features
A mixed episode is defined by the presence of a hypomanic or depressive episode that is accompanied by symptoms of the opposite polarity. This is commonly referred to as a mood episode with mixed features (e.g. depression with mixed features or hypomania with mixed features), but can also be referred to as mixed episodes or mixed states. For example, a patient with depression with mixed features may have a depressed mood, but has simultaneous symptoms of rapid speech, increased energy, and flight of ideas. Conversely, a patient with hypomania with mixed features will present with the full criteria for a hypomanic episode, but with concurrent symptoms of decreased appetite, loss of interest, and low energy.Episodes with mixed features can last up to several months. They occur more frequently in patients with an earlier onset of bipolar disorder, are associated with higher frequency of episodes, and are associated with a greater risk of substance use, anxiety disorders, and suicidality. In addition, they are associated with increased treatment resistance compared to non-mixed episodes.

Relapse
Bipolar disorder is often a lifelong condition, and patients should be followed up regularly for relapse prevention. Although BP-II is thought to be less severe than BP-I in regard to symptom intensity, BP-II is associated with higher frequencies of rapid cycling and depressive episodes. In the case of a relapse, patients may experience new onset sleep disturbance, racing thoughts and/or speech, anxiety, irritability, and increase in emotional intensity. Family and/or friends may notice that patients are arguing more frequently with them, spending more money than usual, are increasing their binging on food, drugs, or alcohol, and may suddenly start taking on many projects at once. These symptoms often occur and are considered early warning signs.Psychosocial factors in a persons life can trigger a relapse in patients with BP-II. These include stressful life events, criticism from peers or relatives, and a disrupted circadian rhythm. In addition, the addition of antidepressant medications can trigger a hypomanic episode.

Comorbid conditions
Comorbid conditions are extremely common in individuals with BP-II. In fact, individuals are twice as likely to present a comorbid disorder than not. These include anxiety, eating, personality (cluster B), and substance use disorders. For BP-II, the most conservative estimate of lifetime prevalence of alcohol or other substance use disorders is 20%. In patients with comorbid substance use disorder and BP-II, episodes have a longer duration and treatment compliance decreases. Preliminary studies suggest that comorbid substance use is also linked to increased risk of suicidality.

Diagnosis
BP-II is diagnosed according to the criteria established in the American Psychiatric Associations Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). In addition, alternative diagnostic criteria is established in the World Health Organizations International Classification of Diseases-10th Revision (ICD-10). The diagnostic criteria are established from self-reported experiences from patients or their family members, the psychiatric assessment, and the mental status examination. In addition, Screening instruments like the Mood Disorders Questionnaire are helpful tools in determining a patients status on the bipolar spectrum. In addition, certain features have been shown to increase the chances that depressed patients have a bipolar disorder, including atypical symptoms of depression like hypersomnia and hyperphagia, a family history of bipolar disorder, medication-induced hypomania, recurrent or psychotic depression, antidepressant refractory depression, and early or postpartum depression.

DSM-5 criteria
According to the DSM-5, a patient diagnosed with BP-II will have experienced at least one hypomanic episode, at least one major depressive episodes, and no manic episode. Furthermore, the occurrence of the mood episodes are not better explained by schizoaffective disorder, schizophrenia, delusional disorder, or other specified or unspecified schizophrenia spectrum and other psychotic disorder. The final criteria that must be met is that the mood episodes cause clinically significant distress or impairment in social, occupational, or other important areas of functioning (from the depressive symptoms or the unpredictability of cycling between periods of depression and hypomania).A hypomanic episode is established if a patients symptoms last for most of the day each day for at least four days. Furthermore, three or more of the following symptoms must be present: Inflated sense of self-esteem or grandiose thoughts, feeling well rested despite getting low amounts of sleep (3 hours), talkativeness, racing thoughts, distractibility, and increase in goal-directed activity or psychomotor agitation, or excessive involvement in activities with high risk of painful consequences. Per DSM-5 criteria, a major depressive episode consists of the presence of a depressed mood or loss of interest/pleasure in activities (anhedonia). In addition to the former symptoms, five out of the nine following symptoms must occur for more than two weeks (to the extent in which it impairs functioning): weight loss/gain, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, feelings of worthlessness/inappropriate guilt, decreased concentration, or thoughts of death/suicide.Specifiers:

With current or most recent episode hypomanic or depressed
With partial remission or full remission
With mild, moderate, or severe severity
With anxious distress
With catatonic features
With mood congruent psychotic features
With peripartum onset
With seasonal pattern (applies only to the pattern of major depressive episodes)
With rapid cycling.

ICD-11
According to the ICD-11, a BP-II patient will have experienced episodic experiences of one or more hypomaniac episodes and one or more major depressive episodes, and no history of a manic episode or mixed episode. These symptoms cannot be explained by other diagnoses such as

Cyclothymia
ADHD
Oppositional Defiant Disorder
Schizophrenia and other primary psychotic disorders
Substance-Use Disorder
Personality Disorders
Other Mental illness
Physical issues such as a brain tumorThe specifiers are the same as the DSM-5 with the exception of catatonic features and if symptoms have occurred with or without psychosis about 6 weeks after childbirth

Differential diagnoses
The signs and symptoms of BP-II may overlap significantly with those of other conditions. Thus, a comprehensive history, medication review, and laboratory work are key to diagnosing BP-II and differentiating it from other conditions. The differential diagnosis of BP-II is as follows: unipolar major depression, borderline personality disorder, posttraumatic stress disorder, substance use disorders, and attention deficit hyperactivity disorder.: 1653–7  In clinical practice, the difficulty of diagnosing BP-II depends on the accurate detection of hypomania, which is frequently dismissed by patients. Patients can present with increased productivity and energy with the absence of signs of instability or disturbance. As such, there is a risk that BP-II is misdiagnosed as generalized anxiety disorder or unipolar major depression. An accurate evaluation of differential diagnoses are crucial, as they guide treatment and prognostic implications.Major differences between BP-I and BP-II have been identified in their clinical features, comorbidity rates and family histories. During depressive episodes, BP-II patients tend to show higher rates of psychomotor agitation, guilt, shame, suicidal ideation, and suicide attempts. BP-II patients have shown higher lifetime comorbidity rates of phobias, anxiety disorders, substance use, and eating disorders. In addition, there is a higher correlation between BP-II patients and family history of psychiatric illness, including major depression and substance-related disorders compared to BP-I. The occurrence rate of psychiatric illness in first degree relatives of BP-II patients was 26.5%, versus 15.4% in BP-I patients.

Management
Although BP-II is a prevalent condition associated with morbidity and mortality, there has been an absence of robust clinical trials and systematic reviews that investigate the efficacy of pharmacologic treatments for the hypomanic and depressive phases of BP-II. Thus, the current treatment guidelines for the symptoms of BP-II are derived and extrapolated from the treatment guidelines in BP-I, along with limited randomized controlled trials published in the literature.: 1697 The treatment of BP-II consists of the following: treatment of hypomania, treatment of major depression, and maintenance therapy for the prevention of relapse of hypomania or depression. As BP-II is a chronic condition, the goal of treatment is to achieve remission of symptoms and prevention of self-harm in patients. Treatment modalities of BP-II include medication-based pharmacotherapy, along with various forms of psychotherapy.

Medications
The most common pharmacologic agents utilized in the treatment of BP-II includes mood stabilizers, antipsychotics, and antidepressants.

Mood stabilizers
Mood stabilizers used in the treatment of hypomanic and depressive episodes of BP-II include lithium, and the anticonvulsant medications valproate, carbamazepine, lamotrigine, and topiramate.There is strong evidence that lithium is effective in treating both the depressive and hypomanic symptoms in BP-II, along with the reduction of hypomanic switch in patients treated with antidepressants. Furthermore, lithium is the only mood stabilizer to demonstrate a decrease in suicide and self-harm in patients with mood disorders. Due to lithiums narrow therapeutic index, lithium levels must be monitored regularly for prevention of lithium toxicity.
There is also evidence that the anticonvulsants valproate, lamotrigine, carbamazepine, and topiramate are effective in the reduction of symptoms of hypomanic and depressive episodes of bipolar disorder. Potential mechanisms contributing to these effects include a decrease in brain excitation due to blockage of low-voltage sodium-gated channels, decrease in glutamate and excitatory amino acids, and potentiation of levels of GABA. There is evidence that lamotrigine decreases the risk of relapse in rapid-cycling BP-II. It is more effective in BP-II than BP-I, suggesting that lamotrigine is more effective for the treatment of depressive rather than manic episodes. Doses ranging from 100 to 200 mg have been reported to have the most efficacy, while experimental doses of 400 mg have rendered little response. A large, multicenter trial comparing carbamazepine and lithium over two and a half years found that carbamazepine was superior in terms of preventing future episodes of BP-II, although lithium was superior in individuals with BP-I. There is also some evidence for the use of valproate and topiramate, although the results for the use of gabapentin have been disappointing.

Antipsychotics
Antipsychotics are utilized as a second line option for hypomanic episodes, typically indicated patients who do not respond to mood stabilizers. However, quetiapine is the only antipsychotic that has demonstrated efficacy in multiple meta-analyses of Randomized controlled trials for treating acute BP-II depression, and is a first-line option for patients with BP-II depression.: 1697  Other antipsychotics that are used to treat BP-II include lurasidone, olanzapine, cariprazine, aripiprazole, asenapine, paliperidone, risperidone, ziprasidone, haloperidol, and chlorpromazine. As a class, the first generation antipsychotics are associated with movement disorders, along with anticholinergic side effects compared with second generation antipsychotics.

Antidepressants
There is evidence to support the use of SSRI and SNRI antidepressants in BP-II, but the use of these treatments are controversial. Potential risks of antidepressant pharmacotherapy in patients with bipolar disorder include increased mood cycling, development of rapid cycling, dysphoria, and switch to hypomania. In addition, the evidence for their efficacy in bipolar depression is mixed. Thus, in most cases, antidepressant monotherapy in patients with BP-II is not recommended. However, antidepressants may provide benefit some patients when used in addition to mood stabilizers and antipsychotics, as these drugs reduce the risk of manic/hypomanic switching. However, the risk still exists, and should be used with caution.

Non-pharmaceutical therapies
Although medication therapy is the standard of care for treatment of both BP-I and BP-II, additional non-pharmaceutical therapies can also help those with the illness. Benefits include prevention of relapse and improved maintenance medication adherence. These include psychotherapy (e.g. cognitive behavioral therapy, psychodynamic therapy, psychoanalysis, interpersonal therapy, behavioral therapy, cognitive therapy, and family-focused therapy), social rhythm therapy, art therapy, music therapy, psychoeducation, mindfulness, and light therapy. Meta-analyses in the literature has shown that psychotherapy plus pharmacotherapy was associated with a lower relapse rate compared with patients treated with pharmacotherapy alone. However, relapse can still occur, despite continued medication and therapy. People with bipolar disorder may develop dissociation to match each mood they experience. For some, this is done intentionally, as a means by which to escape trauma or pain from a depressive period, or simply to better organize ones life by setting boundaries for ones perceptions and behaviors.

Prognosis
There is evidence to suggest that BP-II has a more chronic course of illness than BP-I. This constant and pervasive course of the illness leads to an increased risk in suicide and more hypomanic and major depressive episodes with shorter periods between episodes than BP-I patients experience. The natural course of BP-II, when left untreated, leads to patients spending the majority of their lives with some symptoms, primarily stemming from depression. Their recurrent depression results in personal distress and disability.This disability can present itself in the form of psychosocial impairment, which has been suggested to be worse in BP-II patients than in BP-I patients. Another facet of this illness that is associated with a poorer prognosis is rapid cycling, which denotes the occurrence of four or more major Depressive, Hypomanic, and/or mixed episodes in a 12-month period. Rapid cycling is quite common in those with BP-II, much more so in women than in men (70% vs. 40%), and without treatment leads to added sources of disability and an increased risk of suicide. Women are more prone to rapid cycling between hypomanic episodes and depressive episodes. To improve a patients prognosis, long-term therapy is most favorably recommended for controlling symptoms, maintaining remission and preventing relapses. With treatment, patients have been shown to present a decreased risk of suicide (especially when treated with lithium) and a reduction of frequency and severity of their episodes, which in turn moves them toward a stable life and reduces the time they spend ill. To maintain their state of balance, therapy is often continued indefinitely, as around 50% of the patients who discontinue it relapse quickly and experience either full-blown episodes or sub-syndromal symptoms that bring significant functional impairments.

Functioning
The deficits in functioning associated with BP-II stem mostly from the recurrent depression that BP-II patients experience. Depressive symptoms are much more disabling than hypomanic symptoms and are potentially as, or more disabling than mania symptoms. Functional impairment has been shown to be directly linked with increasing percentages of depressive symptoms, and because sub-syndromal symptoms are more common—and frequent—in BP-II, they have been implicated heavily as a major cause of psychosocial disability. There is evidence that shows the mild depressive symptoms, or even sub-syndromal symptoms, are responsible for the non-recovery of social functioning, which furthers the idea that residual depressive symptoms are detrimental for functional recovery in patients being treated for BP-II. It has been suggested that symptom interference in relation to social and interpersonal relationships in BP-II is worse than symptom interference in other chronic medical illnesses such as cancer. This social impairment can last for years, even after treatment that has resulted in a resolution of mood symptoms.The factors related to this persistent social impairment are residual depressive symptoms, limited illness insight (a very common occurrence in patients with BP-II), and impaired executive functioning. Impaired ability in executive functions is directly tied to poor psychosocial functioning, a common side-effect in patients with BP-II.The impact on a patients psychosocial functioning stems from the depressive symptoms (more common in BP-II than BP-I). An increase in these symptoms severity seems to correlate with a significant increase in psychosocial disability. Psychosocial disability can present itself in poor semantic memory, which in turn affects other cognitive domains like verbal memory and (as mentioned earlier) executive functioning leading to a direct and persisting impact on psychosocial functioning.An abnormal semantic memory organization can manipulate thoughts and lead to the formation of delusions and possibly affect speech and communication problems, which can lead to interpersonal issues. BP-II patients have also been shown to present worse cognitive functioning than those patients with BP-I, though they demonstrate about the same disability when it comes to occupational functioning, interpersonal relationships, and autonomy. This disruption in cognitive functioning takes a toll on their ability to function in the workplace, which leads to high rates of work loss in BP-II patient populations. After treatment and while in remission, BP-II patients tend to report a good psychosocial functioning but they still score less than patients without the disorder. These lasting impacts further suggest that a prolonged period of untreated BP-II can lead to permanent adverse effects on functioning.

Recovery and recurrence
BP-II has a chronic relapsing nature. It has been suggested that BP-II patients have a higher degree of relapse than BP-I patients. Generally, within four years of an episode, around 60% of patients will relapse into another episode. Some patients are symptomatic half the time, either with full on episodes or symptoms that fall just below the threshold of an episode.Because of the nature of the illness, long-term therapy is the best option and aims to not only control the symptoms but to maintain sustained remission and prevent relapses from occurring. Even with treatment, patients do not always regain full functioning, especially in the social realm. There is a very clear gap between symptomatic recovery and full functional recovery for both BP-I and BP-II patients. As such, and because those with BP-II spend more time with depressive symptoms that do not quite qualify as a major depressive episode, the best chance for recovery is to have therapeutic interventions that focus on the residual depressive symptoms and to aim for improvement in psychosocial and cognitive functioning. Even with treatment, a certain amount of responsibility is placed in the patients hands; they have to be able to assume responsibility for their illness by accepting their diagnosis, taking the required medication, and seeking help when needed to do well in the future.Treatment often lasts after remission is achieved, and the treatment that worked is continued during the continuation phase (lasting anywhere from 6–12 months) and maintenance can last 1–2 years or, in some cases, indefinitely. One of the treatments of choice is Lithium, which has been shown to be very beneficial in reducing the frequency and severity of depressive episodes. Lithium prevents mood relapse and works especially well in BP-II patients who experience rapid-cycling. Almost all BP-II patients who take lithium have a decrease in the amount of time they spend ill and a decrease in mood episodes.Along with medication, other forms of therapy have been shown to be beneficial for BP-II patients. A treatment called a "well-being plan" serves several purposes: it informs the patients, protects them from future episodes, teaches them to add value to their life, and works toward building a strong sense of self to fend off depression and reduce the desire to succumb to the seductive hypomanic highs. The plan has to aim high. Otherwise, patients will relapse into depression. A large part of this plan involves the patient being very aware of warning signs and stress triggers so that they take an active role in their recovery and prevention of relapse.

Mortality
Several studies have shown that the risk of suicide is higher in patients who have BP-II than those with BP-I, and especially higher than patients with major depressive disorder.In results of a summary of several lifetime study experiments, it was found that 24% of BP-II patients experienced suicidal ideation or suicide attempts compared to 17% in BP-I patients and 12% in major depressive patients. Bipolar disorders, in general, are the third leading cause of death in 15- to 24-year-olds. BP-II patients were also found to employ more lethal means and have more complete suicides overall.BP-II patients have several risk factors that increase their risk of suicide. The illness is very recurrent and results in severe disabilities, interpersonal relationship problems, barriers to academic, financial, and vocational goals, and a loss of social standing in their community, all of which increase the likelihood of suicide. Mixed symptoms and rapid-cycling, both very common in BP-II, are also associated with an increased risk of suicide. The tendency for BP-II to be misdiagnosed and treated ineffectively, or not at all in some cases, leads to an increased risk.As a result of the high suicide risk for this group, reducing the risk and preventing attempts remains a main part of the treatment; a combination of self-monitoring, close supervision by a therapist, and faithful adherence to their medication regimen will help to reduce the risk and prevent the likelihood of suicide.Suicide is a common endpoint for many patients with severe psychiatric illness. The mood disorders (depression and bipolar) are by far the most common psychiatric conditions associated with suicide. At least 25% to 50% of patients with bipolar disorder also attempt suicide at least once. Aside from lithium—which is the most demonstrably effective treatment against suicide—little is known about contributions of specific mood-altering treatments to minimizing mortality rates in persons with either major mood disorders or bipolar depression specifically. Suicide is usually a manifestation of severe psychiatric distress that is often associated with a diagnosable and treatable form of depression or other mental illness. In a clinical setting, an assessment of suicidal risk must precede any attempt to treat psychiatric illness.

Epidemiology
The global estimated lifetime prevalence of bipolar disorder among adults range from 1 to 3 percent. The annual incidence is estimated to vary from 0.3 to 1.2 percent worldwide. According to the World Mental Health Survey Initiative, the lifetime prevalence of BP-II was found to be 0.4%, with a 12-month prevalence of 0.3%. Other meta-analyses have found lifetime prevalence of BP-II up to 1.57%. In the United States, the estimated lifetime prevalence of BP-II was found to be 1.1%, with a 12-month prevalence of 0.8%. The mean age of onset for BP-II was 20 years. Thus far, there have been no studies that have conclusively demonstrated that an unequal distribution of bipolar disorders across sex and ethnicity exists.It must be noted that a vast majority of studies and meta-analysis do not differentiate between BP-I and BP-II, and current epidemiology data may not accurately describe true prevalence and incidence. In addition, BP-II is underdiagnosed in practice, and it is easy to miss milder forms of the condition.

History
In 19th century psychiatry, mania covered a broad range of intensity, and hypomania was equated by some to concepts of partial insanity or monomania. A more specific usage was advanced by the German neuro-psychiatrist Emanuel Ernst Mendel in 1881, who wrote "I recommend (taking under consideration the word used by Hippocrates) to name those types of mania that show a less severe phenomenological picture, hypomania". Narrower operational definitions of hypomania were developed from the 1960s/1970s.
The first diagnostic distinction to be made between manic-depression involving mania and involving hypomania came from Carl Gustav Jung in 1903. In his paper, Jung introduced the non-psychotic version of the illness with the statement, "I would like to publish a number of cases whose peculiarity consists in chronic hypomanic behavior" where "it is not a question of real mania at all but of a hypomanic state which cannot be regarded as psychotic." Jung illustrated the hypomanic variation with five case histories, each involving hypomanic behavior, occasional bouts of depression, and mixed mood states, which involved personal and interpersonal upheaval for each patient.In 1975, Jungs original distinction between mania and hypomania gained support. Fieve and Dunner published an article recognizing that only individuals in a manic state require hospitalization. It was proposed that the presentation of either the one state or the other differentiates two distinct diseases; the proposition was initially met with skepticism. However, studies since confirm that BP-II is a phenomenologically distinct disorder.Empirical evidence, combined with treatment considerations, led the DSM-IV Mood Disorders Work Group to add BP-II as its own entity in the 1994 publication. Only one other mood disorder was added to this edition, indicating the conservative nature of the DSM-IV work group. In May 2013, the DSM-5 was released. Two revisions to the existing BP-II criteria are anticipated. The first expected change will reduce the required duration of a hypomanic state from four to two days </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 Diphtheria and can you explain it in depth? [/INST] Diphtheria is an infection caused by the bacterium Corynebacterium diphtheriae. Most infections are asymptomatic or have a mild clinical course, but in some outbreaks more than 10% of those diagnosed with the disease may die.  Signs and symptoms may vary from mild to severe and usually start two to five days after exposure. Symptoms often come on fairly gradually, beginning with a sore throat and fever. In severe cases, a grey or white patch develops in the throat. This can block the airway and create a barking cough as in croup. The neck may swell in part due to enlarged lymph nodes. A form of diphtheria which involves the skin, eyes or genitals also exists. Complications may include myocarditis, inflammation of nerves, kidney problems, and bleeding problems due to low levels of platelets. Myocarditis may result in an abnormal heart rate and inflammation of the nerves may result in paralysis.Diphtheria is usually spread between people by direct contact or through the air. It may also be spread by contaminated objects. Some people carry the bacterium without having symptoms, but can still spread the disease to others. The three main types of C. diphtheriae cause different severities of disease. The symptoms are due to a toxin produced by the bacterium. Diagnosis can often be made based on the appearance of the throat with confirmation by microbiological culture. Previous infection may not protect against infection.A diphtheria vaccine is effective for prevention and available in a number of formulations. Three or four doses, given along with tetanus vaccine and pertussis vaccine, are recommended during childhood. Further doses of diphtheria–tetanus vaccine are recommended every ten years. Protection can be verified by measuring the antitoxin level in the blood. Diphtheria can be prevented in those exposed as well as treated with the antibiotics erythromycin or benzylpenicillin. A tracheotomy is sometimes needed to open the airway in severe cases.In 2015, 4,500 cases were officially reported worldwide, down from nearly 100,000 in 1980. About a million cases a year are believed to have occurred before the 1980s. Diphtheria currently occurs most often in sub-Saharan Africa, India, and Indonesia. In 2015, it resulted in 2,100 deaths, down from 8,000 deaths in 1990. In areas where it is still common, children are most affected. It is rare in the developed world due to widespread vaccination but can re-emerge if vaccination rates decrease. In the United States, 57 cases were reported between 1980 and 2004. Death occurs in 5% to 10% of those diagnosed. The disease was first described in the 5th century BC by Hippocrates. The bacterium was identified in 1882 by Edwin Klebs.

Signs and symptoms
The symptoms of diphtheria usually begin two to seven days after infection. They include fever of 38 °C (100.4 °F) or above; chills; fatigue; bluish skin coloration (cyanosis); sore throat; hoarseness; cough; headache; difficulty swallowing; painful swallowing; difficulty breathing; rapid breathing; foul-smelling and bloodstained nasal discharge; and lymphadenopathy. Within two to three days, diphtheria may destroy healthy tissues in the respiratory system. The dead tissue forms a thick, gray coating that can build up in the throat or nose. This thick gray coating is called a "pseudomembrane". It can cover tissues in the nose, tonsils, voice box, and throat, making it very hard to breathe and swallow. Symptoms can also include cardiac arrhythmias, myocarditis, and cranial and peripheral nerve palsies.

Diphtheritic croup
Laryngeal diphtheria can lead to a characteristic swollen neck and throat, or "bull neck". The swollen throat is often accompanied by a serious respiratory condition, characterized by a brassy or "barking" cough, stridor, hoarseness, and difficulty breathing; and historically referred to variously as "diphtheritic croup", "true croup", or sometimes simply as "croup". Diphtheritic croup is extremely rare in countries where diphtheria vaccination is customary. As a result, the term "croup" nowadays most often refers to an unrelated viral illness that produces similar but milder respiratory symptoms.

Transmission
Human-to-human transmission of diphtheria typically occurs through the air when an infected individual coughs or sneezes. Breathing in particles released from the infected individual leads to infection. Contact with any lesions on the skin can also lead to transmission of diphtheria, but this is uncommon. Indirect infections can occur, as well. If an infected individual touches a surface or object, the bacteria can be left behind and remain viable. Also, some evidence indicates diphtheria has the potential to be zoonotic, but this has yet to be confirmed. Corynebacterium ulcerans has been found in some animals, which would suggest zoonotic potential.

Mechanism
Diphtheria toxin (DT) is produced only by C. diphtheriae infected with a certain type of bacteriophage.  Toxinogenicity is determined by phage conversion (also called lysogenic conversion); i.e, the ability of the bacterium to make DT changes as a consequence of infection by a particular phage. DT is encoded by the tox gene. Strains of corynephage are either tox+ (e.g., corynephage β) or tox- (e.g., corynephage γ). The tox gene becomes integrated into the bacterial genome. The chromosome of C. diphtheriae has two different but functionally equivalent bacterial attachment sites (attB) for integration of β prophage into the chromosome.
Diphtheria toxin precursor is a protein of molecular weight 60 kDa. Certain proteases, such as trypsin, selectively cleave DT to generate two peptide chains, amino-terminal fragment A (DT-A) and carboxyl-terminal fragment B (DT-B), which are held together by a disulfide bond. DT-B is a recognition subunit that gains entry of DT into the host cell by binding to the EGF-like domain of heparin-binding EGF-like growth factor  on the cell surface. This signals the cell to internalize the toxin within an endosome via receptor-mediated endocytosis. Inside the endosome, DT is split by a trypsin-like protease into DT-A and DT-B. The acidity of the endosome causes DT-B to create pores in the endosome membrane, thereby catalysing the release of DT-A into the cytoplasm.Fragment A inhibits the synthesis of new proteins in the affected cell by catalyzing ADP-ribosylation of elongation factor EF-2—a protein that is essential to the translation step of protein synthesis. This ADP-ribosylation involves the transfer of an ADP-ribose from NAD+ to a diphthamide (a modified histidine) residue within the EF-2 protein. Since EF-2 is needed for the moving of tRNA from the A-site to the P-site of the ribosome during protein translation, ADP-ribosylation of EF-2 prevents protein synthesis.ADP-ribosylation of EF-2 is reversed by giving high doses of nicotinamide (a form of vitamin B3), since this is one of the reactions end products, and high amounts drive the reaction in the opposite direction.

Diagnosis
The current clinical case definition of diphtheria used by the United States Centers for Disease Control and Prevention  is based on both laboratory and clinical criteria.

Laboratory criteria
Isolation of C. diphtheriae from a Gram stain or throat culture from a clinical specimen,
Histopathologic diagnosis of diphtheria by Alberts stain

Toxin demonstration
In vivo tests (guinea pig inoculation): Subcutaneous and intracutaneous tests
In vitro test: Eleks gel precipitation test, detection of tox gene by PCR, ELISA, ICA

Clinical criteria
Upper respiratory tract illness with sore throat
Low-grade fever (above 39 °C (102 °F) is rare)
An adherent, dense, grey pseudomembrane covering the posterior aspect of the pharynx: in severe cases, it can extend to cover the entire tracheobronchial tree.

Case classification
Probable: a clinically compatible case that is not laboratory-confirmed and is not epidemiologically linked to a laboratory-confirmed case
Confirmed: a clinically compatible case that is either laboratory-confirmed or epidemiologically linked to a laboratory-confirmed caseEmpirical treatment should generally be started in a patient in whom suspicion of diphtheria is high.

Prevention
Vaccination against diphtheria is commonly done in infants and delivered as a combination vaccine, such as a DPT vaccine (diphtheria, pertussis, tetanus). Pentavalent vaccines, which vaccinate against diphtheria and four other childhood diseases simultaneously, are frequently used in disease prevention programs in developing countries by organizations such as UNICEF.

Treatment
The disease may remain manageable, but in more severe cases, lymph nodes in the neck may swell, and breathing and swallowing are more difficult. People in this stage should seek immediate medical attention, as obstruction in the throat may require intubation or a tracheotomy. Abnormal cardiac rhythms can occur early in the course of the illness or weeks later and can lead to heart failure. Diphtheria can also cause paralysis in the eye, neck, throat, or respiratory muscles. Patients with severe cases are put in a hospital intensive care unit and given diphtheria antitoxin (consisting of antibodies isolated from the serum of horses that have been challenged with diphtheria toxin). Since antitoxin does not neutralize toxin that is already bound to tissues, delaying its administration increases risk of death. Therefore, the decision to administer diphtheria antitoxin is based on clinical diagnosis, and should not await laboratory confirmation.Antibiotics have not been demonstrated to affect healing of local infection in diphtheria patients treated with antitoxin. Antibiotics are used in patients or carriers to eradicate C. diphtheriae and prevent its transmission to others. The Centers for Disease Control and Prevention recommends either:

Metronidazole
Erythromycin is given (orally or by injection) for 14 days (40 mg/kg per day with a maximum of 2 g/d), or
Procaine penicillin G is given intramuscularly for 14 days (300,000 U/d for patients weighing <10 kg and 600,000 U/d for those weighing >10 kg); patients with allergies to penicillin G or erythromycin can use rifampin or clindamycin.In cases that progress beyond a throat infection, diphtheria toxin spreads through the blood and can lead to potentially life-threatening complications that affect other organs, such as the heart and kidneys. Damage to the heart caused by the toxin affects the hearts ability to pump blood or the kidneys ability to clear wastes. It can also cause nerve damage, eventually leading to paralysis. About 40% to 50% of those left untreated can die.

Epidemiology
Diphtheria is fatal in between 5% and 10% of cases. In children under five years and adults over 40 years, the fatality rate may be as much as 20%. In 2013, it resulted in 3,300 deaths, down from 8,000 deaths in 1990. Better standards of living, mass immunization, improved diagnosis, prompt treatment, and more effective health care have led to a decrease in cases worldwide.

History
In 1613, Spain experienced an epidemic of diphtheria. The year is known as El Año de los Garrotillos (The Year of Strangulations) in the history of Spain.In 1735, a diphtheria epidemic swept through New England.Before 1826, diphtheria was known by different names across the world. In England, it was known as Boulogne sore throat, as it spread from France. In 1826, Pierre Bretonneau gave the disease the name diphthérite (from Greek διφθέρα, diphthera leather) describing the appearance of pseudomembrane in the throat.In 1856, Victor Fourgeaud described an epidemic of diphtheria in California.In 1878, Queen Victorias daughter Princess Alice and her family became infected with diphtheria, causing two deaths, Princess Marie of Hesse and by Rhine and Princess Alice herself.In 1883, Edwin Klebs identified the bacterium causing diphtheria and named it Klebs–Loeffler bacterium. The club shape of this bacterium helped Edwin to differentiate it from other bacteria. Over the period of time, it was called Microsporon diphtheriticum, Bacillus diphtheriae, and Mycobacterium diphtheriae. Current nomenclature is Corynebacterium diphtheriae.Friedrich Loeffler was the first person to cultivate C. diphtheriae in 1884. He used Kochs postulates to prove association between C. diphtheriae and diphtheria. He also showed that the bacillus produces an exotoxin.

Joseph P. ODwyer introduced the ODwyer tube for laryngeal intubation in patients with an obstructed larynx in 1885. It soon replaced tracheostomy as the emergency diphtheric intubation method.In 1888, Emile Roux and Alexandre Yersin showed that a substance produced by C. diphtheriae caused symptoms of diphtheria in animals.In 1890, Shibasaburo Kitasato and Emil von Behring immunized guinea pigs with heat-treated diphtheria toxin. They also immunized goats and horses in the same way and showed that an "antitoxin" made from serum of immunized animals could cure the disease in non-immunized animals. Behring used this antitoxin (now known to consist of antibodies that neutralize the toxin produced by C. diphtheriae) for human trials in 1891, but they were unsuccessful. Successful treatment of human patients with horse-derived antitoxin began in 1894, after production and quantification of antitoxin had been optimized. Von Behring won the first Nobel Prize in medicine in 1901 for his work on diphtheria.In 1895, H. K. Mulford Company of Philadelphia started production and testing of diphtheria antitoxin in the United States. Park and Biggs described the method for producing serum from horses for use in diphtheria treatment.In 1897, Paul Ehrlich developed a standardized unit of measure for diphtheria antitoxin. This was the first ever standardization of a biological product, and played an important role in future developmental work on sera and vaccines.In 1901, 10 of 11 inoculated St. Louis children died from contaminated diphtheria antitoxin. The horse from which the antitoxin was derived died of tetanus. This incident, coupled with a tetanus outbreak in Camden, New Jersey, played an important part in initiating federal regulation of biologic products.On 7 January 1904, Ruth Cleveland died of diphtheria at the age of 12 years in Princeton, New Jersey. Ruth was the eldest daughter of former President Grover Cleveland and the former first lady Frances Folsom.In 1905, Franklin Royer, from Philadelphias Municipal Hospital, published a paper urging timely treatment for diphtheria and adequate doses of antitoxin. In 1906, Clemens Pirquet and Béla Schick described serum sickness in children receiving large quantities of horse-derived antitoxin.Between 1910 and 1911, Béla Schick developed the Schick test to detect pre-existing immunity to diphtheria in an exposed person. Only those who had not been exposed to diphtheria were vaccinated. A massive, five-year campaign was coordinated by Dr. Schick. As a part of the campaign, 85 million pieces of literature were distributed by the Metropolitan Life Insurance Company with an appeal to parents to "Save your child from diphtheria." A vaccine was developed in the next decade, and deaths began declining significantly in 1924.

In 1919, in Dallas, Texas, 10 children were killed and 60 others made seriously ill by toxic antitoxin which had passed the tests of the New York State Health Department. Mulford Company of Philadelphia (manufacturers) paid damages in every case.In the 1920s, each year an estimated 100,000 to 200,000 diphtheria cases and 13,000 to 15,000 deaths occurred in the United States. Children represented a large majority of these cases and fatalities. One of the most infamous outbreaks of diphtheria occurred in 1925, in Nome, Alaska; the "Great Race of Mercy" to deliver diphtheria antitoxin is now celebrated by the Iditarod Trail Sled Dog Race.In 1926, Alexander Thomas Glenny increased the effectiveness of diphtheria toxoid (a modified version of the toxin used for vaccination) by treating it with aluminum salts. Vaccination with toxoid was not widely used until the early 1930s. In 1939, Dr. Nora Wattie Principal Medical Officer (Maternity and Child Welfare) introduced immunisation clinics across Glasgow, and promoted mother and child health education, resulting in virtual eradication of the infection in the city.Widespread vaccination pushed cases in the United States down from 4.4 per 100,000 inhabitants in 1932 to 2.0 in 1937. In Nazi Germany, where authorities preferred treatment and isolation over vaccination (until about 1939–41), cases rose over the same period from 6.1 to 9.6 per 100,000 inhabitants.Between June 1942 and February 1943, 714 cases of diphtheria were recorded at Sham Shui Po Barracks resulting in 112 deaths because the Imperial Japanese Army did not release supplies of anti-diphtheria serum.In 1943, diphtheria outbreaks accompanied war and disruption in Europe. The 1 million cases in Europe resulted in 50,000 deaths.In Kyoto during 1948, 68 of 606 children died after diphtheria immunization due to improper manufacture of aluminum phosphate toxoid.In 1974, the World Health Organization included DPT vaccine in their Expanded Programme on Immunization for developing countries.In 1975, an outbreak of cutaneous diphtheria in Seattle, Washington, was reported .After the breakup of the former Soviet Union in 1991, vaccination rates in its constituent countries fell so low that an explosion of diphtheria cases occurred. In 1991, 2,000 cases of diphtheria occurred in the USSR. Between 1991 and 1998 as many as 200,000 cases in the Commonwealth of Independent States were reported, with 5,000 deaths. In 1994, the Russian Federation had 39,703 diphtheria cases. By contrast, in 1990, only 1,211 cases were reported.In early May 2010, a case of diphtheria was diagnosed in Port-au-Prince, Haiti, after the devastating 2010 Haiti earthquake. The 15-year-old male patient died while workers searched for antitoxin.In 2013, three children died of diphtheria in Hyderabad, India.In early June 2015, a case of diphtheria was diagnosed at Vall dHebron University Hospital in Barcelona, Spain. The 6-year-old child who died of the illness had not been previously vaccinated due to parental opposition to vaccination. It was the first case of diphtheria in the country since 1986 as reported by "El Mundo" or from 1998, as reported by WHO.In March 2016, a 3-year-old girl died of diphtheria in the University Hospital of Antwerp, Belgium.In June 2016, a 3-year-old, 5-year-old, and 7-year-old girl died of diphtheria in Kedah, Malacca, and Sabah, Malaysia.In January 2017, more than 300 cases were recorded in Venezuela.In 2017, outbreaks occurred in a Rohingya refugee camp in Bangladesh, and in children unvaccinated due to the Yemeni Civil War.In November and December 2017, an outbreak of diphtheria occurred in Indonesia with more than 600 cases found and 38 fatalities.In November 2019, two cases of diphtheria occurred in the Lothian area of Scotland. Additionally, in November 2019 an unvaccinated 8-year-old boy died of diphtheria in Athens, Greece.In July 2022, two cases of diphtheria occurred in northern New South Wales, Australia.

References
Further reading
Holmes, R .K. (2005). "Diphtheria and other corynebacterial infections".  In Kasper;  et al. (eds.). Harrisons Principles of Internal Medicine (16th ed.). New York: McGraw-Hill. ISBN 978-0-07-139140-5.
"Antitoxin dars 1735 and 1740." The William and Mary Quarterly, 3rd Ser., Vol 6, No 2. p. 338.
Shulman, S. T </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 Sentinel node and can you explain it in depth? [/INST] In computer programming, a sentinel node is a specifically designated node used with linked lists and trees as a traversal path terminator. This type of node does not hold or reference any data managed by the data structure.

Benefits
Sentinels are used as an alternative over using NULL as the path terminator in order to get one or more of the following benefits:

Marginally increased speed of operations
Increased data structure robustness (arguably)

Drawbacks
Marginally increased algorithmic complexity and code size.
If the data structure is accessed concurrently (which means that all nodes being accessed have to be protected at least for “read-only”), for a sentinel-based implementation the sentinel node has to be protected for “read-write” by a mutex. This extra mutex in quite a few use scenarios can cause severe performance degradation </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 Periapical periodontitis and can you explain it in depth? [/INST] Periapical periodontitis or apical periodontitis (AP) is an acute or chronic inflammatory lesion around the apex of a tooth root, most commonly caused by bacterial invasion of the pulp of the tooth. It is a likely outcome of untreated dental caries (tooth decay), and in such cases it can be considered a sequela in the natural history of tooth decay, irreversible pulpitis and pulpal necrosis. Other causes can include occlusal trauma due to high spots after restoration work, extrusion from the tooth of root filling material, or bacterial invasion and infection from the gums </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 Anodontia and can you explain it in depth? [/INST] Anodontia is a rare genetic disorder characterized by the congenital absence of all primary or permanent teeth. It is divided into two subsections, complete absence of teeth or only some absence of teeth. It is associated with the group of skin and nerve syndromes called the ectodermal dysplasias. Anodontia is usually part of a syndrome and seldom occurs as an isolated entity. There is usually no exact cause for anodontia. The defect results in the dental lamina obstruction during embryogenesis due to local, systemic and genetic factors.
Congenital absence of permanent teeth can present as hypodontia, usually missing one or two permanent teeth, or oligodontia that is the congenital absence of six or more teeth. Congenital absence of all wisdom teeth, or third molars, is relatively common. Anodontia is the congenital absence of teeth and can occur in some or all teeth; whereas partial anodontia (or hypodontia), involves two dentitions or only teeth of the permanent dentition (Dorlands 1998). Approximately 1% of the population has oligodontia. Many denominations are attributed to this anomaly: partial anodontia, hypodontia, oligodontia, the congenital absence, anodontia, bilateral aplasia. Anodontia being the term used in controlled vocabulary Medical Subject Headings (MeSH) from MEDLINE which was developed by the United States National Library of Medicine. The congenital absence of at least one permanent tooth is the most common dental anomaly and may contribute to masticator dysfunction, speech impairment, aesthetic problems, and malocclusion (Shapiro and Farrington 1983). Absence of lateral incisors represents a major stereotype. Individuals with this condition are perceived as socially most aggressive compared with people without anodontia (Shaw 1981). The occurrence of anodontia is less so than hypodontia which has a prevalence of 0.1-0.7% in primary teeth and 3–7.5% in permanent teeth.

Signs and symptoms
The main sign of anodontia is when a child has not developed any of their permanent teeth by the age of 12. Another sign of anodontia can include the absence of baby teeth when the baby has reached 12 to 13 months.Symptoms that are associated with anodontia include: alopecia, lack of sweat glands, cleft lip or palate, and missing fingernails. Typically, these symptoms are seen because anodontia is typically associated with ectodermal dysplasia. In the rare case that ectodermal dysplasia is not present, anodontia will be caused from an unknown genetic mutation.

Cause
Anodontia typically occurs with the presence of ectodermal dysplasia, which is a group of disorders where two or more ectodermally derived structures will have abnormal development. In the rare case that ectodermal dysplasia is not associated or present, anodontia will be caused by an unknown genetic mutation. Although no specific gene has been identified, there have been many different genes found to be associated with anodontia including EDA, EDAR, and EDARADD genes. Other genes such as MSX1, PAX9, IRF6, GREM2, AXIN2, LRP6, SMOC2, LTBP3, PITX2, and WNT10B. The WNT10A gene is considered to be the major gene involved in hypodontia and oligodontia. These genes are involved in hypodontia and oligodontia. If Anodontia is present in the maternal or paternal side, the chances of this being inherited are increased.

Mechanisms and Pathophysiology
Anodontia is a genetic disorder that is typically occurs in result of another syndrome. Different results can occur depending on which gene is inherited. It remains unclear which specific gene is the direct cause but it is known that several genes can play a role when inherited. Many genes are involved with this and other relating disorders. The main genes involved include: EDA, EDAR, and EDARADD genes. One working gene and one non-working gene are inherited, one from an affected parent and one from a non-affected parent, which then result in a 50% chance of the child inheriting the genetic disorder. Anodontia alone will not have an effect on any other body part besides teeth being missing.

Associated syndromes
Hypodontia and anodontia are frequently associated with a multitude of genetic disorders and syndromes, approximately 70. Syndromes particularly involved with ectodermal involvement are a prime circumstance for anodontia to occur, some examples of these are: Riegers, Robinsons and focal dermal hypoplasia. Three syndromes which classically have signs of anodontia are oculomandibulodyscephaly, mesoectodermal dysplasia and ectodermal dysplasia. In cases of oculomandibulodyscephaly there are no permanent teeth but there are deciduous teeth present. In mesoectodermal dysplasia the symptoms are anodontia and hypodontia. In cases of ectodermal dysplasia oligodontia is also present.
Other symptoms associated with anodontia include: Alopecia, loss of sweat glands, cleft lip or palate, or missing finger nails.

Diagnosis
Anodontia can be diagnosed when a baby does not begin to develop teeth around the age of 12 to 13 months or when a child does not develop their permanent teeth by the age of 10. The dentist can use a special X-ray, such as a panoramic image, to check if there are any teeth developing. There is also a higher risk for a child to develop anodontia if their parent has this disorder as well. In the absence of all permanent teeth, anodontia will be diagnosed. If between one to five teeth are missing, this will be diagnosed as hypodontia. In the absence of six or more teeth, this will be diagnosed as oligodontia.

Complications
The complications associated with anodontia can vary but the majority results in problems with aesthetic appearance, speaking, and masticatory function. Complications may occur with the placement of the dental implant. Although it is rare, some complications may include the screw of the implant becoming loose or sore spots.

Prevention and Treatment
Anodontia cannot be prevented due to it being a genetic disorder. Prosthetic replacement of missing teeth is possible using dental implant technology or dentures. This treatment can be successful in giving patients with anodontia a more aesthetically pleasing appearance. The use of an implant prosthesis in the lower jaw could be recommended for younger patients as it is shown to significantly improve the craniofacial growth, social development and self-image. The study associated with this evidence worked with individuals who had ectodermal dysplasia of varying age groups of up to 11, 11 to 18 and more than 18 years. It was noted that the risk of implant failure was significantly higher in patients younger than 18 years, but there is significant reason to use this methodology of treatment in those older. Overall the use of an implant-prosthesis has a considerable functional, aesthetic and psychological advantage when compared to a conventional denture, in the patients.

Prognosis
Patients diagnosed with anodontia are expected to have a normal life expectancy. Once anodontia is diagnosed, dental implants or dentures will need to worn in order to treat this disorder. There is an 88.5% to 100% chance for dental implants in patients with ectodermal dysplasia or tooth agenesis to be successful when placed after the age of 18.

Epidemiology
The prevalence of anodontia is unknown but it is a very rare disorder. Anodontia occurs in less than 2-8% of the general population in regards to permanent teeth and 0.1-0.7% in primary teeth. Gender and ethnicity do not play a role in anodontia.

Research
A recent study in 2019 by R. Constance Wiener and Christopher water looked at anodontia, hypodontia, and oligodontia in children West Virginia. There is a high prevalence of children with missing permanent teeth in West Virginia compared to the rest of the nation.  During this study, 500 panoramic images were taken of children between the ages of 6 to 11. Out of the 500 images taken, 60 children had at least one or more missing permanent teeth. The results showed that more females had one or more missing permanent teeth than males. From the 60 children who had missing permanent teeth, 15.5% were female and 8.8% were males.A case study conducted in 2016 of a 6 year old boy presented with anodontia. There was no family history of anodontia and the patient did not present any other symptoms for ectodermal dysplasia. It was observed the hypodontia was present in the maxillary arch and the only teeth present were the left primary first molar and the bilateral primary second molars. It was also observed that the buccal mucosa, palate, and floor of the mouth were considered normal. The patient proceeded with oral rehabilitation and give removable denture to wear </s>