<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Dental plaque and explain in detail? [/INST] Dental plaque is a biofilm of microorganisms (mostly bacteria, but also fungi) that grows on surfaces within the mouth. It is a sticky colorless deposit at first, but when it forms tartar, it is often brown or pale yellow. It is commonly found between the teeth, on the front of teeth, behind teeth, on chewing surfaces, along the gumline (supragingival), or below the gumline cervical margins (subgingival). Dental plaque is also known as microbial plaque, oral biofilm, dental biofilm, dental plaque biofilm or bacterial plaque biofilm. Bacterial plaque is one of the major causes for dental decay and gum disease.Progression and build-up of dental plaque can give rise to tooth decay – the localised destruction of the tissues of the tooth by acid produced from the bacterial degradation of fermentable sugar – and periodontal problems such as gingivitis and periodontitis; hence it is important to disrupt the mass of bacteria and remove it. Plaque control and removal can be achieved with correct daily or twice-daily tooth brushing and use of interdental aids such as dental floss and interdental brushes.Oral hygiene is important as dental biofilms may become acidic causing demineralization of the teeth (also known as dental caries) or harden into dental calculus (also known as tartar). Calculus cannot be removed through tooth brushing or with interdental aids, but only through professional cleaning.

Plaque formation
Dental plaque is a biofilm that attaches to tooth surfaces, restorations and prosthetic appliances (including dentures and bridges) if left undisturbed. Understanding the formation, composition and characteristics of plaque helps in its control. An acquired pellicle is a layer of saliva that is composed of mainly glycoproteins and forms shortly after cleaning of the teeth or exposure of new teeth. Bacteria then attach to the pellicle layer, form micro-colonies, and mature on the tooth, which can result in oral diseases. The following table provides a more detailed (six-step) explanation of biofilm formation:

Components of plaque
Different types of bacteria are normally present in the mouth. These bacteria, as well as leukocytes, neutrophils, macrophages, and lymphocytes, are part of the normal oral cavity and contribute to the individuals health. Approximately 80–90% of the weight of plaque is water. While 70% of the dry weight is bacteria, the remaining 30% consists of polysaccharides and glycoproteins.

Bacteria
The bulk of the microorganisms that form the biofilm are Streptococcus mutans and other anaerobes, though the precise composition varies by location in the mouth. Examples of such anaerobes include fusobacterium and actinobacteria. S. mutans and other anaerobes are the initial colonisers of the tooth surface, and play a major role in the establishment of the early biofilm community. Streptococcus mutans uses the enzyme glucansucrase to convert sucrose into a sticky, extracellular, dextran-based polysaccharide that allows the bacteria to cohere, forming plaque. (Sucrose is the only sugar that bacteria can use to form this sticky polysaccharide). These microorganisms all occur naturally in the oral cavity and are normally harmless. However, failure to remove plaque by regular tooth-brushing allows them to proliferate unchecked and thereby build up in a thick layer, which can by virtue of their ordinary metabolism cause any of various dental diseases for the host. Those microorganisms nearest the tooth surface typically obtain energy by fermenting dietary sucrose; during fermentation they begin to produce acids.
The bacterial equilibrium position varies at different stages of formation. Below is a summary of the bacteria that may be present during the phases of plaque maturation:

Early biofilm: primarily Gram-positive cocci
Older biofilm (3–4 days): increased numbers of filaments and fusiforms
4–9 days undisturbed: more complex flora with rods, filamentous forms
7–14 days: Vibrio species, spirochetes, more Gram-negative organisms

Dental plaque as a biofilm
Dental plaque is considered a biofilm adhered to the tooth surface. It is a meticulously formed microbial community, that is organised to a particular structure and function. Plaque is rich in species, given the fact that about 1000 different bacterial species have been recognised using modern techniques.A clean tooth surface would immediately be colonised by salivary pellicles, which acts as an adhesive. This allows the first bacteria (early colonisers) to attach to the tooth, then colonise and grow. After some growth of early colonisers, the biofilm becomes more compliant to other species of bacteria, known as late colonisers.

Early colonisers
mainly Streptococcus species (60–90%)
Eikenella spp.
Haemophilus spp.
Prevotella spp.
Propionibacterium spp.
Capnocytophaga spp.
Veillonella spp.

Late colonisers
Aggregatibacter actinomycetemcomitans
Prevotella intermedia
Eubacterium spp.
Treponema spp.
Porphyromonas gingivalisFusobacterium nucleatum is found between the early and late colonisers, linking them together.
Some salivary components are crucial for plaques ecosystem, such as salivary alpha-amylase which plays a role in binding and adhesion. Proline-rich proteins (PRP) and statherins are also involved in the formation of plaque.

Supragingival biofilm
Supragingival biofilm is dental plaque that forms above the gums, and is the first kind of plaque to form after the brushing of the teeth. It commonly forms in between the teeth, in the pits and grooves of the teeth and along the gums. It is made up of mostly aerobic bacteria, meaning these bacteria need oxygen to survive. If plaque remains on the tooth for a longer period of time, anaerobic bacteria begin to grow in this plaque.

Subgingival biofilm
Subgingival biofilm is plaque that is located under the gums. It occurs after the formation of the supragingival biofilm by a downward growth of the bacteria from above the gums to below. This plaque is mostly made up of anaerobic bacteria, meaning that these bacteria will only survive if there is no oxygen. As this plaque attaches in a pocket under the gums, they are not exposed to oxygen in the mouth and will therefore thrive if not removed.The extracellular matrix contains proteins, long-chain polysaccharides and lipids.
The most common reasons for ecosystem disruption are the ecological factors discussed in the environment section. The bacteria that exhibit the most fit plasticity for the change in environment dominate the given environment. Often, this leads to opportunistic pathogens which may cause dental caries and periodontal disease. Pathogenic bacteria that have the potential to cause dental caries flourish in acidic environments; those that have the potential to cause periodontal disease flourish in a slightly alkaline environment.Antibodies to the oral pathogens Campylobacter rectus, Veillonella parvula, Prevotella melaninogenica were associated with hypertension.

Environment
Unlike other parts of the body, tooth surfaces are uniquely hard and non shedding. Therefore, the warm and moist environment of the mouth and the presence of teeth, makes a good environment for growth and development of dental plaque. The main ecological factors that contribute to plaque formation are pH, saliva, temperature and redox reactions. The normal pH range of saliva is between 6 and 7 and plaque biofilm is known to flourish in a pH between 6.7 and 8.3. This indicates that the natural environment of the mouth provided by saliva is ideal for the growth of bacteria in the dental plaque. Saliva acts as a buffer, which helps to maintain the pH in the mouth between 6 and 7. In addition to acting as a buffer, saliva and gingival crevicular fluid contain primary nutrients including amino acids, proteins and glycoproteins. This feeds the bacteria involved in plaque formation. The host diet plays only a minor role in providing nutrients for the resident microflora. The normal temperature of the mouth ranges between 35 and 36 °C, and a two-degree (°C) change has been shown to drastically shift the dominant species in the plaque. Redox reactions are carried out by aerobic bacteria. This keeps the oxygen levels in the mouth at a semi-stable homeostatic condition, which allows the bacteria to survive.

Consequences of plaque build-up
Gingivitis
Gingivitis is an inflammatory lesion, mediated by host-parasite interactions that remains localised to the gingival tissue, it is a common result of plaque build-up around the gingival tissues. The bacteria found in the biofilm elicit a host response resulting in localized inflammation of the tissue. This is characterized by the cardinal signs of inflammation including a red, puffy appearance of the gums and bleeding due to brushing or flossing.
Gingivitis due to plaque can be reversible by removal of the plaque. However, if left for an extended period of time, the inflammation may begin to affect the supporting tissues, in a progression referred to as periodontitis.: 96–97  The gingivitis response is a protective mechanism, averting periodontitis in many cases.

Periodontitis
Periodontitis is an infection of the gums which leads to bone destruction around the teeth in the jaw. Periodontitis occurs after gingivitis has been established, but not all individuals who have gingivitis will get periodontitis.: 111  Plaque accumulation is vital in the progression of periodontitis as the bacteria in plaque release enzymes which attack the bone and cause it to break down, and at the same time osteoclasts in the bone break down the bone as a way to prevent further infection. This can be treated with strict oral hygiene such as tooth brushing and cleaning in between the teeth as well as surgical debridement completed by a dental professional.

Diseases linked to periodontitis
Accumulated bacteria, due to the onset of periodontitis from dental plaque, may gain access to distant sites in the body through the circulatory and respiratory system, potentially contributing to various systematic diseases and conditions. Due to the infectious nature of bacteria hosted within the oral cavity, bacteria produced cavity can spread within the system of the human body and causes adverse health conditions. Bacteria access comes from the ulcerated epithelium of the periodontal pocket that results from accumulation of infection within the gingiva. Conditions and diseases can include:

Atheromas

Cardiovascular disease
Respiratory disease
Diabetes mellitus

Caries
Dental caries is an infectious disease caused primarily by Streptococcus mutans, characterized by acid demineralization of the enamel, which can progress to further breakdown of the more organic, inner dental tissue (dentin). The bacterial community would mainly consist of acidogenic and acid-tolerating species (e.g. Mutans streptococci and lactobacilli), while other species with relevant characteristics may also be involved.
Everybody is susceptible to caries but the probability of development depends on the patient’s individual disease indicators, risk factors, and preventive factors. Factors that are considered high-risk for developing carious lesions on the teeth include:

Low fluoride exposure
Time, length, and frequency of sugar consumption
Quality of tooth cleaning
Fluctuations in salivary flow rates and composition
Behavior of the individual
Quality and composition of biofilmsOrganic acids released from dental plaque lead to demineralization of the adjacent tooth surface, and consequently to dental caries. Saliva is also unable to penetrate the build-up of plaque and thus cannot act to neutralize the acid produced by the bacteria and remineralize the tooth surface.

Detection of plaque build-up
There are two main methods of detecting dental plaque in the oral cavity: through the application of a disclosing gel or tablet, and/or visually through observation. Plaque detection is usually detected clinically by plaque disclosing agents. Disclosing agents contain dye which turns bright red to indicate plaque build-up.It is important for an individual to be aware of what to look for when doing a self-assessment for dental plaque. It is important to be aware that everyone has dental plaque, however, the severity of the build-up and the consequences of not removing the plaque can vary.

Plaque disclosing gel
Plaque disclosing products, also known as disclosants, make plaque clinically visible. Clean surfaces of the teeth do not absorb the disclosant, only rough surfaces. Plaque disclosing gels can be either completed at home or in the dental clinic. Before using these at home or in the dental clinic check with your general practitioners for any allergies to iodine, food colouring or any other ingredients that may be present in these products. These gels provide a visual aid in assessing plaque biofilm presence and can also show the maturity of the dental plaque.

Disclosing tablets
Disclosing tablets are similar to that of disclosing gels, except that they are placed in the mouth and chewed on for approximately one minute. The remaining tablet or saliva is then spit out. Disclosing gels will show the presence of the plaque, but will often not show the level of maturity of the plaque </s>


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


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


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Perinatal asphyxia and explain in detail? [/INST] Perinatal asphyxia (also known as neonatal asphyxia or birth asphyxia) is the medical condition resulting from deprivation of oxygen to a newborn infant that lasts long enough during the birth process to cause physical harm, usually to the brain. It is also the inability to establish and sustain adequate or spontaneous respiration upon delivery of the newborn. It remains a serious condition which causes significant mortality and morbidity. It is an emergency condition and requires adequate and quick resuscitation measures. Perinatal asphyxia is also an oxygen deficit from the 28th week of gestation to the first seven days following delivery. It is also an insult to the fetus or newborn due to lack of oxygen or lack of perfusion to various organs and may be associated with a lack of ventilation. In accordance with WHO, perinatal asphyxia is characterised by: profound metabolic acidosis, with a PH < 7.20 on umbilical cord arterial blood sample, persistence of an APGAR score of 3 at the 5th minute,                                                           clinical neurologic sequelae in the immediate neonatal period, or evidence of multiorgan system dysfunction in the immediate neonatal period. Hypoxic damage can occur to most of the infants organs (heart, lungs, liver, gut, kidneys), but brain damage is of most concern and perhaps the least likely to quickly or completely heal. In more pronounced cases, an infant will survive, but with damage to the brain manifested as either mental, such as developmental delay or intellectual disability, or physical, such as spasticity.
It results most commonly from antepartum causes like a drop in maternal blood pressure or some other substantial interference with blood flow to the infants brain during delivery. This can occur due to inadequate circulation or perfusion, impaired respiratory effort, or inadequate ventilation. Perinatal asphyxia happens in 2 to 10 per 1000 newborns that are born at term, and more for those that are born prematurely. WHO estimates that 4 million neonatal deaths occur yearly due to birth asphyxia, representing 38% of deaths of children under 5 years of age.Perinatal asphyxia can be the cause of hypoxic ischemic encephalopathy or intraventricular hemorrhage, especially in preterm births. An infant with severe perinatal asphyxia usually has poor color (cyanosis), perfusion, responsiveness, muscle tone, and respiratory effort, as reflected in a low 5 minute Apgar score. Extreme degrees of asphyxia can cause cardiac arrest and death </s>


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


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Bakers cyst and explain in detail? [/INST] A Bakers cyst, also known as a popliteal cyst, is a type of fluid collection behind the knee. Often there are no symptoms. If symptoms do occur these may include swelling and pain behind the knee, or knee stiffness. If the cyst breaks open, pain may significantly increase with swelling of the calf. Rarely complications such as deep vein thrombosis, peripheral neuropathy, ischemia, or compartment syndrome may occur.Risk factors include other knee problems such as osteoarthritis, meniscal tears, or rheumatoid arthritis. The underlying mechanism involves the flow of synovial fluid from the knee joint to the gastrocnemio-semimembranosus bursa, resulting in its expansion. The diagnosis may be confirmed with ultrasound or magnetic resonance imaging (MRI).Treatment is initially with supportive care. If this is not effective aspiration and steroid injection or surgical removal may be carried out. Around 20% of people have a Bakers cyst. They occur most commonly in those 35 to 70 years old. It is named after the surgeon who first described it, William Morrant Baker (1838–1896).

Signs and symptoms
Symptoms may include swelling behind the knee, stiffness, and pain. If the cyst breaks open, pain may increase, and there may be swelling of the calf. Rupture of a Bakers cyst may also cause bruising below the medial malleolus of the ankle (Crescent sign).

Cause
In adults, Bakers cysts usually arise from almost any form of knee arthritis (e.g., rheumatoid arthritis) or cartilage (particularly a meniscus) tear.   Bakers cysts in children do not point to underlying joint disease. Bakers cysts arise between the tendons of the medial head of the gastrocnemius and the semimembranosus muscles. They are posterior to the medial femoral condyle.
The synovial sac of the knee joint can, under certain circumstances, produce a posterior bulge, into the popliteal space, the space behind the knee. When this bulge becomes large enough, it becomes palpable and cystic. Most Bakers cysts maintain this direct communication with the synovial cavity of the knee, but sometimes, the new cyst pinches off. A Bakers cyst can rupture and produce acute pain behind the knee and in the calf and swelling of the calf muscles.

Diagnosis
Diagnosis is by examination. A Bakers cyst is easier to see from behind with the patient standing with knees fully extended. It is most easily palpated (felt) with the knee partially flexed. Diagnosis is confirmed by ultrasonography, although if needed and there is no suspicion of a popliteal artery aneurysm then aspiration of synovial fluid from the cyst may be undertaken with care. An MRI image can reveal presence of a Bakers cyst.
An infrequent but potentially life-threatening complication, which may need to be excluded by blood tests and ultrasonography, is a deep vein thrombosis (DVT).  Quick assessment of the possibility of DVT may be required where a Bakers cyst has compressed vascular structures, causing leg edema, as this sets up conditions for a DVT to develop.
A burst cyst commonly causes calf pain, swelling and redness that may mimic thrombophlebitis.

Treatment
Bakers cysts usually require no treatment unless they are symptomatic. It is very rare that the symptoms are actually coming from the cyst </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Reperfusion injury and explain in detail? [/INST] Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue (re- + perfusion) after a period of ischemia or lack of oxygen (anoxia or hypoxia).  The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than (or along with) restoration of normal function.
Reperfusion injury is distinct from cerebral hyperperfusion syndrome (sometimes called "Reperfusion syndrome"), a state of abnormal cerebral vasodilation.

Mechanisms
Reperfusion of ischemic tissues is often associated with microvascular injury, particularly due to increased permeability of capillaries and arterioles that lead to an increase of diffusion and fluid filtration across the tissues. Activated endothelial cells produce more reactive oxygen species but less nitric oxide following reperfusion, and the imbalance results in a subsequent inflammatory response.
The inflammatory response is partially responsible for the damage of reperfusion injury.  White blood cells, carried to the area by the newly returning blood, release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage. The restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane.  Damage to the cells membrane may in turn cause the release of more free radicals. Such reactive species may also act indirectly in redox signaling to turn on apoptosis.  White blood cells may also bind to the endothelium of small capillaries, obstructing them and leading to more ischemia.Reperfusion injury plays a major part in the biochemistry of hypoxic brain injury in stroke. Similar failure processes are involved in brain failure following reversal of cardiac arrest; control of these processes is the subject of ongoing research.  Repeated bouts of ischemia and reperfusion injury also are thought to be a factor leading to the formation and failure to heal of chronic wounds such as pressure sores and diabetic foot ulcer.  Continuous pressure limits blood supply and causes ischemia, and the inflammation occurs during reperfusion.  As this process is repeated, it eventually damages tissue enough to cause a wound.The main reason for the acute phase of ischemia-reperfusion injury  is oxygen deprivation and, therefore, arrest of generation of ATP (cellular energy currency) by mitochondria oxidative phosphorylation. Tissue damage due to the general energy deficit during ischemia is followed by reperfusion (increase of oxygen level) when the injury is enhanced. Mitochondrial complex I is thought to be the most vulnerable enzyme to tissue ischemia/reperfusion but the mechanism of damage is different in different tissues. For example brain ischemia/reperfusion injury is mediated via complex I redox-dependent inactivation. It was found that lack of oxygen leads to conditions in which mitochondrial complex I loses its natural cofactor, flavin mononucleotide (FMN) and become inactive. When oxygen is present the enzyme catalyzes a physiological reaction of NADH oxidation by ubiquinone, supplying electrons downstream of the respiratory chain (complexes III and IV). Ischemia leads to dramatic increase of succinate level. In the presence of succinate mitochondria catalyze reverse electron transfer so that fraction of electrons from succinate is directed upstream to FMN of complex I. Reverse electron transfer results in a reduction of complex I FMN, increased generation of ROS, followed by a loss of the reduced cofactor (FMNH2) and impairment of mitochondria energy production. The FMN loss by complex I and I/R injury can be alleviated by the administration of FMN precursor, riboflavin.Reperfusion can cause hyperkalemia.Reperfusion injury is a primary concern in liver transplantation surgery.

Treatment
Therapeutic hypothermia
However, the therapeutic effect of hypothermia does not confine itself to metabolism and membrane stability. Another school of thought focuses on hypothermias ability to prevent the injuries that occur after circulation returns to the brain, or what is termed reperfusion injuries.  In fact an individual suffering from an ischemic insult continues suffering injuries well after circulation is restored. In rats it has been shown that neurons often die a full 24 hours after blood flow returns.  Some theorize that this delayed reaction derives from the various inflammatory immune responses that occur during reperfusion. These inflammatory responses cause intracranial pressure, pressure which leads to cell injury and in some situations cell death. Hypothermia has been shown to help moderate intracranial pressure and therefore to minimize the harmful effect of a patients inflammatory immune responses during reperfusion. Beyond this, reperfusion also increases free radical production. Hypothermia too has been shown to minimize a patients production of deadly free radicals during reperfusion. Many now suspect it is because hypothermia reduces both intracranial pressure and free radical production that hypothermia improves patient outcome following a blockage of blood flow to the brain.

Hydrogen sulfide treatment
There are some preliminary studies in mice that seem to indicate that treatment with hydrogen sulfide (H2S) can have a protective effect against reperfusion injury.

Cyclosporin
In addition to its well-known immunosuppressive capabilities, the one-time administration of cyclosporin at the time of percutaneous coronary intervention (PCI) has been found to deliver a 40 percent reduction in infarct size in a small group proof of concept study of human patients with reperfusion injury published in The New England Journal of Medicine in 2008.Cyclosporin has been confirmed in studies to inhibit the actions of cyclophilin D, a protein which is induced by excessive intracellular calcium flow to interact with other pore components and help open the MPT pore. Inhibiting cyclophilin D has been shown to prevent the opening of the MPT pore and protect the mitochondria and cellular energy production from excessive calcium inflows.However, the studies CIRCUS and CYCLE (published in September 2015 and February 2016 respectively) looked at the use of cyclosporin as a one time IV dose given right before perfusion therapy (PCI).  Both studies found there is no statistical difference in outcome with cyclosporin administration.Reperfusion leads to biochemical imbalances within the cell that lead to cell death and increased infarct size. More specifically, calcium overload and excessive production of reactive oxygen species in the first few minutes after reperfusion set off a cascade of biochemical changes that result in the opening of the so-called mitochondrial permeability transition pore (MPT pore) in the mitochondrial membrane of cardiac cells.The opening of the MPT pore leads to the inrush of water into the mitochondria, resulting in mitochondrial dysfunction and collapse </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Rhinolith and explain in detail? [/INST] A rhinolith is a stone present in the nasal cavity.  The word is derived from the roots rhino- and -lith, literally meaning "nose stone". It is an uncommon medical phenomenon, not to be confused with dried nasal mucus. A rhinolith usually forms around the nucleus of a small exogenous foreign body, blood clot or secretion by slow deposition of calcium and magnesium carbonate and phosphate salts. Over a period of time, they grow into large irregular masses that fill the nasal cavity. They may cause pressure necrosis of the nasal septum or lateral wall of nose. Rhinoliths can cause nasal obstruction, epistaxis, headache, sinusitis and epiphora </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Ectrodactyly and explain in detail? [/INST] Ectrodactyly, split hand, or cleft hand (derived from Greek ektroma abortion and daktylos finger) involves the deficiency or absence of one or more central digits of the hand or foot and is also known as split hand/split foot malformation (SHFM). The hands and feet of people with ectrodactyly (ectrodactyls) are often described as "claw-like" and may include only the thumb and one finger (usually either the little finger, ring finger, or a syndactyly of the two) with similar abnormalities of the feet.It is a substantial rare form of a congenital disorder in which the development of the hand is disturbed. It is a type I failure of formation – longitudinal arrest. The central ray of the hand is affected and usually appears without proximal deficiencies of nerves, vessels, tendons, muscles and bones in contrast to the radial and ulnar deficiencies. The cleft hand appears as a V-shaped cleft situated in the centre of the hand. The digits at the borders of the cleft might be syndactilyzed, and one or more digits can be absent. In most types, the thumb, ring finger and little finger are the less affected parts of the hand. The incidence of cleft hand varies from 1 in 90,000 to 1 in 10,000 births depending on the used classification. Cleft hand can appear unilateral or bilateral, and can appear isolated or associated with a syndrome.
Split hand/foot malformation (SHFM) is characterized by underdeveloped or absent central digital rays, clefts of hands and feet, and variable syndactyly of the remaining digits. SHFM is a heterogeneous condition caused by abnormalities at one of multiple loci, including SHFM1 (SHFM1 at 7q21-q22), SHFM2 (Xq26), SHFM3 (FBXW4/DACTYLIN at 10q24), SHFM4 (TP63 at 3q27), and SHFM5 (DLX1 and DLX 2 at 2q31). SHFM3 is unique in that it is caused by submicroscopic tandem chromosome duplications of FBXW4/DACTYLIN. SHFM3 is considered isolated ectrodactyly and does not show a mutation of the tp63 gene.

Presentation
Ectrodactyly can be caused by various changes to 7q.  When 7q is altered by a deletion or a translocation, ectrodactyly can sometimes be associated with hearing loss.  Ectrodactyly, or Split hand/split foot malformation (SHFM) type 1 is the only form of split hand/ malformation associated with sensorineural hearing loss.

Genetics
A large number of human gene defects can cause ectrodactyly.  The most common mode of inheritance is autosomal dominant with reduced penetrance, while autosomal recessive and X-linked forms occur more rarely.  Ectrodactyly can also be caused by a duplication on 10q24. Detailed studies of a number of mouse models for ectrodactyly have also revealed that a failure to maintain median apical ectodermal ridge (AER) signalling can be the main pathogenic mechanism in triggering this abnormality.A number of factors make the identification of the genetic defects underlying human ectrodactyly a complicated process: the limited number of families linked to each split hand/foot malformation (SHFM) locus, the large number of morphogens involved in limb development, the complex interactions between these morphogens, the involvement of modifier genes, and the presumed involvement of multiple gene or long-range regulatory elements in some cases of ectrodactyly.  In the clinical setting these genetic characteristics can become problematic and making predictions of carrier status and severity of the disease impossible to predict.In 2011, a novel mutation in DLX5 was found to be involved in SHFM.Ectrodactyly is frequently seen with other congenital anomalies.  Syndromes in which ectrodactyly is associated with other abnormalities can occur when two or more genes are affected by a chromosomal rearrangement.  Disorders associated with ectrodactyly include Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) syndrome, which is closely correlated to the ADULT syndrome and Limb-mammary (LMS) syndrome, Ectrodactyly-Cleft Palate (ECP) syndrome, Ectrodactyly-Ectodermal Dysplasia-Macular Dystrophy syndrome, Ectrodactyly-Fibular Aplasia/Hypoplasia (EFA) syndrome, and Ectrodactyly-Polydactyly. More than 50 syndromes and associations involving ectrodactyly are distinguished in the London Dysmorphology Database.

Pathophysiology
The pathophysiology of cleft hand is thought to be a result of a wedge-shaped defect of the apical ectoderm of the limb bud (AER: apical ectodermal ridge). Polydactyly, syndactyly and cleft hand can occur within the same hand, therefore some investigators suggest that these entities occur from the same mechanism.
This mechanism is not yet defined.

Genetics
The cause of cleft hand lies, for what is known, partly in genetics. The inheritance of cleft hand is autosomal dominant and has a variable penetrance of 70%.
Cleft hand can be a spontaneous mutation during pregnancy (de novo mutation). The exact chromosomal defect in isolated cleft hand is not yet defined. However, the genetic causes of cleft hand related to syndromes have more clarity.
The identified mutation for SHSF syndrome (split-hand/split-foot syndrome) a duplication on 10q24, and not a mutation of the tp63 gene as in families affected by EEC syndrome (ectrodactyly–ectodermal dysplasia–cleft syndrome). The p63 gene plays a critical role in the development of the apical ectodermal ridge (AER), this was found in mutant mice with dactylaplasia.

Embryology
Some studies have postulated that polydactyly, syndactyly and cleft hand have the same teratogenic mechanism. In vivo tests showed that limb anomalies were found alone or in combination with cleft hand when they were given Myleran.
These anomalies take place in humans around day 41 of gestation.

Diagnosis
Classification
There are several classifications for cleft hand, but the most used classification is described by Manske and Halikis see table 3. This classification is based on the first web space. The first web space is the space between the thumb and the index finger.
Table 3: Classification for cleft hand described by Manske and Halikis

Treatment
The treatment of cleft hand is usually invasive and can differ each time because of the heterogeneity of the condition. The function of a cleft hand is mostly not restricted, yet improving the function is one of the goals when the thumb or first webspace is absent.The social and stigmatising aspects of a cleft hand require more attention. The hand is a part of the body which is usually shown during communication. When this hand is obviously different and deformed, stigmatisation or rejection can occur. Sometimes, in families with cleft hand with good function, operations for cosmetic aspects are considered marginal  and the families choose not to have surgery.

Indications
Surgical treatment of the cleft hand is based on several indications:
Improving function
Absent thumb
Deforming syndactyly (mostly between digits of unequal length like index and thumb)
Transverse bones (this will progress the deformity; growth of these bones will widen the cleft)
Narrowed first webspace
The feetAesthetical aspects

Reducing deformity

Timing of surgical interventions
The timing of surgical interventions is debatable. Parents have to decide about their child in a very vulnerable time of their parenthood. Indications for early treatment are progressive deformities, such as syndactyly between index and thumb or transverse bones between the digital rays. Other surgical interventions are less urgent and can wait for 1 or 2 years.

Classification and treatment
When surgery is indicated, the choice of treatment is based on the classification. Table 4 shows the treatment of cleft hand divided into the classification of Manske and Halikis.
Techniques described by Ueba, Miura and Komada and the procedure of Snow-Littler are guidelines; since clinical and anatomical presentation within the types differ, the actual treatment is based on the individual abnormality.Table 4: Treatment based on the classification of Manske and Halikis

Snow-Littler
The goal of this procedure is to create a wide first web space and to minimise the cleft in the hand. The index digit will be transferred to the ulnar side of the cleft. Simultaneously a correction of index malrotation and deviation is performed. To minimise the cleft, it is necessary to fix together the metacarpals which used to border the cleft. Through repositioning flaps, the wound can be closed.

Ueba
Ueba described a less complicated surgery.  Transverse flaps are used to resurface the palm, the dorsal side of the transposed digit and the ulnar part of the first web space. A tendon graft is used to connect the common extensor tendons of the border digits of the cleft to prevent digital separation during extension. The closure is simpler, but has cosmetic disadvantage because of the switch between palmar and dorsal skin.

Miura and Komada
The release of the first webspace has the same principle as the Snow-Littler procedure. The difference is the closure of the first webspace; this is done by simple closure or closure with Z-plasties.

History
Literature shows that cleft hand is described centuries ago. The first reference to what might be considered a cleft hand was by Ambroise Paré in 1575. Hartsink (1770) wrote the first report of true cleft hand. In 1896, the first operation of the cleft hand was performed by Doctor Charles N. Dowed of New York City. However, the first certain description of what we know as a cleft hand as we know it today was described at the end of the 19th century.

Symbrachydactyly
Historically, a U-type cleft hand was also known as atypical cleft hand. The classification in which typical and atypical cleft hand are described was mostly used for clinical aspects and is shown in table 1. Nowadays, this "atypical cleft hand" is referred to as symbrachydactyly and is not a subtype of cleft hand.

Notable cases
Bree Walker Once a popular television anchor woman in Los Angeles, she has appeared in the television drama Nip/Tuck as an inspirational character who battles her disease and counsels another family who have children with ectrodactyly
Grady Stiles Sr. and Grady Stiles Jr.: known publicly as Lobster Boy and family, famous side show acts, featured on the AMC reality show, Freakshow.
The Vadoma tribe in northern Zimbabwe
Mikhail Tal, Soviet chess player, World Chess Champion 1960–61
Lee Hee-ah, a Korean pianist with only two fingers on each hand.
Cédric Grégoire (better known as Lord Lokhraed) is the guitarist and lead vocalist of French black metal band Nocturnal Depression and has ectrodactyly on his fretting hand, which has only two fingers.
Black Scorpion, freak show performer.
Sam Schröder, 2020 US Open Quad Champion.
Francesca Jones, British pro tennis player, former #149 in WTA rankings.

Other animals
Ectrodactyly is not only a genetic characteristic in humans, but can also occur in frogs and toads, mice,  salamanders, cows, chickens, rabbits, marmosets, cats and dogs, and even West Indian manatees.  The following examples are studies showing the natural occurrence of ectrodactyly in animals, without the disease being reproduced and tested in a laboratory </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Trichorrhexis invaginata and explain in detail? [/INST] Trichorrhexis invaginata is a distinctive hair shaft abnormality that may occur sporadically, either in normal hair or with other hair shaft abnormalities, or regularly as a marker for Nethertons syndrome.: 638 : 766–7   The primary defect appears to be abnormal keratinization of the hair shaft in the keratogenous zone, allowing for intussusception of the fully keratinized and hard distal shaft into the incompletely keratinized and soft proximal portion of the shaft.: 638

Genetics
"Bamboo hair" is a  rare autosomal recessive genodermatosis characterized by congenital ichthyosiform erythroderma, trichorrhexis invaginata, and atopic diathesis with failure to thrive. Chronic skin inflammation results in scaling and exfoliation, predisposing these patients to life-threatening infections, sepsis, and dehydration. The Netherton syndrome Mendelian Inheritance in Man is inherited as an autosomal recessive disorder due to mutations of both copies of the SPINK5 gene (localized to band 5q31-32), which encodes the serine protease inhibitor LEKTI (lymphoepithelial Kazal-type-related inhibitor). LEKTI is expressed in epithelial and mucosal surfaces and in the thymus. Each SPINK5 mutation leads to a different length of LEKTI protein, resulting in genotype/phenotype correlations in cutaneous severity, susceptibility to atopic dermatitis, growth retardation, skin infection, increased stratum corneum protease activities, and elevated kallikrein levels in the stratum corneum.Trichorrhexis invaginata, or bamboo hair, is a hair shaft abnormality that occurs as a result of an intermittent keratinizing defect of the hair cortex </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Muehrckes nails and explain in detail? [/INST] Muehrckes nails or Muehrckes lines (apparent leukonychia striata) are changes in the fingernail that may be a sign of an underlying medical condition. The term refers to a set of one or more pale transverse bands extending all the way across the nail, parallel to the lunula. In contrast to Beaus lines, they are not grooved (no 3-dimensional deformity), and in contrast to Mees lines, the thumb is usually not involved.Muehrckes lines are a strong indicator of hypoalbuminemia, which can result from a variety of different causes.The lines are actually in the vascular bed underneath the nail plate. As such, they do not move with nail growth, and disappear when pressure is applied to the nail (blanching the underlying nail bed): this distinguishes them from "true leukonychia striata" such as Mees lines. As in Terrys and half-and-half nails, the pattern is thought to be formed by bands of localized edema exerting pressure on the surrounding capillaries.

Physiology
The appearance of Muehrckes lines is associated specifically with marked hypoalbuminemia (serum albumin ≤ 2.2 g/dL) indicating decreased protein synthesis, which may occur during periods of metabolic stress (e.g. systemic infection, trauma, AIDS, chemotherapy), or in hypoalbuminemic states such as the nephrotic syndrome or dietary protein deficiency. They are also seen in patients with end-stage kidney disease on hemodialysis, Hodgkins disease, pellagra, and sickle cell anaemia.The lines remain visible as long as protein intake is inadequate or synthesis is impaired, and they should disappear upon return to normal function.In extreme conditions, Muehrckes lines may also arise from physical changes in peripheral circulation: one case study reported appearance of the lines in a healthy subject following ascent to 8,848 meters (29,029 ft) on Mount Everest.

History
Muehrckes lines were described by American physician Robert C. Muehrcke (1921–2003) in 1956 </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Oxygen toxicity and explain in detail? [/INST] Oxygen toxicity is a condition resulting from the harmful effects of breathing molecular oxygen (O2) at increased partial pressures. Severe cases can result in cell damage and death, with effects most often seen in the central nervous system, lungs, and eyes. Historically, the central nervous system condition was called the Paul Bert effect, and the pulmonary condition the Lorrain Smith effect, after the researchers who pioneered the discoveries and descriptions in the late 19th century. Oxygen toxicity is a concern for underwater divers, those on high concentrations of supplemental oxygen (particularly premature babies), and those undergoing hyperbaric oxygen therapy.
The result of breathing increased partial pressures of oxygen is hyperoxia, an excess of oxygen in body tissues. The body is affected in different ways depending on the type of exposure. Central nervous system toxicity is caused by short exposure to high partial pressures of oxygen at greater than atmospheric pressure. Pulmonary and ocular toxicity result from longer exposure to increased oxygen levels at normal pressure. Symptoms may include disorientation, breathing problems, and vision changes such as myopia. Prolonged exposure to above-normal oxygen partial pressures, or shorter exposures to very high partial pressures, can cause oxidative damage to cell membranes, collapse of the alveoli in the lungs, retinal detachment, and seizures. Oxygen toxicity is managed by reducing the exposure to increased oxygen levels. Studies show that, in the long term, a robust recovery from most types of oxygen toxicity is possible.
Protocols for avoidance of the effects of hyperoxia exist in fields where oxygen is breathed at higher-than-normal partial pressures, including underwater diving using compressed breathing gases, hyperbaric medicine, neonatal care and human spaceflight. These protocols have resulted in the increasing rarity of seizures due to oxygen toxicity, with pulmonary and ocular damage being mainly confined to the problems of managing premature infants.
In recent years, oxygen has become available for recreational use in oxygen bars. The US Food and Drug Administration has warned those who have conditions such as heart or lung disease not to use oxygen bars. Scuba divers use breathing gases containing up to 100% oxygen, and should have specific training in using such gases.

Classification
The effects of oxygen toxicity may be classified by the organs affected, producing three principal forms:
Central nervous system, characterised by convulsions followed by unconsciousness, occurring under hyperbaric conditions;
Pulmonary (lungs), characterised by difficulty in breathing and pain within the chest, occurring when breathing increased pressures of oxygen for extended periods;
Ocular (retinopathic conditions), characterised by alterations to the eyes, occurring when breathing increased pressures of oxygen for extended periods.Central nervous system oxygen toxicity can cause seizures, brief periods of rigidity followed by convulsions and unconsciousness, and is of concern to divers who encounter greater than atmospheric pressures. Pulmonary oxygen toxicity results in damage to the lungs, causing pain and difficulty in breathing. Oxidative damage to the eye may lead to myopia or partial detachment of the retina. Pulmonary and ocular damage are most likely to occur when supplemental oxygen is administered as part of a treatment, particularly to newborn infants, but are also a concern during hyperbaric oxygen therapy.
Oxidative damage may occur in any cell in the body but the effects on the three most susceptible organs will be the primary concern. It may also be implicated in damage to red blood cells (haemolysis),  the liver, heart, endocrine glands (adrenal glands, gonads, and thyroid), or kidneys, and general damage to cells.In unusual circumstances, effects on other tissues may be observed: it is suspected that during spaceflight, high oxygen concentrations may contribute to bone damage. Hyperoxia can also indirectly cause carbon dioxide narcosis in patients with lung ailments such as chronic obstructive pulmonary disease or with central respiratory depression. Hyperventilation of atmospheric air at atmospheric pressures does not cause oxygen toxicity, because sea-level air has a partial pressure of oxygen of 0.21 bar (21 kPa) whereas toxicity does not occur below 0.3 bar (30 kPa).

Signs and symptoms
Central nervous system
Central nervous system oxygen toxicity manifests as symptoms such as visual changes (especially tunnel vision), ringing in the ears (tinnitus), nausea, twitching (especially of the face), behavioural changes (irritability, anxiety, confusion), and dizziness. This may be followed by a tonic–clonic seizure consisting of two phases: intense muscle contraction occurs for several seconds (tonic phase); followed by rapid spasms of alternate muscle relaxation and contraction producing convulsive jerking (clonic phase). The seizure ends with a period of unconsciousness (the postictal state). The onset of seizure depends upon the partial pressure of oxygen in the breathing gas and exposure duration. However, exposure time before onset is unpredictable, as tests have shown a wide variation, both amongst individuals, and in the same individual from day to day. In addition, many external factors, such as underwater immersion, exposure to cold, and exercise will decrease the time to onset of central nervous system symptoms. Decrease of tolerance is closely linked to retention of carbon dioxide. Other factors, such as darkness and caffeine, increase tolerance in test animals, but these effects have not been proven in humans.

Lungs
Pulmonary toxicity symptoms result from an inflammation that starts in the airways leading to the lungs and then spreads into the lungs (tracheobronchial tree). The symptoms appear in the upper chest region (substernal and carinal regions). This begins as a mild tickle on inhalation and progresses to frequent coughing. If breathing increased partial pressures of oxygen continues, patients experience a mild burning on inhalation along with uncontrollable coughing and occasional shortness of breath (dyspnea). Physical findings related to pulmonary toxicity have included bubbling sounds heard through a stethoscope (bubbling rales), fever, and increased blood flow to the lining of the nose (hyperaemia of the nasal mucosa). X-rays of the lungs show little change in the short term, but extended exposure leads to increasing diffuse shadowing throughout both lungs. Pulmonary function measurements are reduced, as noted by a reduction in the amount of air that the lungs can hold (vital capacity) and changes in expiratory function and lung elasticity. Tests in animals have indicated a variation in tolerance similar to that found in central nervous system toxicity, as well as significant variations between species. When the exposure to oxygen above 0.5 bar (50 kPa) is intermittent, it permits the lungs to recover and delays the onset of toxicity.

Eyes
In premature babies, signs of damage to the eye (retinopathy of prematurity, or ROP) are observed via an ophthalmoscope as a demarcation between the vascularised and non-vascularised regions of an infants retina. The degree of this demarcation is used to designate four stages: (I) the demarcation is a line; (II) the demarcation becomes a ridge; (III) growth of new blood vessels occurs around the ridge; (IV) the retina begins to detach from the inner wall of the eye (choroid).

Causes
Oxygen toxicity is caused by exposure to oxygen at partial pressures greater than those to which the body is normally exposed. This occurs in three principal settings: underwater diving, hyperbaric oxygen therapy, and the provision of supplemental oxygen, particularly to premature infants. In each case, the risk factors are markedly different.

Central nervous system toxicity
Exposures, from minutes to a few hours, to partial pressures of oxygen above 1.6 bars (160 kPa)—about eight times normal atmospheric partial pressure—are usually associated with central nervous system oxygen toxicity and are most likely to occur among patients undergoing hyperbaric oxygen therapy and divers. Since sea level atmospheric pressure is about 1 bar (100 kPa), central nervous system toxicity can only occur under hyperbaric conditions, where ambient pressure is above normal. Divers breathing air at depths beyond 60 m (200 ft) face an increasing risk of an oxygen toxicity "hit" (seizure). Divers breathing a gas mixture enriched with oxygen, such as nitrox, can similarly have a seizure at shallower depths, should they descend below the maximum operating depth allowed for the mixture.

Lung toxicity
The lungs and the remainder of the respiratory tract are exposed to the highest concentration of oxygen in the human body and are therefore the first organs to show toxicity. Pulmonary toxicity occurs only with exposure to partial pressures of oxygen greater than 0.5 bar (50 kPa), corresponding to an oxygen fraction of 50% at normal atmospheric pressure. The earliest signs of pulmonary toxicity begin with evidence of tracheobronchitis, or inflammation of the upper airways, after an asymptomatic period between 4 and 22 hours at greater than 95% oxygen, with some studies suggesting symptoms usually begin after approximately 14 hours at this level of oxygen.At partial pressures of oxygen of 2 to 3 bar (200 to 300 kPa)—100% oxygen at 2 to 3 times atmospheric pressure—these symptoms may begin as early as 3 hours after exposure to oxygen. Experiments on rats breathing oxygen at pressures between 1 and 3 bars (100 and 300 kPa) suggest that pulmonary manifestations of oxygen toxicity may not be the same for normobaric conditions as they are for hyperbaric conditions. Evidence of decline in lung function as measured by pulmonary function testing can occur as quickly as 24 hours of continuous exposure to 100% oxygen, with evidence of diffuse alveolar damage and the onset of acute respiratory distress syndrome usually occurring after 48 hours on 100% oxygen. Breathing 100% oxygen also eventually leads to collapse of the alveoli (atelectasis), while—at the same partial pressure of oxygen—the presence of significant partial pressures of inert gases, typically nitrogen, will prevent this effect.Preterm newborns are known to be at higher risk for bronchopulmonary dysplasia with extended exposure to high concentrations of oxygen. Other groups at higher risk for oxygen toxicity are patients on mechanical ventilation with exposure to levels of oxygen greater than 50%, and patients exposed to chemicals that increase risk for oxygen toxicity such the chemotherapeutic agent bleomycin. Therefore, current guidelines for patients on mechanical ventilation in intensive care recommends keeping oxygen concentration less than 60%. Likewise, divers who undergo treatment of decompression sickness are at increased risk of oxygen toxicity as treatment entails exposure to long periods of oxygen breathing under hyperbaric conditions, in addition to any oxygen exposure during the dive.

Ocular toxicity
Prolonged exposure to high inspired fractions of oxygen causes damage to the retina. Damage to the developing eye of infants exposed to high oxygen fraction at normal pressure has a different mechanism and effect from the eye damage experienced by adult divers under hyperbaric conditions. Hyperoxia may be a contributing factor for the disorder called retrolental fibroplasia or retinopathy of prematurity (ROP) in infants. In preterm infants, the retina is often not fully vascularised. Retinopathy of prematurity occurs when the development of the retinal vasculature is arrested and then proceeds abnormally. Associated with the growth of these new vessels is fibrous tissue (scar tissue) that may contract to cause retinal detachment. Supplemental oxygen exposure, while a risk factor, is not the main risk factor for development of this disease. Restricting supplemental oxygen use does not necessarily reduce the rate of retinopathy of prematurity, and may raise the risk of hypoxia-related systemic complications.Hyperoxic myopia has occurred in closed circuit oxygen rebreather divers with prolonged exposures. It also occurs frequently in those undergoing repeated hyperbaric oxygen therapy. This is due to an increase in the refractive power of the lens, since axial length and keratometry readings do not reveal a corneal or length basis for a myopic shift. It is usually reversible with time.A possible side effect of hyperbaric oxygen therapy is the initial or further development of cataracts, which are a increase in opacity of the lens of the eye which reduces visual acuity, and can eventually result in blindness. This is a rare event, associated with lifetime exposure to raised oxygen concentration, and may be under-reported as it develops very slowly. The cause is not fully understood, but evidence suggests that raised oxygen levels may cause accelerated deterioration of the vitreous humour due to degradation of lens crystallins by cross-linking, forming aggregates capable of scattering light. This may be an end-state development of the more commonly observed myopic shift associated with hyperbaric treatment.

Mechanism
The biochemical basis for the toxicity of oxygen is the partial reduction of oxygen by one or two electrons to form reactive oxygen species, which are natural by-products of the normal metabolism of oxygen and have important roles in cell signalling. One species produced by the body, the superoxide anion (O−2), is possibly involved in iron acquisition. Higher than normal concentrations of oxygen lead to increased levels of reactive oxygen species. Oxygen is necessary for cell metabolism, and the blood supplies it to all parts of the body. When oxygen is breathed at high partial pressures, a hyperoxic condition will rapidly spread, with the most vascularised tissues being most vulnerable. During times of environmental stress, levels of reactive oxygen species can increase dramatically, which can damage cell structures and produce oxidative stress.While all the reaction mechanisms of these species within the body are not yet fully understood, one of the most reactive products of oxidative stress is the hydroxyl radical (·OH), which can initiate a damaging chain reaction of lipid peroxidation in the unsaturated lipids within cell membranes. High concentrations of oxygen also increase the formation of other free radicals, such as nitric oxide, peroxynitrite, and trioxidane, which harm DNA and other biomolecules. Although the body has many antioxidant systems such as glutathione that guard against oxidative stress, these systems are eventually overwhelmed at very high concentrations of free oxygen, and the rate of cell damage exceeds the capacity of the systems that prevent or repair it. Cell damage and cell death then result.

Diagnosis
Diagnosis of central nervous system oxygen toxicity in divers prior to seizure is difficult as the symptoms of visual disturbance, ear problems, dizziness, confusion and nausea can be due to many factors common to the underwater environment such as narcosis, congestion and coldness. However, these symptoms may be helpful in diagnosing the first stages of oxygen toxicity in patients undergoing hyperbaric oxygen therapy. In either case, unless there is a prior history of epilepsy or tests indicate hypoglycaemia, a seizure occurring in the setting of breathing oxygen at partial pressures greater than 1.4 bar (140 kPa) suggests a diagnosis of oxygen toxicity.Diagnosis of bronchopulmonary dysplasia in newborn infants with breathing difficulties is difficult in the first few weeks. However, if the infants breathing does not improve during this time, blood tests and x-rays may be used to confirm bronchopulmonary dysplasia. In addition, an echocardiogram can help to eliminate other possible causes such as congenital heart defects or pulmonary arterial hypertension.The diagnosis of retinopathy of prematurity in infants is typically suggested by the clinical setting. Prematurity, low birth weight, and a history of oxygen exposure are the principal indicators, while no hereditary factors have been shown to yield a pattern.

Prevention
The prevention of oxygen toxicity depends entirely on the setting. Both underwater and in space, proper precautions can eliminate the most pernicious effects. Premature infants commonly require supplemental oxygen to treat complications of preterm birth. In this case prevention of bronchopulmonary dysplasia and retinopathy of prematurity must be carried out without compromising a supply of oxygen adequate to preserve the infants life.

Underwater
Oxygen toxicity is a catastrophic hazard in scuba diving, because a seizure results in high risk of death by drowning. The seizure may occur suddenly and with no warning symptoms. The effects are sudden convulsions and unconsciousness, during which victims can lose their regulator and drown. One of the advantages of a full-face diving mask is prevention of regulator loss in the event of a seizure. Mouthpiece retaining straps are a relatively inexpensive alternative with a similar but less effective function. As there is an increased risk of central nervous system oxygen toxicity on deep dives, long dives and dives where oxygen-rich breathing gases are used, divers are taught to calculate a maximum operating depth for oxygen-rich breathing gases, and cylinders containing such mixtures should be clearly marked with that depth.The risk of seizure appears to be a function of dose – a cumulative combination of partial pressure and duration. The threshold for oxygen partial pressure below which seizures never occur has not been established, and may depend on many variables, some of them personal. the risk to a specific person can vary considerably depending on individual sensitivity, level of exercise, and carbon dioxide retention, which is influenced by work of breathing.In some diver training courses for these types of diving, divers are taught to plan and monitor what is called the oxygen clock of their dives. This is a notional alarm clock, which ticks more quickly at increased oxygen pressure and is set to activate at the maximum single exposure limit recommended in the National Oceanic and Atmospheric Administration Diving Manual. For the following partial pressures of oxygen the limits are: 45 minutes at 1.6 bar (160 kPa), 120 minutes at 1.5 bar (150 kPa), 150 minutes at 1.4 bar (140 kPa), 180 minutes at 1.3 bar (130 kPa) and 210 minutes at 1.2 bar (120 kPa), but it is impossible to predict with any reliability whether or when toxicity symptoms will occur. Many nitrox-capable dive computers calculate an oxygen loading and can track it across multiple dives. The aim is to avoid activating the alarm by reducing the partial pressure of oxygen in the breathing gas or by reducing the time spent breathing gas of greater oxygen partial pressure. As the partial pressure of oxygen increases with the fraction of oxygen in the breathing gas and the depth of the dive, the diver obtains more time on the oxygen clock by diving at a shallower depth, by breathing a less oxygen-rich gas, or by shortening the duration of exposure to oxygen-rich gases. This function is provided by some technical diving decompression computers and rebreather control and monitoring hardware.Diving below 56 m (184 ft) on air would expose a diver to increasing danger of oxygen toxicity as the partial pressure of oxygen exceeds 1.4 bar (140 kPa), so a gas mixture must be used which contains less than 21% oxygen (a hypoxic mixture). Increasing the proportion of nitrogen is not viable, since it would produce a strongly narcotic mixture. However, helium is not narcotic, and a usable mixture may be blended either by completely replacing nitrogen with helium (the resulting mix is called heliox), or by replacing part of the nitrogen with helium, producing a trimix.Pulmonary oxygen toxicity is an entirely avoidable event while diving. The limited duration and naturally intermittent nature of most diving makes this a relatively rare (and even then, reversible) complication for divers. Established guidelines enable divers to calculate when they are at risk of pulmonary toxicity. In saturation diving it can be avoided by limiting the oxygen content of gas in living areas to below 0.4 bar.

Hyperbaric setting
The presence of a fever or a history of seizure is a relative contraindication to hyperbaric oxygen treatment. The schedules used for treatment of decompression illness allow for periods of breathing air rather than 100% oxygen (oxygen breaks) to reduce the chance of seizure or lung damage. The U.S. Navy uses treatment tables based on periods alternating between 100% oxygen and air. For example, USN table 6 requires 75 minutes (three periods of 20 minutes oxygen/5 minutes air) at an ambient pressure of 2.8 standard atmospheres (280 kPa), equivalent to a depth of 18 metres (60 ft). This is followed by a slow reduction in pressure to 1.9 atm (190 kPa) over 30 minutes on oxygen. The patient then remains at that pressure for a further 150 minutes, consisting of two periods of 15 minutes air/60 minutes oxygen, before the pressure is reduced to atmospheric over 30 minutes on oxygen.Vitamin E and selenium were proposed and later rejected as a potential method of protection against pulmonary oxygen toxicity. There is however some experimental evidence in rats that vitamin E and selenium aid in preventing in vivo lipid peroxidation and free radical damage, and therefore prevent retinal changes following repetitive hyperbaric oxygen exposures.

Normobaric setting
Bronchopulmonary dysplasia is reversible in the early stages by use of break periods on lower pressures of oxygen, but it may eventually result in irreversible lung injury if allowed to progress to severe damage. One or two days of exposure without oxygen breaks are needed to cause such damage.Retinopathy of prematurity is largely preventable by screening. Current guidelines require that all babies of less than 32 weeks gestational age or having a birth weight less than 1.5 kg (3.3 lb) should be screened for retinopathy of prematurity at least every two weeks. The National Cooperative Study in 1954 showed a causal link between supplemental oxygen and retinopathy of prematurity, but subsequent curtailment of supplemental oxygen caused an increase in infant mortality. To balance the risks of hypoxia and retinopathy of prematurity, modern protocols now require monitoring of blood oxygen levels in premature infants receiving oxygen.

Hypobaric setting
In low-pressure environments oxygen toxicity may be avoided since the toxicity is caused by high partial pressure of oxygen, not merely by high oxygen fraction. This is illustrated by modern pure oxygen use in spacesuits, which must operate at low pressure (also historically, very high percentage oxygen and lower than normal atmospheric pressure was used in early spacecraft, for example, the Gemini and Apollo spacecraft). In such applications as extra-vehicular activity, high-fraction oxygen is non-toxic, even at breathing mixture fractions approaching 100%, because the oxygen partial pressure is not allowed to chronically exceed 0.3 bar (4.4 psi).

Management
During hyperbaric oxygen therapy, the patient will usually breathe 100% oxygen from a mask while inside a hyperbaric chamber pressurised with air to about 2.8 bar (280 kPa). Seizures during the therapy are managed by removing the mask from the patient, thereby dropping the partial pressure of oxygen inspired below 0.6 bar (60 kPa).A seizure underwater requires that the diver be brought to the surface as soon as practicable. Although for many years the recommendation has been not to raise the diver during the seizure itself, owing to the danger of arterial gas embolism (AGE), there is some evidence that the glottis does not fully obstruct the airway. This has led to the current recommendation by the Diving Committee of the Undersea and Hyperbaric Medical Society that a diver should be raised during the seizures clonic (convulsive) phase if the regulator is not in the divers mouth—as the danger of drowning is then greater than that of AGE—but the ascent should be delayed until the end of the clonic phase otherwise. Rescuers ensure that their own safety is not compromised during the convulsive phase. They then ensure that where the victims air supply is established it is maintained, and carry out a controlled buoyant lift. Lifting an unconscious body is taught by most recreational diver training agencies as an advanced skill, and for professional divers it is a basic skill, as it is one of the primary functions of the standby diver. Upon reaching the surface, emergency services are always contacted as there is a possibility of further complications requiring medical attention. The U.S. Navy has procedures for completing the decompression stops where a recompression chamber is not immediately available.The occurrence of symptoms of bronchopulmonary dysplasia or acute respiratory distress syndrome is treated by lowering the fraction of oxygen administered, along with a reduction in the periods of exposure and an increase in the break periods where normal air is supplied. Where supplemental oxygen is required for treatment of another disease (particularly in infants), a ventilator may be needed to ensure that the lung tissue remains inflated. Reductions in pressure and exposure will be made progressively, and medications such as bronchodilators and pulmonary surfactants may be used.Divers manage the risk of pulmonary damage by limiting exposure to levels shown to be generally acceptable by experimental evidence, using a system of accumulated oxygen toxicity units which are based on exposure time at specified partial pressures. In the event of emergency treatment for decompression illness, it may be necessary to exceed normal exposure limits to manage more critical symptoms.Retinopathy of prematurity may regress spontaneously, but should the disease progress beyond a threshold (defined as five contiguous or eight cumulative hours of stage 3 retinopathy of prematurity), both cryosurgery and laser surgery have been shown to reduce the risk of blindness as an outcome. Where the disease has progressed further, techniques such as scleral buckling and vitrectomy surgery may assist in re-attaching the retina.

Repetitive exposure
Repeated exposure to potentially toxic oxygen concentrations in breathing gas is fairly common in hyperbaric activity, particularly in hyperbaric medicine, saturation diving, underwater habitats, and repetitive decompression diving. Research at the National Oceanic and Atmospheric Administration (NOAA) by R.W. Hamilton and others determined acceptable levels of exposure for single and repeated exposures. A distinction is made between acceptable exposure for acute and chronic toxicity, but these are really the extremes of a possible continuous range of exposures. A further distinction can be made between routine exposure and exposure required for emergency treatment, where a higher risk of oxygen toxicity may be justified to achieve a reduction of a more critical injury, particularly when in a relatively safe controlled and monitored environment.
The Repex (repetitive exposure) method, developed in 1988, allows oxygen toxicity dosage to be calculated using a single dose value equivalent to 1 minute at atmospheric pressure called an Oxygen Tolerance Unit (OTU), is used to avoid toxic effects over several days of operetional exposure. Some dive computers will automatically track the dosage bases on depth and selected gas mixture. The limits allow a greater exposure when the person has not been exposed recently, and daily allowable dose decreases with an increase in consecutive days with exposure. These values may not be fully supported by current data.
A more recent proposal uses a simple power equation, Toxicity Index (TI) = t2 × PO2c, where t is time and c is the power term. This was derived from the chemical reactions producing reactive oxygen or nitrogen species, and has been shown to give good predictions for CNS toxicity with c = 6.8 and for pulmonary toxicity for c = 4.57.For pulmonary toxicity, time is in hours, and PO2 in atmospheres absolute, TI should be limited to 250.
For CNS toxicity, time is in minutes, PO2 in atmospheres absolute, and a TI of 26,108 indicates a 1% risk.

Prognosis
Although the convulsions caused by central nervous system oxygen toxicity may lead to incidental injury to the victim, it remained uncertain for many years whether damage to the nervous system following the seizure could occur and several studies searched for evidence of such damage. An overview of these studies by Bitterman in 2004 concluded that following removal of breathing gas containing high fractions of oxygen, no long-term neurological damage from the seizure remains.The majority of infants who have survived following an incidence of bronchopulmonary dysplasia will eventually recover near-normal lung function, since lungs continue to grow during the first 5–7 years and the damage caused by bronchopulmonary dysplasia is to some extent reversible (even in adults). However, they are likely to be more susceptible to respiratory infections for the rest of their lives and the severity of later infections is often greater than that in their peers.Retinopathy of prematurity (ROP) in infants frequently regresses without intervention and eyesight may be normal in later years. Where the disease has progressed to the stages requiring surgery, the outcomes are generally good for the treatment of stage 3 ROP, but are much worse for the later stages. Although surgery is usually successful in restoring the anatomy of the eye, damage to the nervous system by the progression of the disease leads to comparatively poorer results in restoring vision. The presence of other complicating diseases also reduces the likelihood of a favourable outcome.

Epidemiology
The incidence of central nervous system toxicity among divers has decreased since the Second World War, as protocols have developed to limit exposure and partial pressure of oxygen inspired. In 1947, Donald recommended limiting the depth allowed for breathing pure oxygen to 7.6 m (25 ft), which equates to an oxygen partial pressure of 1.8 bar (180 kPa). Over time this limit has been reduced, until today a limit of 1.4 bar (140 kPa) during a recreational dive and 1.6 bar (160 kPa) during shallow decompression stops is generally recommended. Oxygen toxicity has now become a rare occurrence other than when caused by equipment malfunction and human error. Historically, the U.S. Navy has refined its Navy Diving Manual Tables to reduce oxygen toxicity incidents. Between 1995 and 1999, reports showed 405 surface-supported dives using the helium–oxygen tables; of these, oxygen toxicity symptoms were observed on 6 dives (1.5%). As a result, the U.S. Navy in 2000 modified the schedules and conducted field tests of 150 dives, none of which produced symptoms of oxygen toxicity. Revised tables were published in 2001.The variability in tolerance and other variable factors such as workload have resulted in the U.S. Navy abandoning screening for oxygen tolerance. Of the 6,250 oxygen-tolerance tests performed between 1976 and 1997, only 6 episodes of oxygen toxicity were observed (0.1%).Central nervous system oxygen toxicity among patients undergoing hyperbaric oxygen therapy is rare, and is influenced by a number of a factors: individual sensitivity and treatment protocol; and probably therapy indication and equipment used. A study by Welslau in 1996 reported 16 incidents out of a population of 107,264 patients (0.015%), while Hampson and Atik in 2003 found a rate of 0.03%. Yildiz, Ay and Qyrdedi, in a summary of 36,500 patient treatments between 1996 and 2003, reported only 3 oxygen toxicity incidents, giving a rate of 0.008%. A later review of over 80,000 patient treatments revealed an even lower rate: 0.0024%. The reduction in incidence may be partly due to use of a mask (rather than a hood) to deliver oxygen.Bronchopulmonary dysplasia is among the most common complications of prematurely born infants and its incidence has grown as the survival of extremely premature infants has increased. Nevertheless, the severity has decreased as better management of supplemental oxygen has resulted in the disease now being related mainly to factors other than hyperoxia.In 1997 a summary of studies of neonatal intensive care units in industrialised countries showed that up to 60% of low birth weight babies developed retinopathy of prematurity, which rose to 72% in extremely low birth weight babies, defined as less than 1 kg (2.2 lb) at birth. However, severe outcomes are much less frequent: for very low birth weight babies—those less than 1.5 kg (3.3 lb) at birth—the incidence of blindness was found to be no more than 8%.

History
Central nervous system toxicity was first described by Paul Bert in 1878. He showed that oxygen was toxic to insects, arachnids, myriapods, molluscs, earthworms, fungi, germinating seeds, birds, and other animals. Central nervous system toxicity may be referred to as the "Paul Bert effect".Pulmonary oxygen toxicity was first described by J. Lorrain Smith in 1899 when he noted central nervous system toxicity and discovered in experiments in mice and birds that 0.43 bar (43 kPa) had no effect but 0.75 bar (75 kPa) of oxygen was a pulmonary irritant. Pulmonary toxicity may be referred to as the "Lorrain Smith effect". The first recorded human exposure was undertaken in 1910 by Bornstein when two men breathed oxygen at 2.8 bar (280 kPa) for 30 minutes, while he went on to 48 minutes with no symptoms. In 1912, Bornstein developed cramps in his hands and legs while breathing oxygen at 2.8 bar (280 kPa) for 51 minutes. Smith then went on to show that intermittent exposure to a breathing gas with less oxygen permitted the lungs to recover and delayed the onset of pulmonary toxicity.Albert R. Behnke et al. in 1935 were the first to observe visual field contraction (tunnel vision) on dives between 1.0 bar (100 kPa) and 4.1 bar (410 kPa). During World War II, Donald and Yarbrough et al. performed over 2,000 experiments on oxygen toxicity to support the initial use of closed circuit oxygen rebreathers. Naval divers in the early years of oxygen rebreather diving developed a mythology about a monster called "Oxygen Pete", who lurked in the bottom of the Admiralty Experimental Diving Unit "wet pot" (a water-filled hyperbaric chamber) to catch unwary divers. They called having an oxygen toxicity attack "getting a Pete".In the decade following World War II, Lambertsen et al. made further discoveries on the effects of breathing oxygen under pressure and methods of prevention. Their work on intermittent exposures for extension of oxygen tolerance and on a model for prediction of pulmonary oxygen toxicity based on pulmonary function are key documents in the development of standard operating procedures when breathing increased pressures of oxygen. Lambertsens work showing the effect of carbon dioxide in decreasing time to onset of central nervous system symptoms has influenced work from current exposure guidelines to future breathing apparatus design.Retinopathy of prematurity was not observed before World War II, but with the availability of supplemental oxygen in the decade following, it rapidly became one of the principal causes of infant blindness in developed countries. By 1960 the use of oxygen had become identified as a risk factor and its administration restricted. The resulting fall in retinopathy of prematurity was accompanied by a rise in infant mortality and hypoxia-related complications. Since then, more sophisticated monitoring and diagnosis have established protocols for oxygen use which aim to balance between hypoxic conditions and problems of retinopathy of prematurity.Bronchopulmonary dysplasia was first described by Northway in 1967, who outlined the conditions that would lead to the diagnosis. This was later expanded by Bancalari and in 1988 by Shennan, who suggested the need for supplemental oxygen at 36 weeks could predict long-term outcomes. Nevertheless, Palta et al. in 1998 concluded that radiographic evidence was the most accurate predictor of long-term effects.

Bitterman et al. in 1986 and 1995 showed that darkness and caffeine would delay the onset of changes to brain electrical activity in rats. In the years since, research on central nervous system toxicity has centred on methods of prevention and safe extension of tolerance. Sensitivity to central nervous system oxygen toxicity has been shown to be affected by factors such as circadian rhythm, drugs, age, and gender. In 1988, Hamilton et al. wrote procedures for the National Oceanic and Atmospheric Administration to establish oxygen exposure limits for habitat operations. Even today, models for the prediction of pulmonary oxygen toxicity do not explain all the results of exposure to high partial pressures of oxygen.

Society and culture
Recreational scuba divers commonly breathe nitrox containing up to 40% oxygen, while technical divers use pure oxygen or nitrox containing up to 80% oxygen to accelerate decompression. Divers who breathe oxygen fractions greater than of air (21%) need to be educated on the dangers of oxygen toxicity and how to manage the risk. To buy nitrox, a diver may be required to show evidence of relevant qualification.Since the late 1990s the recreational use of oxygen has been promoted by oxygen bars, where customers breathe oxygen through a nasal cannula. Claims have been made that this reduces stress, increases energy, and lessens the effects of hangovers and headaches, despite the lack of any scientific evidence to support them. There are also devices on sale that offer "oxygen massage" and "oxygen detoxification" with claims of removing body toxins and reducing body fat. The American Lung Association has stated "there is no evidence that oxygen at the low flow levels used in bars can be dangerous to a normal persons health", but the U.S. Center for Drug Evaluation and Research cautions that people with heart or lung disease need their supplementary oxygen carefully regulated and should not use oxygen bars.Victorian society had a fascination for the rapidly expanding field of science. In "Dr. Oxs Experiment", a short story written by Jules Verne in 1872, the eponymous doctor uses electrolysis of water to separate oxygen and hydrogen. He then pumps the pure oxygen throughout the town of Quiquendone, causing the normally tranquil inhabitants and their animals to become aggressive and plants to grow rapidly. An explosion of the hydrogen and oxygen in Dr Oxs factory brings his experiment to an end. Verne summarised his story by explaining that the effects of oxygen described in the tale were his own invention (they are not in any way supported by empirical evidence).  There is also a brief episode of oxygen intoxication in his "From the Earth to the Moon".

See also
Effect of oxygen on chronic obstructive pulmonary disease
Nitrogen narcosis – Reversible narcotic effects of respiratory nitrogen at elevated partial pressures

References
Sources
Clark, James M; Thom, Stephen R (2003). "Oxygen under pressure".  In Brubakk, Alf O; Neuman, Tom S (eds.). Bennett and Elliotts physiology and medicine of diving (5th ed.). United States: Saunders. pp. 358–418. ISBN 978-0-7020-2571-6. OCLC 51607923.
Clark, John M; Lambertsen, Christian J (1970). "Pulmonary oxygen tolerance in man and derivation of pulmonary oxygen tolerance curves". IFEM Report No. 1-70. Philadelphia, PA: Environmental Biomedical Stress Data Center, Institute for Environmental Medicine, University of Pennsylvania Medical Center. Archived from the original on 7 October 2008. Retrieved 29 April 2008.
Donald, Kenneth W (1947). "Oxygen Poisoning in Man: Part I". British Medical Journal. 1 (4506): 667–72. doi:10.1136/bmj.1.4506.667. PMC 2053251. PMID 20248086.
Donald, Kenneth W (1947). "Oxygen Poisoning in Man: Part II". British Medical Journal. 1 (4507): 712–17. doi:10.1136/bmj.1.4507.712. PMC 2053400. PMID 20248096.
Revised version of Donalds articles also available as:
Donald, Kenneth W (1992). Oxygen and the diver. UK: Harley Swan, 237 pages. ISBN 1-85421-176-5. OCLC 26894235.
Hamilton, Robert W; Thalmann, Edward D (2003). "Decompression practice".  In Brubakk, Alf O; Neuman, Tom S (eds.). Bennett and Elliotts physiology and medicine of diving (5th ed.). United States: Saunders. pp. 475–79. ISBN 978-0-7020-2571-6. OCLC 51607923.
Lang, Michael A, ed. (2001). DAN nitrox workshop proceedings. Durham, NC: Divers Alert Network, 197 pages. Archived from the original on 16 September 2011. Retrieved 20 September 2008.
Regillo, Carl D; Brown, Gary C; Flynn, Harry W (1998). Vitreoretinal Disease: The Essentials. New York: Thieme, 693 pages. ISBN 978-0-86577-761-3. OCLC 39170393.
U.S. Navy Supervisor of Diving (2011). U.S. Navy Diving Manual (PDF). SS521-AG-PRO-010 0910-LP-106-0957, revision 6 with Change A entered. U.S. Naval Sea Systems Command. Archived from the original (PDF) on 10 December 2014. Retrieved 29 January 2015.

Further reading
Lamb, John S. (1999). The Practice of Oxygen Measurement for Divers. Flagstaff: Best Publishing, 120 pages. ISBN 0-941332-68-3. OCLC 44018369.
Lippmann, John; Bugg, Stan (1993). The Diving Emergency Handbook. Teddington, UK: Underwater World Publications. ISBN 0-946020-18-3. OCLC 52056845.
Lippmann, John; Mitchell, Simon (2005). "Oxygen". Deeper into Diving (2nd ed.). Victoria, Australia: J.L. Publications. pp. 121–24. ISBN 0-9752290-1-X. OCLC 66524750.

External links
General
The following external site is a compendium of resources:

Rubicon Research Repository Archived 8 September 2012 at the Wayback Machine – Online collection of the oxygen toxicity researchSpecialised
The following external sites contain resources specific to particular topics:

2008 Divers Alert Network Technical Diving Conference – Video of "Oxygen Toxicity" lecture by Dr </s>