<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 Carbon monoxide poisoning and can you explain it in depth? [/INST] Carbon monoxide poisoning typically occurs from breathing in carbon monoxide (CO) at excessive levels. Symptoms are often described as "flu-like" and commonly include headache, dizziness, weakness, vomiting, chest pain, and confusion. Large exposures can result in loss of consciousness, arrhythmias, seizures, or death. The classically described "cherry red skin" rarely occurs. Long-term complications may include chronic fatigue, trouble with memory, and movement problems.CO is a colorless and odorless gas which is initially non-irritating. It is produced during incomplete burning of organic matter. This can occur from motor vehicles, heaters, or cooking equipment that run on carbon-based fuels. Carbon monoxide primarily causes adverse effects by combining with hemoglobin to form carboxyhemoglobin (HbCO) preventing the blood from carrying oxygen and expelling carbon dioxide as carbaminohemoglobin. Additionally, many other hemoproteins such as myoglobin, Cytochrome P450, and mitochondrial cytochrome oxidase are affected, along with other metallic and non-metallic cellular targets.Diagnosis is typically based on a HbCO level of more than 3% among nonsmokers and more than 10% among smokers. The biological threshold for carboxyhemoglobin tolerance is typically accepted to be 15% COHb, meaning toxicity is consistently observed at levels in excess of this concentration. The FDA has previously set a threshold of 14% COHb in certain clinical trials evaluating the therapeutic potential of carbon monoxide. In general, 30% COHb is considered severe carbon monoxide poisoning. The highest reported non-fatal carboxyhemoglobin level was 73% COHb.Efforts to prevent poisoning include carbon monoxide detectors, proper venting of gas appliances, keeping chimneys clean, and keeping exhaust systems of vehicles in good repair. Treatment of poisoning generally consists of giving 100% oxygen along with supportive care. This should generally be carried out until symptoms are no longer present and the HbCO level is less than 3%/10%.Carbon monoxide poisoning is relatively common, resulting in more than 20,000 emergency room visits a year in the United States. It is the most common type of fatal poisoning in many countries. In the United States, non-fire related cases result in more than 400 deaths a year. Poisonings occur more often in the winter, particularly from the use of portable generators during power outages. The toxic effects of CO have been known since ancient history. The discovery that hemoglobin is affected by CO emerged with an investigation by James Watt and Thomas Beddoes into the therapeutic potential of hydrocarbonate in 1793, and later confirmed by Claude Bernard between 1846 and 1857.

Background
Carbon monoxide is not toxic to all forms of life, and the toxicity is a classical dose-dependent example of hormesis. Small amounts of carbon monoxide are naturally produced through many enzymatic and non-enzymatic reactions across phylogenetic kingdoms where it can serve as an important neurotransmitter (subcategorized as a gasotransmitter) and a potential therapeutic agent. In the case of prokaryotes, some bacteria produce, consume and respond to carbon monoxide whereas certain other microbes are susceptible to its toxicity. Currently, there are no known adverse effects on photosynthesizing plants.The harmful effects of carbon monoxide are generally considered to be due to tightly binding with the prosthetic heme moiety of hemoproteins that results in interference with cellular operations, for example: carbon monoxide binds with hemoglobin to form carboxyhemoglobin which affects gas exchange and cellular respiration. Inhaling excessive concentrations of the gas can lead to hypoxic injury, nervous system damage, and even death.
As pioneered by Esther Killick, different species and different people across diverse demographics may have different carbon monoxide tolerance levels. The carbon monoxide tolerance level for any person is altered by several factors, including genetics (hemoglobin mutations), behavior such as activity level, rate of ventilation, a pre-existing cerebral or cardiovascular disease, cardiac output, anemia, sickle cell disease and other hematological disorders, geography and barometric pressure, and metabolic rate.

History
Humans have maintained a complex relationship with carbon monoxide since first learning to control fire circa 800,000 BC. Primitive caveman probably discovered the toxicity of carbon monoxide upon introducing fire into their dwellings. The early development of metallurgy and smelting technologies emerging circa 6,000 BC through the Bronze Age likewise plagued humankind with carbon monoxide exposure. Apart from the toxicity of carbon monoxide, indigenous Native Americans may have experienced the neuroactive properties of carbon monoxide through shamanistic fireside rituals.Early civilizations developed mythological tales to explain the origin of fire, such as Vulcan, Pkharmat, and Prometheus from Greek mythology who shared fire with humans. Aristotle (384–322 BC) first recorded that burning coals produced toxic fumes. Greek physician Galen (129–199 AD) speculated that there was a change in the composition of the air that caused harm when inhaled, and symptoms of CO poisoning appeared in Cassius Iatrosophistas Quaestiones Medicae et Problemata Naturalia circa 130 AD. Julian the Apostate, Caelius Aurelianus, and several others similarly documented early knowledge of the toxicity symptoms of carbon monoxide poisoning as caused by coal fumes in the ancient era.Documented cases by Livy and Cicero allude to carbon monoxide being used as a method of suicide in ancient Rome. Emperor Lucius Verus used smoke to execute prisoners. Many deaths have been linked to carbon monoxide poisoning including Emperor Jovian, Empress Fausta, and Seneca. The most high-profile death by carbon monoxide poisoning may possibly have been Cleopatra or Edgar Allan Poe.In the fifteenth century, coal miners believed sudden death was caused by evil spirits; carbon monoxide poisoning has been linked to supernatural and paranormal experiences, witchcraft, etc. throughout the following centuries including in the modern present day exemplified by Carrie Poppys investigations.Georg Ernst Stahl mentioned carbonarii halitus in 1697 in reference to toxic vapors thought to be carbon monoxide. Friedrich Hoffmann conducted the first modern scientific investigation into carbon monoxide poisoning from coal in 1716, notably rejecting villagers attributing death to demonic superstition. Herman Boerhaave conducted the first scientific experiments on the effect of carbon monoxide (coal fumes) on animals in the 1730s. Joseph Priestley is credited with first synthesizing carbon monoxide in 1772 which he had called heavy inflammable air, and Carl Wilhelm Scheele isolated carbon monoxide from coal in 1773 suggesting it to be the toxic entity.The dose-dependent risk of carbon monoxide poisoning as hydrocarbonate was investigated in the late 1790s by Thomas Beddoes, James Watt, Tiberius Cavallo, James Lind, Humphry Davy, and many others in the context of inhalation of factitious airs, much of which occurred at the Pneumatic Institution.William Cruickshank discovered carbon monoxide as a molecule containing one carbon and one oxygen atom in 1800, thereby initiating the modern era of research exclusively focused on carbon monoxide. The mechanism for toxicity was first suggested by James Watt in 1793, followed by Adrien Chenot in 1854 and finally demonstrated by Claude Bernard after 1846 as published in 1857 and also independently published by Felix Hoppe-Seyler in the same year.The first controlled clinical trial studying the toxicity of carbon monoxide occurred in 1973.

Historical detection
Carbon monoxide poisoning has plagued coal miners for many centuries. In the context of mining, carbon monoxide is widely known as whitedamp. John Scott Haldane identified carbon monoxide as the lethal constituent of afterdamp, the gas created by combustion, after examining many bodies of miners killed in pit explosions. By 1911, Haldane introduced the use of small animals for miners to detect dangerous levels of carbon monoxide underground, either white mice or canaries which have little tolerance for carbon monoxide thereby offering an early warning, i.e. Canary in a coal mine. The canary in British pits was replaced in 1986 by the electronic gas detector.
The first qualitative analytical method to detect carboxyhemoglobin emerged in 1858 with a colorimetric method developed by Felix Hoppe-Seyler, and the first quantitative analysis method emerged in 1880 with Josef von Fodor.

Historical treatment
The use of oxygen emerged with anecdotal reports such as Humphry Davy having been treated with oxygen in 1799 upon inhaling three quarts of hydrocarbonate (water gas). Samuel Witter developed an oxygen inhalation protocol in response to carbon monoxide poisoning in 1814. Similarly, an oxygen inhalation protocol was recommend for malaria (literally translated to "bad air") in 1830 based on malaria symptoms aligning with carbon monoxide poisoning. Other oxygen protocols emerged in the late 1800s. The use of hyperbaric oxygen in rats following poisoning was studied by Haldane in 1895 while its use in humans began in the 1960s.

Incidents
The worst accidental mass poisoning from carbon monoxide was the Balvano train disaster which occurred on 3 March 1944 in Italy, when a freight train with many illegal passengers stalled in a tunnel, leading to the death of over 500 people.Over 50 people are suspected to have died from smoke inhalation as a result of the Branch Davidian Massacre during the Siege of Waco in 1993.

Weaponization
In ancient history, Hannibal executed Roman prisoners with coal fumes during the Second Punic War.The extermination of stray dogs by a carbon monoxide gas chamber was described in 1874. In 1884, an article appeared in Scientific American describing the use of a carbon monoxide gas chamber for slaughterhouse operations as well as euthanizing a variety of animals.As part of the Holocaust during World War II, the Nazis used gas vans at Chelmno extermination camp and elsewhere to murder an estimated over 700,000 people by carbon monoxide poisoning. This method was also used in the gas chambers of several death camps such as Treblinka, Sobibor, and Belzec. Gassing with carbon monoxide started in Action T4. The gas was supplied by IG Farben in pressurized cylinders and fed by tubes into the gas chambers built at various mental hospitals, such as Hartheim Euthanasia Centre. Exhaust fumes from tank engines, for example, were used to supply the gas to the chambers.Recently, carbon monoxide gas chambers have been used to facilitate capital punishment exemplified by execution practices at the San Quentin State Prison.

Physiology
Carbon monoxide is produced naturally by many physiologically relevant enzymatic and non-enzymatic reactions best exemplified by heme oxygenase catalyzing the biotransformation of heme (an iron protoporphyrin) into biliverdin and eventually bilirubin. Aside from physiological signaling, most carbon monoxide is stored as carboxyhemoglobin at non-toxic levels below 3% HbCO.

Therapeutics
Small amounts of CO are beneficial and enzymes exist that produce it at times of oxidative stress. A variety of drugs are being developed to introduce small amounts of CO, these drugs are commonly called carbon monoxide-releasing molecules. Historically, the therapeutic potential of factitious airs, notably carbon monoxide as hydrocarbonate, was investigated by Thomas Beddoes, James Watt, Tiberius Cavallo, James Lind, Humphry Davy, and others in many labs such as the Pneumatic Institution.

Signs and symptoms
On average, exposures at 100 ppm or greater is dangerous to human health. In the United States, the OSHA limits long-term workplace exposure levels to less than 50 ppm averaged over an 8-hour period; in addition, employees are to be removed from any confined space if an upper limit ("ceiling") of 100 ppm is reached.

Acute poisoning
The main manifestations of carbon monoxide poisoning develop in the organ systems most dependent on oxygen use, the central nervous system and the heart. The initial symptoms of acute carbon monoxide poisoning include headache, nausea, malaise, and fatigue. These symptoms are often mistaken for a virus such as influenza or other illnesses such as food poisoning or gastroenteritis. Headache is the most common symptom of acute carbon monoxide poisoning; it is often described as dull, frontal, and continuous. Increasing exposure produces cardiac abnormalities including fast heart rate, low blood pressure, and cardiac arrhythmia; central nervous system symptoms include delirium, hallucinations, dizziness, unsteady gait, confusion, seizures, central nervous system depression, unconsciousness, respiratory arrest, and death. Less common symptoms of acute carbon monoxide poisoning include myocardial ischemia, atrial fibrillation, pneumonia, pulmonary edema, high blood sugar, lactic acidosis, muscle necrosis, acute kidney failure, skin lesions, and visual and auditory problems. Carbon monoxide exposure may lead to a significantly shorter life span due to heart damage.One of the major concerns following acute carbon monoxide poisoning is the severe delayed neurological manifestations that may occur. Problems may include difficulty with higher intellectual functions, short-term memory loss, dementia, amnesia, psychosis, irritability, a strange gait, speech disturbances, Parkinsons disease-like syndromes, cortical blindness, and a depressed mood. Depression may occur in those who did not have pre-existing depression. These delayed neurological sequelae may occur in up to 50% of poisoned people after 2 to 40 days. It is difficult to predict who will develop delayed sequelae; however, advanced age, loss of consciousness while poisoned, and initial neurological abnormalities may increase the chance of developing delayed symptoms.

Chronic poisoning
Chronic exposure to relatively low levels of carbon monoxide may cause persistent headaches, lightheadedness, depression, confusion, memory loss, nausea, hearing disorders and vomiting. It is unknown whether low-level chronic exposure may cause permanent neurological damage. Typically, upon removal from exposure to carbon monoxide, symptoms usually resolve themselves, unless there has been an episode of severe acute poisoning. However, one case noted permanent memory loss and learning problems after a three-year exposure to relatively low levels of carbon monoxide from a faulty furnace.Chronic exposure may worsen cardiovascular symptoms in some people. Chronic carbon monoxide exposure might increase the risk of developing atherosclerosis. Long-term exposures to carbon monoxide present the greatest risk to persons with coronary heart disease and in females who are pregnant.In experimental animals, carbon monoxide appears to worsen noise-induced hearing loss at noise exposure conditions that would have limited effects on hearing otherwise. In humans, hearing loss has been reported following carbon monoxide poisoning. Unlike the findings in animal studies, noise exposure was not a necessary factor for the auditory problems to occur.

Fatal poisoning
One classic sign of carbon monoxide poisoning is more often seen in the dead rather than the living – people have been described as looking red-cheeked and healthy (see below). However, since this "cherry-red" appearance is more common in the dead, it is not considered a useful diagnostic sign in clinical medicine. In autopsy examinations, the appearance of carbon monoxide poisoning is notable because unembalmed dead persons are normally bluish and pale, whereas dead carbon-monoxide poisoned people may appear unusually lifelike in coloration. The colorant effect of carbon monoxide in such postmortem circumstances is thus analogous to its use as a red colorant in the commercial meat-packing industry.

Epidemiology
The true number of cases of carbon monoxide poisoning is unknown, since many non-lethal exposures go undetected. From the available data, carbon monoxide poisoning is the most common cause of injury and death due to poisoning worldwide. Poisoning is typically more common during the winter months. This is due to increased domestic use of gas furnaces, gas or kerosene space heaters, and kitchen stoves during the winter months, which if faulty and/or used without adequate ventilation, may produce excessive carbon monoxide. Carbon monoxide detection and poisoning also increases during power outages, when electric heating and cooking appliances become inoperative and residents may temporarily resort to fuel-burning space heaters, stoves, and grills (some of which are safe only for outdoor use but nonetheless are errantly burned indoors).It has been estimated that more than 40,000 people per year seek medical attention for carbon monoxide poisoning in the United States. 95% of carbon monoxide poisoning deaths in the United States are due to gas space heaters. In many industrialized countries, carbon monoxide is the cause of more than 50% of fatal poisonings. In the United States, approximately 200 people die each year from carbon monoxide poisoning associated with home fuel-burning heating equipment. Carbon monoxide poisoning contributes to the approximately 5613 smoke inhalation deaths each year in the United States. The CDC reports, "Each year, more than 500 Americans die from unintentional carbon monoxide poisoning, and more than 2,000 commit suicide by intentionally poisoning themselves." For the 10-year period from 1979 to 1988, 56,133 deaths from carbon monoxide poisoning occurred in the United States, with 25,889 of those being suicides, leaving 30,244 unintentional deaths. A report from New Zealand showed that 206 people died from carbon monoxide poisoning in the years of 2001 and 2002. In total carbon monoxide poisoning was responsible for 43.9% of deaths by poisoning in that country. In South Korea, 1,950 people had been poisoned by carbon monoxide with 254 deaths from 2001 through 2003. A report from Jerusalem showed 3.53 per 100,000 people were poisoned annually from 2001 through 2006. In Hubei, China, 218 deaths from poisoning were reported over a 10-year period with 16.5% being from carbon monoxide exposure.

Causes
Carbon monoxide is a product of combustion of organic matter under conditions of restricted oxygen supply, which prevents complete oxidation to carbon dioxide (CO2). Sources of carbon monoxide include cigarette smoke, house fires, faulty furnaces, heaters, wood-burning stoves, internal combustion vehicle exhaust, electrical generators, propane-fueled equipment such as portable stoves, and gasoline-powered tools such as leaf blowers, lawn mowers, high-pressure washers, concrete cutting saws, power trowels, and welders. Exposure typically occurs when equipment is used in buildings or semi-enclosed spaces.Riding in the back of pickup trucks has led to poisoning in children. Idling automobiles with the exhaust pipe blocked by snow has led to the poisoning of car occupants. Any perforation between the exhaust manifold and shroud can result in exhaust gases reaching the cabin. Generators and propulsion engines on boats, especially houseboats, has resulted in fatal carbon monoxide exposures.Poisoning may also occur following the use of a self-contained underwater breathing apparatus (SCUBA) due to faulty diving air compressors.In caves carbon monoxide can build up in enclosed chambers due to the presence of decomposing organic matter. In coal mines incomplete combustion may occur during explosions resulting in the production of afterdamp. The gas is up to 3% CO and may be fatal after just a single breath. Following an explosion in a colliery, adjacent interconnected mines may become dangerous due to the afterdamp leaking from mine to mine. Such an incident followed the Trimdon Grange explosion which killed men in the Kelloe mine.Another source of poisoning is exposure to the organic solvent dichloromethane, also known as methylene chloride, found in some paint strippers, as the metabolism of dichloromethane produces carbon monoxide. In November 2019, an EPA ban on dichloromethane in paint strippers for consumer use took effect in the United States.

Prevention
Detectors
Prevention remains a vital public health issue, requiring public education on the safe operation of appliances, heaters, fireplaces, and internal-combustion engines, as well as increased emphasis on the installation of carbon monoxide detectors. Carbon monoxide is tasteless, odourless, and colourless, and therefore can not be detected by visual cues or smell.The United States Consumer Product Safety Commission has stated, "carbon monoxide detectors are as important to home safety as smoke detectors are," and recommends each home have at least one carbon monoxide detector, and preferably one on each level of the building. These devices, which are relatively inexpensive and widely available, are either battery- or AC-powered, with or without battery backup. In buildings, carbon monoxide detectors are usually installed around heaters and other equipment. If a relatively high level of carbon monoxide is detected, the device sounds an alarm, giving people the chance to evacuate and ventilate the building. Unlike smoke detectors, carbon monoxide detectors do not need to be placed near ceiling level.
The use of carbon monoxide detectors has been standardized in many areas. In the US, NFPA 720–2009, the carbon monoxide detector guidelines published by the National Fire Protection Association, mandates the placement of carbon monoxide detectors/alarms on every level of the residence, including the basement, in addition to outside sleeping areas. In new homes, AC-powered detectors must have battery backup and be interconnected to ensure early warning of occupants at all levels. NFPA 720-2009 is the first national carbon monoxide standard to address devices in non-residential buildings. These guidelines, which now pertain to schools, healthcare centers, nursing homes, and other non-residential buildings, include three main points:
1. A secondary power supply (battery backup) must operate all carbon monoxide notification appliances for at least 12 hours,
2. Detectors must be on the ceiling in the same room as permanently installed fuel-burning appliances, and
3. Detectors must be located on every habitable level and in every HVAC zone of the building.Gas organizations will often recommend getting gas appliances serviced at least once a year.

Legal requirements
The NFPA standard is not necessarily enforced by law. As of April 2006, the US state of Massachusetts requires detectors to be present in all residences with potential CO sources, regardless of building age and whether they are owner-occupied or rented. This is enforced by municipal inspectors and was inspired by the death of 7-year-old Nicole Garofalo in 2005 due to snow blocking a home heating vent. Other jurisdictions may have no requirement or only mandate detectors for new construction or at time of sale.
Despite similar deaths in vehicles with clogged exhaust pipes (for example in the Northeastern United States blizzard of 1978 and February 2013 noreaster) and the commercial availability of the equipment, there is no legal requirement for automotive CO detectors.

World Health Organization recommendations
The following guideline values (ppm values rounded) and periods of time-weighted average exposures have been determined in such a way that the carboxyhaemoglobin (COHb) level of 2.5% is not exceeded, even when a normal subject engages in light or moderate exercise:

100 mg/m3 (87 ppm) for 15 min
60 mg/m3 (52 ppm) for 30 min
30 mg/m3 (26 ppm) for 1 h
10 mg/m3 (9 ppm) for 8 h
7 mg/m3 (6 ppm) for 24 h (for indoor air quality, so as not to exceed 2% COHb for chronic exposure)

Diagnosis
As many symptoms of carbon monoxide poisoning also occur with many other types of poisonings and infections (such as the flu), the diagnosis is often difficult. A history of potential carbon monoxide exposure, such as being exposed to a residential fire, may suggest poisoning, but the diagnosis is confirmed by measuring the levels of carbon monoxide in the blood. This can be determined by measuring the amount of carboxyhemoglobin compared to the amount of hemoglobin in the blood.The ratio of carboxyhemoglobin to hemoglobin molecules in an average person may be up to 5%, although cigarette smokers who smoke two packs per day may have levels up to 9%. In symptomatic poisoned people they are often in the 10–30% range, while persons who die may have postmortem blood levels of 30–90%.As people may continue to experience significant symptoms of CO poisoning long after their blood carboxyhemoglobin concentration has returned to normal, presenting to examination with a normal carboxyhemoglobin level (which may happen in late states of poisoning) does not rule out poisoning.

Measuring
Carbon monoxide may be quantitated in blood using spectrophotometric methods or chromatographic techniques in order to confirm a diagnosis of poisoning in a person or to assist in the forensic investigation of a case of fatal exposure.
A CO-oximeter can be used to determine carboxyhemoglobin levels. Pulse CO-oximeters estimate carboxyhemoglobin with a non-invasive finger clip similar to a pulse oximeter. These devices function by passing various wavelengths of light through the fingertip and measuring the light absorption of the different types of hemoglobin in the capillaries. The use of a regular pulse oximeter is not effective in the diagnosis of carbon monoxide poisoning as these devices may be unable to distinguish carboxyhemoglobin from oxyhemoglobin.Breath CO monitoring offers an alternative to pulse CO-oximetry. Carboxyhemoglobin levels have been shown to have a strong correlation with breath CO concentration. However, many of these devices require the user to inhale deeply and hold their breath to allow the CO in the blood to escape into the lung before the measurement can be made. As this is not possible in people who are unresponsive, these devices may not appropriate for use in on-scene emergency care detection of CO poisoning.

Differential diagnosis
There are many conditions to be considered in the differential diagnosis of carbon monoxide poisoning. The earliest symptoms, especially from low level exposures, are often non-specific and readily confused with other illnesses, typically flu-like viral syndromes, depression, chronic fatigue syndrome, chest pain, and migraine or other headaches. Carbon monoxide has been called a "great mimicker" due to the presentation of poisoning being diverse and nonspecific. Other conditions included in the differential diagnosis include acute respiratory distress syndrome, altitude sickness, lactic acidosis, diabetic ketoacidosis, meningitis, methemoglobinemia, or opioid or toxic alcohol poisoning.

Treatment
Initial treatment for carbon monoxide poisoning is to immediately remove the person from the exposure without endangering further people. Those who are unconscious may require CPR on site. Administering oxygen via non-rebreather mask shortens the half-life of carbon monoxide from 320 minutes, when breathing normal air, to only 80 minutes. Oxygen hastens the dissociation of carbon monoxide from carboxyhemoglobin, thus turning it back into hemoglobin. Due to the possible severe effects in the baby, pregnant women are treated with oxygen for longer periods of time than non-pregnant people.

Hyperbaric oxygen
Hyperbaric oxygen is also used in the treatment of carbon monoxide poisoning, as it may hasten dissociation of CO from carboxyhemoglobin and cytochrome oxidase to a greater extent than normal oxygen. Hyperbaric oxygen at three times atmospheric pressure reduces the half life of carbon monoxide to 23 (~80/3 minutes) minutes, compared to 80 minutes for oxygen at regular atmospheric pressure. It may also enhance oxygen transport to the tissues by plasma, partially bypassing the normal transfer through hemoglobin. However, it is controversial whether hyperbaric oxygen actually offers any extra benefits over normal high flow oxygen, in terms of increased survival or improved long-term outcomes. There have been randomized controlled trials in which the two treatment options have been compared; of the six performed, four found hyperbaric oxygen improved outcome and two found no benefit for hyperbaric oxygen. Some of these trials have been criticized for apparent flaws in their implementation. A review of all the literature concluded that the role of hyperbaric oxygen is unclear and the available evidence neither confirms nor denies a medically meaningful benefit. The authors suggested a large, well designed, externally audited, multicentre trial to compare normal oxygen with hyperbaric oxygen. While hyperbaric oxygen therapy is used for severe poisonings, the benefit over standard oxygen delivery is unclear.

Other
Further treatment for other complications such as seizure, hypotension, cardiac abnormalities, pulmonary edema, and acidosis may be required. Increased muscle activity and seizures should be treated with dantrolene or diazepam; diazepam should only be given with appropriate respiratory support. Hypotension requires treatment with intravenous fluids; vasopressors may be required to treat myocardial depression. Cardiac dysrhythmias are treated with standard advanced cardiac life support protocols. If severe, metabolic acidosis is treated with sodium bicarbonate. Treatment with sodium bicarbonate is controversial as acidosis may increase tissue oxygen availability. Treatment of acidosis may only need to consist of oxygen therapy. The delayed development of neuropsychiatric impairment is one of the most serious complications of carbon monoxide poisoning. Brain damage is confirmed following MRI or CAT scans. Extensive follow up and supportive treatment is often required for delayed neurological damage. Outcomes are often difficult to predict following poisoning, especially people who have symptoms of cardiac arrest, coma, metabolic acidosis, or have high carboxyhemoglobin levels. One study reported that approximately 30% of people with severe carbon monoxide poisoning will have a fatal outcome. It has been reported that electroconvulsive therapy (ECT) may increase the likelihood of delayed neuropsychiatric sequelae (DNS) after carbon monoxide (CO) poisoning. A device that also provides some carbon dioxide to stimulate faster breathing (sold under the brand name ClearMate) may also be used.

Pathophysiology
The precise mechanisms by which the effects of carbon monoxide are induced upon bodily systems are complex and not yet fully understood. Known mechanisms include carbon monoxide binding to hemoglobin, myoglobin and mitochondrial cytochrome c oxidase and restricting oxygen supply, and carbon monoxide causing brain lipid peroxidation.

Hemoglobin
Carbon monoxide has a higher diffusion coefficient compared to oxygen, and the main enzyme in the human body that produces carbon monoxide is heme oxygenase, which is located in nearly all cells and platelets. Most endogenously produced CO is stored bound to hemoglobin as carboxyhemoglobin. The simplistic understanding for the mechanism of carbon monoxide toxicity is based on excess carboxyhemoglobin decreasing the oxygen-delivery capacity of the blood to tissues throughout the body. In humans, the affinity between hemoglobin and carbon monoxide is approximately 240 times stronger than the affinity between hemoglobin and oxygen. However, certain mutations such as the Hb-Kirklareli mutation has a relative 80,000 times greater affinity for carbon monoxide than oxygen resulting in systemic carboxyhemoglobin reaching a sustained level of 16% COHb.Hemoglobin is a tetramer with four prosthetic heme groups to serve as oxygen binding sites. The average red blood cell contains 250 million hemoglobin molecules, therefore 1 billion heme sites capable of binding gas. The binding of carbon monoxide at any one of these sites increases the oxygen affinity of the remaining three sites, which causes the hemoglobin molecule to retain oxygen that would otherwise be delivered to the tissue; therefore carbon monoxide binding at any site may be as dangerous as carbon monoxide binding to all sites. Delivery of oxygen is largely driven by the Bohr effect and Haldane effect. To provide a simplified synopsis of the molecular mechanism of systemic gas exchange in laymans terms, upon inhalation of air it was widely thought oxygen binding to any of the heme sites triggers a conformational change in the globin/protein unit of hemoglobin which then enables the binding of additional oxygen to each of the other vacant heme sites. Upon arrival to the cell/tissues, oxygen release into the tissue is driven by "acidification" of the local pH (meaning a relatively higher concentration of acidic protons/hydrogen ions) caused by an increase in the biotransformation of carbon dioxide waste into carbonic acid via carbonic anhydrase. In other words, oxygenated arterial blood arrives at cells in the "hemoglobin R-state" which has deprotonated/unionized amino acid residues (regarding nitrogen/amines) due to the less-acidic arterial pH environment (arterial blood averages pH 7.407 whereas venous blood is slightly more acidic at pH 7.371). The "T-state" of hemoglobin is deoxygenated in venous blood partially due to protonation/ionization caused by the acidic environment hence causing a conformation unsuited for oxygen-binding (in other words, oxygen is ejected upon arrival to the cell because acid "attacks" the amines of hemoglobin causing ionization/protonation of the amine residues resulting in a conformation change unsuited for retaining oxygen). Furthermore, the mechanism for formation of carbaminohemoglobin generates additional acidic hydrogen ions that may further stabilize the protonated/ionized deoxygenated hemoglobin. Upon return of venous blood into the lung and subsequent exhalation of carbon dioxide, the blood is "de-acidified" (see also: hyperventilation) allowing for the deprotonation/unionization of hemoglobin to then re-enable oxygen-binding as part of the transition to arterial blood (note this process is complex due to involvement of chemoreceptors and other physiological functionalities). Carbon monoxide is not ejected due to acid, therefore carbon monoxide poisoning disturbs this physiological process hence the venous blood of poisoning patients is bright red akin to arterial blood since the carbonyl/carbon monoxide is retained. Hemoglobin is dark in deoxygenated venous blood, but it has a bright red color when carrying blood in oxygenated arterial blood and when converted into carboxyhemoglobin in both arterial and venous blood, so poisoned cadavers and even commercial meats treated with carbon monoxide acquire an unnatural lively reddish hue.At toxic concentrations, carbon monoxide as carboxyhemoglobin significantly interferes with respiration and gas exchange by simultaneously inhibiting acquisition and delivery of oxygen to cells and preventing formation of carbaminohemoglobin which accounts for approximately 30% of carbon dioxide exportation. Therefore, a patient with carbon monoxide poisoning may experience severe hypoxia and acidosis (potentially both respiratory acidosis and metabolic acidosis) in addition to the toxicities of excess carbon monoxide inhibiting numerous hemoproteins, metallic and non-metallic targets which affect cellular machinery.

Myoglobin
Carbon monoxide also binds to the hemeprotein myoglobin. It has a high affinity for myoglobin, about 60 times greater than that of oxygen. Carbon monoxide bound to myoglobin may impair its ability to utilize oxygen. This causes reduced cardiac output and hypotension, which may result in brain ischemia. A delayed return of symptoms have been reported. This results following a recurrence of increased carboxyhemoglobin levels; this effect may be due to a late release of carbon monoxide from myoglobin, which subsequently binds to hemoglobin.

Cytochrome oxidase
Another mechanism involves effects on the mitochondrial respiratory enzyme chain that is responsible for effective tissue utilization of oxygen. Carbon monoxide binds to cytochrome oxidase with less affinity than oxygen, so it is possible that it requires significant intracellular hypoxia before binding. This binding interferes with aerobic metabolism and efficient adenosine triphosphate synthesis. Cells respond by switching to anaerobic metabolism, causing anoxia, lactic acidosis, and eventual cell death. The rate of dissociation between carbon monoxide and cytochrome oxidase is slow, causing a relatively prolonged impairment of oxidative metabolism.

Central nervous system effects
The mechanism that is thought to have a significant influence on delayed effects involves formed blood cells and chemical mediators, which cause brain lipid peroxidation (degradation of unsaturated fatty acids). Carbon monoxide causes endothelial cell and platelet release of nitric oxide, and the formation of oxygen free radicals including peroxynitrite. In the brain this causes further mitochondrial dysfunction, capillary leakage, leukocyte sequestration, and apoptosis. The result of these effects is lipid peroxidation, which causes delayed reversible demyelination of white matter in the central nervous system known as Grinker myelinopathy, which can lead to edema and necrosis within the brain </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 Cryptogenic organizing pneumonia and can you explain it in depth? [/INST] Cryptogenic organizing pneumonia (COP), formerly known as bronchiolitis obliterans organizing pneumonia (BOOP), is an inflammation of the bronchioles (bronchiolitis) and surrounding tissue in the lungs. It is a form of idiopathic interstitial pneumonia.It is often a complication of an existing chronic inflammatory disease such as rheumatoid arthritis, dermatomyositis, or it can be a side effect of certain medications such as amiodarone. COP was first described by Gary Epler in 1985.The clinical features and radiological imaging resemble infectious pneumonia. However, diagnosis is suspected after there is no response to multiple antibiotics, and blood and sputum cultures are negative for organisms.

Terminology
"Organizing" refers to unresolved pneumonia (in which the alveolar exudate persists and eventually undergoes fibrosis) in which fibrous tissue forms in the alveoli. The phase of resolution and/or remodeling following bacterial infections is commonly referred to as organizing pneumonia, both clinically and pathologically.
The American Thoracic Society and the European Respiratory Society hold that "cryptogenic organizing pneumonia" is the preferred clinical term for this disease for multiple reasons:
Avoid confusion with bronchiolitis obliterans, which may not be visualized in every case of this disease.
Avoid confusion with constrictive bronchiolitis
Emphasize the cryptogenic nature of the disease

Signs and symptoms
The classic presentation of COP is the development of nonspecific systemic (e.g., fevers, chills, night sweats, fatigue, weight loss) and respiratory (e.g. difficulty breathing, cough) symptoms in association with filling of the lung alveoli that is visible on chest x-ray. This presentation is usually so suggestive of an infection that the majority of patients with COP have been treated with at least one failed course of antibiotics by the time the true diagnosis is made. Symptoms are usually subacute, occurring over weeks to months with dry cough (seen in 71% of people), dyspnea (shortness of breath)(62%) and fever (44%) being the most common symptoms.

Causes
Pulmonary infection by bacteria, viruses and parasites
Drugs: antineoplastic drugs, erlotinib, amiodarone
Chemical exposure, most notably to diacetylVaping: On October 17, 2019, the American Journal of Clinical Pathology reported that lung biopsies from patients with vaping-associated pulmonary illness show acute lung injury patterns, including organizing pneumonia.
Ionizing radiations
Inflammatory diseases
Systemic lupus
Rheumatoid arthritis (RA-associated COP)
Scleroderma
Bronchial obstruction
Proximal bronchial squamous cell carcinoma
SARS-CoV-2
Analysis of COVID-19 CT imaging along with postmortem lung biopsies and autopsies suggest that the majority of patients with COVID-19 pulmonary involvement also have secondary organizing pneumonia (OP) or its histological variant, acute fibrinous and organizing pneumonia, which are both well-known complications of viral infections. It was identified in 1985, although its symptoms had been noted before but not recognised as a separate lung disease. The risk of COP is higher for people with inflammatory diseases like lupus, dermatomyositis, rheumatoid arthritis, and scleroderma. It most commonly presents in the 5th or 6th decade of life and it is exceedingly rare in children.

Pathophysiology
Organizing pneumonia is usually preceded by some type of lung injury that causes a localized denudation or disruption in continuity of the epithelial basal laminae of the type 1 alveolar pneumocytes that line the alveoli. This injury to the epithelial basal lamina results in inflammatory cells and plasma proteins leaking into the alveolar space and forming fibrin, resulting in an initial fibroblast driven intra-alveolar fibroproliferation. The fibroblasts differentiate into myofibroblasts and continue to form fibrosis resulting in intra-alveolar fibroinflammatory buds (Massons Bodies) that are characteristic of organizing pneumonia. These Massons bodies consist of inflammatory cells contained in an extracellular matrix consisting of type I collagen, fibronectin, procollagen type III, tenascin C and proteoglycans. Angiogenesis , or the formation of blood vessels, occurs in the Massons bodies and this is driven by vascular endothelial growth factor. Remodeling occurs, resulting in the intra-alveolar fibroinflammatory buds (Massons Bodies) moving into the interstitial space and forming collagen globules that are then covered by type 1 alveolar epithelial cells with well developed basement membranes. These type 1 alveolar epithelial cells (pneumocytes) then proliferate, restoring the continuity and function of the alveolar unit. This process is in contrast to the histopathologic changes seen in usual interstitial pneumonia where extensive fibrosis and inflammation occur leading to fibroblastic foci to form in the alveolar spaces resulting in obliteration of the alveolar space, scarring and significant damage to lung architecture (the alveoli).Tissue inhibitors of metalloproteinases (which inhibit breakdown of the extracellular matrix connective tissue) are more active in usual interstitial pneumonia as compared to organizing pneumonia, this is thought to lead to a greater deposition of connective tissue in the alveolar space in interstitial pneumonia as compared to organizing pneumonia and may explain the progressive, irreversible fibrosis seen in usual interstitial pneumonia. Gelatinolytic activity (resulting in the breakdown of extracellular matrix connective tissue) is greater in organizing pneumonia as compared to usual interstitial pneumonia, and this is thought to contribute to the reversible fibroproliferation characteristic of organizing pneumonia.

Diagnosis
On clinical examination, crackles are common, and more rarely, patients may have clubbing (<5% of cases). Laboratory findings are nonspecific but inflammatory markers such as the erythrocyte sedimentation rate or C-reactive protein and the lymphocyte count are frequently elevated. If the organizing pneumonia is secondary to a connective tissue disorder, then the associated laboratory values such as the anti-nuclear antibody, rheumatoid factor, anti-citrullinated protein antibodies, anti-dsDNA antibodies and other similar connective tissue associated antibodies are elevated.Pulmonary function testing in people with organizing pneumonia, either cryptogenic or due to secondary causes, shows a restrictive defect with a decrease in the gas absorptive capacity of the lungs (seen as a decrease in the diffusion capacity of carbon monoxide). Airflow obstruction is usually not seen on pulmonary function testing.Bronchoscopy with bronchoalveolar lavage is recommended in possible cases of organizing pneumonia to rule out infection and other causes of alveolar infiltrates. The bronchoalveolar lavage in organizing pneumonia shows a lymphocytic predominant inflammation of the alveoli with increases in neutrophils and eosinophils. Resolution of inflammatory cells in the bronchoalveolar lavage is usually delayed in organizing pneumonia, lagging behind clinical and radiographic improvement.Biopsy findings in patients with organizing pneumonia consist of loose connective tissue plugs involving the alveoli, alveolar ducts and bronchioles. The loose connective tissue plugs occupying the alveolar spaces often connect to other connective tissue plugs in nearby alveoli via the pores of Kohn creating a characteristic butterfly pattern on histology. There is usually minimal to no interstitial inflammatory changes in biopsies of organizing pneumonia.

Imaging
The chest x-ray is distinctive with features that appear similar to an extensive pneumonia, with both lungs showing widespread white patches. The white patches may seem to migrate from one area of the lung to another as the disease persists or progresses. Computed tomography (CT) may be used to confirm the diagnosis. Often the findings are typical enough to allow the doctor to make a diagnosis without ordering additional tests. To confirm the diagnosis, a doctor may perform a lung biopsy using a bronchoscope. Many times, a larger specimen is needed and must be removed surgically.
Plain chest radiography shows normal lung volumes, with characteristic patchy unilateral or bilateral consolidation. Small nodular opacities occur in up to 50% of patients and large nodules in 15% </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 Alpha-thalassemia and can you explain it in depth? [/INST] Alpha-thalassemia (α-thalassemia, α-thalassaemia) is a form of thalassemia involving the genes HBA1 and HBA2. Thalassemias are a group of inherited blood conditions which result in the impaired production of hemoglobin, the molecule that carries oxygen in the blood. Normal hemoglobin consists of two alpha chains and two beta chains; in alpha-thalassemia, there is a quantitative decrease in the amount of alpha chains, resulting in fewer normal hemoglobin molecules. Furthermore, alpha-thalassemia leads to the production of unstable beta globin molecules which cause increased red blood cell destruction. The degree of impairment is based on which clinical phenotype is present (how many genes are affected).

Signs and symptoms
The presentation of individuals with alpha-thalassemia consists of:

Cause
Alpha-thalassemias are most commonly inherited in a Mendelian recessive manner. They are also associated with deletions of chromosome 16p. Alpha thalassemia can also be acquired under rare circumstances.

Pathophysiology
The mechanism sees that α thalassemias results in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns. The excess β chains form unstable tetramers called hemoglobin H or HbH of four beta chains. The excess γ chains form tetramers which are poor carriers of O2 since their affinity for O2 is too high, so it is not dissociated in the periphery. Homozygote α0 thalassaemias, where numerous γ4 but no α-globins occur at all (referred to as Hb Barts), often result in death soon after birth.

Diagnosis
Diagnosis of alpha-thalassemia is primarily by laboratory evaluation and molecular diagnosis. Alpha-thalassemia can be mistaken for iron-deficiency anaemia on a full blood count or blood film, as both conditions have a microcytic anaemia. Serum iron and serum ferritin can be used to exclude iron-deficiency anaemia.

Types
Two genetic loci exist for α globin, thus four alleles are in diploid cells. Two alleles are maternal and two alleles are paternal in origin.  The severity of the α-thalassemias is correlated with the number of affected α-globin alleles: the greater, the more severe will be the manifestations of the disease. When noting the genotype, an "α" indicates a functional alpha chain, and - a pathological one.

Laboratory diagnosis
The ability to measure hemoglobin Barts makes it useful in newborn screening tests.  If hemoglobin Barts is detected on a newborn screen, the patient is usually referred for further evaluation since detection of hemoglobin Barts can indicate either one alpha globin gene deletion, making the baby a silent alpha thalassemia carrier, two alpha globin gene deletions (alpha thalassemia), or hemoglobin H disease (three alpha globin gene deletions).Deletion of four alpha globin genes was previously felt to be incompatible with life, but there are currently 69 patients who have survived past infancy. All such children too show high level of hemoglobin Barts on newborn screen along with other variants.Post-newborn ages, initial laboratory diagnosis should include a complete blood count and red blood cell indices. As well, a peripheral blood smear should be carefully reviewed. In hemoglobin H disease, red blood cells containing hemoglobin H inclusions can be visualized on the blood smear using new methylene blue or brilliant cresyl blue stain.Hemoglobin analysis is important for the diagnosis of alpha-thalassemia as it determines the types and percentages of types of hemoglobin present. Several different methods of hemoglobin analysis exist, including hemoglobin electrophoresis, capillary electrophoresis and high-performance liquid chromatography.Molecular analysis of DNA sequences (DNA analysis) can be used for the confirmation of a diagnosis of alpha-thalassemia, particularly for the detection of alpha-thalassemia carriers (deletions or mutations in only one or two alpha-globin genes).

Treatment
Treatment for alpha-thalassemia may include blood transfusions to maintain hemoglobin at a level that reduces symptoms of anemia. The decision to initiate transfusions depends on the clinical severity of the disease. Splenectomy is a possible treatment option to increase total hemoglobin levels in cases of worsening anemia due to an overactive or enlarged spleen, or when transfusion therapy is not possible. However, splenectomy is avoided when other options are available due to an increased risk of serious infections and thrombosis.Additionally, gallstones may be a problem that would require surgery. Secondary complications from febrile episode should be monitored, and most individuals live without any need for treatment. Additionally, stem cell transplantation should be considered as a treatment (and cure), which is best done in early age. Other options, such as gene therapy, are still being developed.A study by Kreger et al combining a retrospective review of three cases of alpha thalassemia major and a literature review of 17 cases found that in utero transfusion can lead to favorable outcomes. Successful hematopoietic cell transplantation was eventually carried out in four patients.

Epidemiology
Worldwide distribution of inherited alpha-thalassemia corresponds to areas of malaria exposure, suggesting a protective role. Thus, alpha-thalassemia is common in sub-Saharan Africa, the Mediterranean Basin, and generally tropical (and subtropical) regions. The epidemiology of alpha-thalassemia in the US reflects this global distribution pattern. More specifically,  HbH disease is seen in Southeast Asia and the Middle East, while Hb Bart hydrops fetalis is acknowledged in Southeast Asia only.
The data indicate that 15% of the Greek and Turkish Cypriots are carriers of beta-thalassaemia genes, while 10% of the population carry alpha-thalassaemia genes.

See also
Beta-thalassemia
Delta-thalassemia
Hemoglobinopathy

References
Further reading
Anie KA, Massaglia P (March 2014). "Psychological therapies for thalassaemia". The Cochrane Database of Systematic Reviews (3): CD002890. doi:10.1002/14651858.cd002890.pub2 </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 Actinomycosis and can you explain it in depth? [/INST] Actinomycosis is a rare infectious bacterial disease caused by Actinomyces species. The name refers to ray-like appearance of the organisms in the granules. About 70% of infections are due to either Actinomyces israelii or A. gerencseriae. Infection can also be caused by Streptomyces somaliensis and Propionibacterium propionicus. The condition is likely to be a polymicrobial anaerobic infection.

Signs and symptoms
The disease is characterised by the formation of painful abscesses in the mouth, lungs, breast, or gastrointestinal tract. Actinomycosis abscesses grow larger as the disease progresses, often over months. In severe cases, they may penetrate the surrounding bone and muscle to the skin, where they break open and leak large amounts of pus, which often contains characteristic granules filled with progeny bacteria. These granules are often called "sulfur granules" due to their yellow appearance, although they may also be white, gray or brown.

Causes
Actinomycosis is primarily caused by any of several members of the bacterial genus Actinomyces. These bacteria are generally anaerobes. In animals, they normally live in the small spaces between the teeth and gums, causing infection only when they can multiply freely in anoxic environments. An affected human often has recently had dental work, poor oral hygiene, periodontal disease, radiation therapy, or trauma (broken jaw) causing local tissue damage to the oral mucosa, all of which predispose the person to developing actinomycosis. A. israelii is a normal commensal species part of the microbiota species of the lower reproductive tract of women. They are also normal commensals among the gut flora of the caecum; thus, abdominal actinomycosis can occur following removal of the appendix. The three most common sites of infection are decayed teeth, the lungs, and the intestines. Actinomycosis infections are typically polymicrobial, containing additional bacterial species; as Actinomyces itself has little invasive ability, these other species often aid in the infection process.

Diagnosis
The diagnosis of actinomycosis can be a difficult one to make. In addition to microbiological examinations, magnetic resonance imaging and immunoassays may be helpful.

Treatment
Actinomyces bacteria are generally sensitive to penicillin, which is frequently used to treat actinomycosis. In cases of penicillin allergy, doxycycline is used.
Sulfonamides such as sulfamethoxazole may be used as an alternative regimen at a total daily dosage of 2–4 grams.  Response to therapy is slow and may take months.
Hyperbaric oxygen therapy may also be used as an adjunct to conventional therapy when the disease process is refractory to antibiotics and surgical treatment.

Epidemiology
Disease incidence is greater in males between the ages of 20 and 60 years than in females. Before antibiotic treatments became available, the incidence in the Netherlands and Germany was one per 100,000 people/year. Incidence in the U.S. in the 1970s was one per 300,000 people/year, while in Germany in 1984, it was estimated to be one per 40,000 people/year. The use of intrauterine devices (IUDs) has increased incidence of genitourinary actinomycosis in females. Incidence of oral actinomycosis, which is harder to diagnose, has increased.

History
In 1877, pathologist Otto Bollinger described the presence of A. bovis in cattle, and shortly afterwards, James Israel discovered A. israelii in humans. In 1890, Eugen Bostroem isolated the causative organism from a culture of grain, grasses, and soil. After Bostroems discovery, a general misconception existed that actinomycosis was a mycosis that affected individuals who chewed grass or straw. The pathogen is still known as the “great masquerader". Bergeys Manual of Systematic Bacteriology classified the organism as bacterial in 1939, but the disease remained classified as a fungus in the 1955 edition of the Control of Communicable Diseases in Man.Violinist Joseph Joachim died of actinomycosis on 15 August 1907.
The Norwegian painter Halfdan Egedius died from actinomycosis on 2 February 1899.

Other animals
Actinomycosis occurs rarely in humans, but rather frequently in cattle as a disease called "lumpy jaw". This name refers to the large abscesses that grow on the head and neck of the infected animal. It can also affect swine, horses, and dogs, and less often wild animals and sheep.

References
Further reading
Anderson, Clifton W.; Jenkins, Ralph H. (December 15, 1938). "Actinomycosis of the Scrotum". New England Journal of Medicine. 219 (24): 953–954. doi:10.1056/NEJM193812152192403.
Codman, E. A. (August 11, 1898). "A Case of Actinomycosis". The Boston Medical and Surgical Journal. 139 (6): 134–135. doi:10.1056/NEJM189808111390606.
Randolph HL Wong; Alan DL Sihoe; KH Thung; Innes YP Wan; Margaret BY Ip; Anthony PC Yim (June 2004). "Actinomycosis: an often forgotten diagnosis". Asian Cardiovasc Thorac Ann. 12 (2): 165–7. doi:10.1177/021849230401200218. PMID 15213087. S2CID 9930882. Review
Munro, John C. (September 13, 1900) </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 Dysbarism and can you explain it in depth? [/INST] Dysbarism refers to medical conditions resulting from changes in ambient pressure. Various activities are associated with pressure changes. Underwater diving is the most frequently cited example, but pressure changes also affect people who work in other pressurized environments (for example, caisson workers), and people who move between different altitudes.

Ambient pressure
Ambient pressure is the pressure in the water around the diver (or the air, with caisson workers etc.). As a diver descends, the ambient pressure increases. At 10 meters (33 feet) in salt water, it is twice the normal pressure than that at the surface. At 40 meters (a common recommended limit for recreational diving) it is 5 times the pressure than at sea level.
Pressure decreases as we rise above sea level, but less dramatically. At 3000 feet altitude (almost 1000 meters), the ambient pressure is almost 90% of sea level pressure. Ambient pressure does not drop to 50% of sea level pressure until 20,000 feet or 6,000 meters altitude.

Effects of pressure on the body
Direct effects on tissues
This is not of practical importance, because the body is mostly composed of barely compressible materials such as water. People often wonder whether scuba divers feel their body being crushed by the pressure, but divers would have to reach depths of thousands of feet before their flesh began to suffer significant compression.

Gas filled spaces
Gas is very compressible. Humans have many air spaces: sinuses, middle ears, gas in our bowels, cavities in our teeth, and largest of all, our lungs. On land in our daily lives, the pressure in our air spaces is usually exactly the same as the pressure outside, because our air spaces are connected to the outside world. If there was a pressure difference between the outside world and one of our air spaces, then we experience painful pressure on the walls of that air space, as air pushes from the higher-pressure side to the lower-pressure side. This is why we sometimes get painful ears on air trips.

Dissolved gas
A percentage of the gas we breathe (air) is always dissolved in our blood, like the gas dissolved in a carbonated drink bottle with the lid on. If a person moves to a higher ambient pressure, then the gas inhaled is at a higher pressure, so more of it dissolves in the blood and diffuses into body tissues (Henrys and Ficks gas laws). If they slowly move back to a lower pressure, then the extra gas comes out slowly until they are back to their normal amount of dissolved gas. But if they move quickly to a lower ambient pressure, then the gas comes out of our blood and tissues violently, in large bubbles, in the same way that quickly removing the cap from a bottle of soft drink produces far more bubbles than slowly opening the bottle.

Types of dysbarism
Different types of illness result from increases in pressure (for example, descent during an underwater dive, descent during a plane flight), versus decreases in pressure (for example, coming up from a caisson, or ascending a mountain). Dysbarism comprises several types of illness:

Decompression sickness (DCS)
Decompression sickness, also called caisson workers disease and the bends, is the most well-known complication of scuba diving. It occurs as divers ascend, and often from ascending too fast or without doing decompression stops. Bubbles are large enough and numerous enough to cause physical injury. It is quite possible that all divers have microbubbles in their blood to some extent, but that most of the time these bubbles are so few and so small that they cause no harm. When DCS occurs, bubbles disrupt tissues in the joints, brain, spinal cord, lungs, and other organs. Symptoms vary enormously. DCS may be as subtle as unusual tiredness after a dive, or an aching elbow, or a mottled skin rash. Or, it may present dramatically, with unconsciousness, seizures, paralysis, shortness of breath, or death. Paraplegia is not uncommon.

Nitrogen narcosis
Nitrogen narcosis is also called “L’ivresse des grandes profondeurs” or "rapture of the deep". Nitrogen comprises 79% of the air, but at surface pressures it has no sedating effect. At greater depths, however, nitrogen affects the brain in the same way as nitrous oxide (also known as laughing gas) and other anaesthetic gases. The effect is similar to the effects of alcohol, and to some extent there is cross-tolerance. Unlike alcohol, the onset and disappearance are near instantaneous. A diver may be quite clear-headed at 20 meters, and yet giddy and silly at 30 meters. Ascending to 20 meters will almost instantly clear the head.

High pressure nervous syndrome (HPNS)
Barotrauma
Barotrauma is injury caused by pressure effects on gas spaces. This may occur during ascent or descent. The ears are the most commonly affected body part </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 Tricuspid valve stenosis 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 Brain abscess and can you explain it in depth? [/INST] Brain abscess (or cerebral abscess) is an abscess caused by inflammation and collection of infected material, coming from local (ear infection, dental abscess, infection of paranasal sinuses, infection of the mastoid air cells of the temporal bone, epidural abscess) or remote (lung, heart, kidney etc.) infectious sources, within the brain tissue. The infection may also be introduced through a skull fracture following a head trauma or surgical procedures. Brain abscess is usually associated with congenital heart disease in young children. It may occur at any age but is most frequent in the third decade of life.

Signs and symptoms
Fever, headache, and neurological problems, while classic, only occur in 20% of people with brain abscess.The famous triad of fever, headache and focal neurologic findings are highly suggestive of brain abscess. These symptoms are caused by a combination of increased intracranial pressure due to a space-occupying lesion (headache, vomiting, confusion, coma), infection (fever, fatigue etc.) and focal neurologic brain tissue damage (hemiparesis, aphasia etc.).The most frequent presenting symptoms are headache, drowsiness, confusion, seizures, hemiparesis or speech difficulties together with fever with a rapidly progressive course. Headache is characteristically worse at night and in the morning, as the intracranial pressure naturally increases when in the supine position. This elevation similarly stimulates the medullary vomiting center and area postrema, leading to morning vomiting.Other symptoms and findings depend largely on the specific location of the abscess in the brain. An abscess in the cerebellum, for instance, may cause additional complaints as a result of brain stem compression and hydrocephalus. Neurological examination may reveal a stiff neck in occasional cases (erroneously suggesting meningitis).

Pathophysiology
Bacterial
Anaerobic and microaerophilic cocci and gram-negative and gram-positive anaerobic bacilli are the predominant bacterial isolates. Many brain abscesses are polymicrobial. The predominant organisms include: Staphylococcus aureus, aerobic and anaerobic streptococci (especially Streptococcus intermedius), Bacteroides, Prevotella, and Fusobacterium species, Enterobacteriaceae, Pseudomonas species, and other anaerobes. Less common organisms include: Haemophillus influenzae, Streptococcus pneumoniae and Neisseria meningitidis.Bacterial abscesses rarely (if ever) arise de novo within the brain, although establishing a cause can be difficult in many cases.  There is almost always a primary lesion elsewhere in the body that must be sought assiduously, because failure to treat the primary lesion will result in relapse.  In cases of trauma, for example in compound skull fractures where fragments of bone are pushed into the substance of the brain, the cause of the abscess is obvious.  Similarly, bullets and other foreign bodies may become sources of infection if left in place.  The location of the primary lesion may be suggested by the location of the abscess: infections of the middle ear result in lesions in the middle and posterior cranial fossae; congenital heart disease with right-to-left shunts often result in abscesses in the distribution of the middle cerebral artery; and infection of the frontal and ethmoid sinuses usually results in collection in the subdural sinuses.

Other organisms
Fungi and parasites may also cause the disease. Fungi and parasites are especially associated with immunocompromised patients. Other causes include: Nocardia asteroides, Mycobacterium, Fungi (e.g. Aspergillus, Candida, Cryptococcus, Mucorales, Coccidioides, Histoplasma capsulatum, Blastomyces dermatitidis, Bipolaris, Exophiala dermatitidis, Curvularia pallescens, Ochroconis gallopava, Ramichloridium mackenziei, Pseudallescheria boydii), Protozoa (e.g. Toxoplasma gondii, Entamoeba histolytica, Trypanosoma cruzi, Schistosoma, Paragonimus), and Helminths (e.g. Taenia solium). Organisms that are most frequently associated with brain abscess in patients with AIDS are poliovirus, Toxoplasma gondii, and Cryptococcus neoformans, though in infection with the latter organism, symptoms of meningitis generally predominate.These organisms are associated with certain predisposing conditions:

Sinus and dental infections—Aerobic and anaerobic streptococci, anaerobic gram-negative bacilli (e.g. Prevotella, Porphyromonas, Bacteroides), Fusobacterium, S. aureus, and Enterobacteriaceae
Penetrating trauma—S. aureus, aerobic streptococci, Enterobacteriaceae, and Clostridium spp.
Pulmonary infections—Aerobic and anaerobic streptococci, anaerobic gram-negative bacilli (e.g. Prevotella, Porphyromonas, Bacteroides), Fusobacterium, Actinomyces, and Nocardia
Congenital heart disease—Aerobic and microaerophilic streptococci, and S. aureus
HIV infection—T. gondii, Mycobacterium, Nocardia, Cryptococcus, and Listeria monocytogenes
Transplantation—Aspergillus, Candida, Cryptococcus, Mucorales, Nocardia, and T. gondii
Neutropenia—Aerobic gram-negative bacilli, Aspergillus, Candida, and Mucorales

Diagnosis
The diagnosis is established by a computed tomography (CT) (with contrast) examination. At the initial phase of the inflammation (which is referred to as cerebritis), the immature lesion does not have a capsule and it may be difficult to distinguish it from other space-occupying lesions or infarcts of the brain.  Within 4–5 days the inflammation and the concomitant dead brain tissue are surrounded with a capsule, which gives the lesion the famous ring-enhancing lesion appearance on CT examination with contrast (since intravenously applied contrast material can not pass through the capsule, it is collected around the lesion and looks as a ring surrounding the relatively dark lesion) </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 Chronic venous insufficiency and can you explain it in depth? [/INST] Chronic venous insufficiency (CVI) is a medical condition in which blood pools in the veins, straining the walls of the vein. The most common cause of CVI is superficial venous reflux which is a treatable condition. As functional venous valves are required to provide for efficient blood return from the lower extremities, this condition typically affects the legs. If the impaired vein function causes significant symptoms, such as swelling and ulcer formation, it is referred to as chronic venous disease. It is sometimes called chronic peripheral venous insufficiency and should not be confused with post-thrombotic syndrome in which the deep veins have been damaged by previous deep vein thrombosis.
Most cases of CVI can be improved with treatments to the superficial venous system or stenting the deep system. Varicose veins for example can now be treated by local anesthetic endovenous surgery.
Rates of CVI are higher in women than in men. Other risk factors include genetics, smoking, obesity, pregnancy, and prolonged standing.

Signs and symptoms
Signs and symptoms of CVI in the leg include the following:

Varicose veins
Itching (pruritus)
Hyperpigmentation
Phlebetic lymphedema
Chronic swelling of the legs and ankles
Venous ulcerationCVI in the leg may cause the following:

Venous stasis
Ulcers
Stasis dermatitis, also known as varicose eczema
Contact dermatitis, a disrupted epidermal barrier due to venous insufficiency, making patients more susceptible than the general population to contact sensitization and subsequent dermatitis.
Atrophie blanche, an end point of a variety of conditions that appears as atrophic plaques of ivory white skin with telangiectasias. It represents late sequelae of lipodermatosclerosis where the skin has lost its nutrient blood flow.
Lipodermatosclerosis,  an indurated plaque in the medial malleolus.
Malignancy, malignant degeneration being a rare but important complication of venous disease since tumors that develop in the setting of an ulcer tend to be more aggressive.
Pain, a feature of venous disease often overlooked and commonly undertreated.
Anxiety
Depression
Inflammation
Cellulitis

Causes
The most common cause of chronic venous insufficiency is reflux of the venous valves of superficial veins. This may in turn be caused by several conditions:

Deep vein thrombosis (DVT), that is, blood clots in the deep veins. Chronic venous insufficiency caused by DVT may be described as postthrombotic syndrome. DVT triggers an inflammatory response subsequently injuring the vein wall.
Superficial vein thrombosis.
Phlebitis
May–Thurner syndrome. This is a rare condition in which blood clots occur in the iliofemoral vein due to compression of the blood vessels in the leg. The specific problem is compression of the left common iliac vein by the overlying right common iliac artery. Many May-Thurner compressions are overlooked when there is no blood clot. More and more of them get nowadays diagnosed and treated (by stenting) due to advanced imaging techniques.Deep and superficial vein thrombosis may in turn be caused by thrombophilia, which is an increased propensity of forming blood clots.Arteriovenous fistula (an abnormal connection or passageway between an artery and a vein) may cause chronic venous insufficiency even with working vein valves.

Diagnosis
History and examination by a clinician for characteristic signs and symptoms are sufficient in many cases in ruling out systemic causes of venous hypertension such as hypervolemia and heart failure. A duplex ultrasound (doppler ultrasonography and b-mode) can detect venous obstruction or valvular incompetence as the cause, and is used for planning venous ablation procedures, but it is not necessary in suspected venous insufficiency where surgical intervention is not indicated.Insufficiency within a venous segment is defined as reflux of more than 0.5 seconds with distal compression. Invasive venography can be used in patients who may require surgery or have suspicion of venous stenosis. Other modalities that may be employed are: ankle-brachial index to exclude arterial pathology, air or photoplethysmography, intravascular ultrasound, and ambulatory venous pressures, which provides a global assessment of venous competence. Venous plethysmography can assess for reflux and muscle pump dysfunction but the test is laborious and rarely done.The venous filling time after the patient is asked to stand up from a seated position also is used to assess for CVI. Rapid filling of the legs less than 20 seconds is abnormal.

Classification
CEAP classification is based on Clinical, Etiological (causal), Anatomical, and Pathophysiological factors. According to Widmer Classification for assessment of chronic venous insufficiency (CVI), diagnosis of chronic venous insufficiency is clearly differentiated from varicose veins. It has been developed to guide decision-making in chronic venous insufficiency evaluation and treatment.The CEAP classification for CVI is as follows:
Clinical
C0: no obvious feature of venous disease
C1: the presence of reticular or spider veins
C2: Obvious varicose veins
C3: Presence of edema but no skin changes
C4: skin discoloration, pigmentation
C5: Ulcer that has healed
C6: Acute ulcer
Etiology
Primary
Secondary (trauma, birth control pill)
Congenital (Klipper trenaunay)
No cause is known
Anatomic
Superficial
Deep
Perforator
No obvious anatomic location
Pathophysiology
Obstruction, thrombosis
Reflux
Obstruction and reflux
No venous pathology

Management
Conservative
Conservative treatment of CVI in the leg involves symptomatic treatment and efforts to prevent the condition from getting worse instead of effecting a cure. This may include

Manual compression lymphatic massage therapy
Red vine leaf extract may have a therapeutic benefit.
Sequential compression pump
Ankle pump
Compression stockings
Blood pressure medicine
Hydroxyethylrutoside medication
Frequent periods of rest elevating the legs above the heart level
Tilting the bed so that the feet are above the heart. This may be achieved by using a 20 cm (7-inch) bed wedge or sleeping in a 6 degree Trendelenburg position.

Surgical
Surgical treatment of CVI attempts a cure by physically changing the veins with incompetent valves </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 Testicular cancer and can you explain it in depth? [/INST] Testicular cancer is cancer that develops in the testicles, a part of the male reproductive system. Symptoms may include a lump in the testicle, or swelling or pain in the scrotum. Treatment may result in infertility.Risk factors include an undescended testis, family history of the disease, and previous history of testicular cancer. The most common type is germ cell tumors which are divided into seminomas and nonseminomas. Other types include sex-cord stromal tumors and lymphomas. Diagnosis is typically based on a physical exam, ultrasound, and blood tests. Surgical removal of the testicle with examination under a microscope is then done to determine the type.Testicular cancer is highly treatable and usually curable. Treatment options may include surgery, radiation therapy, chemotherapy, or stem cell transplantation. Even in cases in which cancer has spread widely, chemotherapy offers a cure rate greater than 80%.Globally testicular cancer affected about 686,000 people in 2015. That year it resulted in 9,400 deaths up from 7,000 deaths in 1990. Rates are lower in the developing than the developed world. Onset most commonly occurs in males 20 to 34 years old, rarely before 15 years old. The five-year survival rate in the United States is about 95%. Outcomes are better when the disease remains localized.

Signs and symptoms
One of the first signs of testicular cancer is often a lump or swelling in the testes. The U.S. Preventive Services Task Force (USPSTF) recommends against routine screening for testicular cancer in asymptomatic adolescent and adults including routine testicular self-exams. However, the American Cancer Society suggests that some men should examine their testicles monthly, especially if they have a family history of cancer, and the American Urological Association recommends monthly testicular self-examinations for all young men.Symptoms may also include one or more of the following:

a lump in one testis which may or may not be painful
sharp pain or a dull ache in the lower abdomen or scrotum
a feeling often described as "heaviness" in the scrotum
firmness of the testicle
breast enlargement (gynecomastia) from hormonal effects of β-hCG
low back pain (lumbago) due to the cancer spreading to the lymph nodes along the backIt is not very common for testicular cancer to spread to other organs, apart from the lungs. If it has, however, the following symptoms may be present:

shortness of breath (dyspnea), cough or coughing up blood (hemoptysis) from metastatic spread to the lungs
a lump in the neck due to metastases to the lymph nodesTesticular cancer, cryptorchidism, hypospadias, and poor semen quality make up the syndrome known as testicular dysgenesis syndrome.

Causes
A major risk factor for the development of testis cancer is cryptorchidism (undescended testicles).  It is generally believed that the presence of a tumor contributes to cryptorchidism;  when cryptorchidism occurs in conjunction with a tumor then the tumor tends to be large.  Other risk factors include inguinal hernias, Klinefelter syndrome, and mumps orchitis.  Physical activity is associated with decreased risk and sedentary lifestyle is associated with increased risk. Early onset of male characteristics is associated with increased risk.  These may reflect endogenous or environmental hormones.Higher rates of testicular cancer in Western nations have been linked to the use of cannabis.

Mechanisms
Most testicular germ cell tumors have too many chromosomes, and most often they are triploid to tetraploid. An isochromosome 12p (the short arm of chromosome 12 on both sides of the same centromere) is present in about 80% of the testicular cancers, and also the other cancers usually have extra material from this chromosome arm through other mechanisms of genomic amplification.

Diagnosis
The main way testicular cancer is diagnosed is via a lump or mass inside a testis. More generally, if a young adult or adolescent has a single enlarged testicle, which may or may not be painful, this should give doctors reason to suspect testicular cancer.

Other conditions may also have symptoms similar to testicular cancer:
Epididymitis or epididymoorchitis
Hematocele
Varicocele
Orchitis
Prostate infections or inflammations (prostatitis), bladder infections or inflammations (cystitis), or kidney (renal) infections (nephritis) or inflammations which have spread to and caused swelling in the vessels of the testicles or scrotum
Testicular torsion or a hernia
Infection, inflammation, retro-peritonitis, or other conditions of the lymph nodes or vessels near the scrotum, testicles, pubis, anorectal area, and groin
Benign tumors or lesions of the testicles
Metastasis to the testicles from another, primary tumor site(s)The nature of any palpated lump in the scrotum is often evaluated by scrotal ultrasound, which can determine exact location, size, and some characteristics of the lump, such as cystic vs solid, uniform vs heterogeneous, sharply circumscribed or poorly defined. The extent of the disease is evaluated by CT scans, which are used to locate metastases.
The differential diagnosis of testicular cancer requires examining the histology of tissue obtained from an inguinal orchiectomy - that is, surgical excision of the entire testis along with attached structures (epididymis and spermatic cord). A biopsy should not be performed, as it raises the risk of spreading cancer cells into the scrotum.Inguinal orchiectomy is the preferred method because it lowers the risk of cancer cells escaping. This is because the lymphatic system of the scrotum, through which white blood cells (and, potentially, cancer cells) flow in and out, links to the lower extremities, while that of the testicle links to the back of the abdominal cavity (the retroperitoneum).  A transscrotal biopsy or orchiectomy will potentially leave cancer cells in the scrotum and create two routes for cancer cells to spread, while in an inguinal orchiectomy only the retroperitoneal route exists.Blood tests are also used to identify and measure tumor markers (usually proteins present in the bloodstream) that are specific to testicular cancer. Alpha-fetoprotein, human chorionic gonadotropin (the "pregnancy hormone"), and LDH-1 are the typical tumor markers used to spot testicular germ cell tumors.A pregnancy test may be used to detect high levels of chorionic gonadotropin; however, the first sign of testicular cancer is usually a painless lump. Note that only about 25% of seminomas have elevated chorionic gonadotropin, so a pregnancy test is not very sensitive for making out testicular cancer.

Screening
The American Academy of Family Physicians recommends against screening males without symptoms for testicular cancer.

Staging
After removal, the testicle is fixed with Bouins solution because it better conserves some morphological details such as nuclear conformation. Then the testicular tumor is staged by a pathologist according to the TNM Classification of Malignant Tumors as published in the AJCC Cancer Staging Manual.  Testicular cancer is categorized as being in one of three stages (which have subclassifications).  The size of the tumor in the testis is irrelevant to staging.  In broad terms, testicular cancer is staged as follows:

Stage I: the cancer remains localized to the testis.
Stage II: the cancer involves the testis and metastasis to retroperitoneal and/or paraaortic lymph nodes (lymph nodes below the diaphragm).
Stage III: the cancer involves the testis and metastasis beyond the retroperitoneal and paraaortic lymph nodes.  Stage 3 is further subdivided into non-bulky stage 3 and bulky stage 3.Further information on the detailed staging system is available on the website of the American Cancer Society.

Classification
Although testicular cancer can be derived from any cell type found in the testicles, more than 95% of testicular cancers are germ cell tumors (GCTs).  Most of the remaining 5% are sex cord–gonadal stromal tumours derived from Leydig cells or Sertoli cells.  Correct diagnosis is necessary to ensure the most effective and appropriate treatment.  To some extent, this can be done via blood tests for tumor markers, but definitive diagnosis requires examination of the histology of a specimen by a pathologist.
Most pathologists use the World Health Organization classification system for testicular tumors:
Germ cell tumors
Precursor lesions
Intratubular germ cell neoplasia
Unclassified type (carcinoma in situ)
Specified types
Tumors of one histologic type (pure forms)
Seminoma
Variant - Seminoma with syncytiotrophoblastic cells
Spermatocytic tumor
Variant - spermatocytic tumor with sarcoma
Embryonal carcinoma
Yolk sac tumor
Trophoblastic tumors
Choriocarcinoma
Variant - monophasic choriocarcinoma
Placental site trophoblastic tumour
Cystic trophoblastic tumor
Teratoma
Variant - Dermoid cyst
Variant - Epidermoid cyst
Variant - Monodermal teratoma (Carcinoid), Primitive neuroectodermal tumor (PNET), Nephroblastoma-like tumor, others.
Variant - Teratomic with somatic-type malignancy
Tumours of more than one histologic type (mixed forms)
Embryonal carcinoma and teratoma
Teratoma and seminoma
Choriocarcinoma and teratoma.embryonal carcinoma
Others
Sex cord/Gonadal stromal tumors
Leydig cell tumor
Sertoli cell tumor
Lipid rich variant
Scleriosing variant
Large cell calcifying variant
Intratubular sertoli cell neoplasia in Peutz–Jeghers syndrome
Granulosa cell tumor
Adult type
Juvenile type
Thecoma fibroma group
Thecoma
Fibroma
Sex cord/gonadal stromal tumor - incompletely differentiated
Sex cord/gonadal stromal tumor - mixed types
Mixed germ cell and sex cord/gonadal stromal tumors
Gonadoblastoma
Germ cell-sex cord/gonadal stromal tumor, unclassified
Miscellaneous tumours of the testis
Lymphomas
Primary testicular diffuse large B-cell lymphoma
Mantle cell lymphoma of the testes
extranodal marginal zone B cell lymphoma of the testes
Extranodal NK/T-cell lymphoma, nasal type of the testes
Peripheral T-cell lymphoma of the testes
activin receptor-like kinase-1–negative anaplastic large cell lymphoma of the testes
pediatric-type follicular lymphoma of the testes
Carcinoid
Tumors of ovarian epithelial types
Serous tumor of borderline malignancy
Serous carcinoma
Well differentiated endometrioid tumor
Mucinous cystadenoma
Mucinous cystadenocarcinoma
Brenner tumor
Nephroblastoma
Paraganglioma
Haematopoietic tumors
Tumours of collecting ducts and rete
Adenoma
Carcinoma
Tumors of the paratesticular structures
Adenomatoid tumor
Malignant and benign mesothelioma
Adenocarcinoma of the epididymis
Papillary cystadenoma of the epididymis
Melanotic neuroectodermal tumor
Desmoplastic small round cell tumor
Mesenchymal tumors of the spermatic cord and testicular adnexae
Lipoma
Liposarcoma
Rhabdomyosarcoma
Aggressive angiomyxoma
Angiomyofibroblastoma-like tumor (see Myxoma)
Fibromatosis
Fibroma
Solitary fibrous tumor
Others
Secondary tumors of the testis

Treatment
The three basic types of treatment are surgery, radiation therapy, and chemotherapy.Surgery is performed by urologists; radiation therapy is administered by radiation oncologists; and chemotherapy is the work of medical oncologists. In most patients with testicular cancer, the disease is cured readily with minimal long-term morbidity. While treatment success depends on the stage, the average survival rate after five years is around 95%, and stage 1 cancer cases, if monitored properly, have essentially a 100% survival rate.

Testicle removal
The initial treatment for testicular cancer is surgery to remove the affected testicle (orchiectomy). While it may be possible, in some cases, to remove testicular cancer tumors from a testis while leaving the testis functional, this is almost never done, as the affected testicle usually contains pre-cancerous cells spread throughout the entire testicle. Thus removing the tumor alone without additional treatment greatly increases the risk that another cancer will form in that testicle.Since only one testis is typically required to maintain fertility, hormone production, and other male functions, the affected testis is almost always removed completely in a procedure called inguinal orchiectomy. (The testicle is almost never removed through the scrotum; an incision is made beneath the belt line in the inguinal area.)  In the UK, the procedure is known as a radical orchidectomy.

Retroperitoneal lymph node dissection
In the case of nonseminomas that appear to be stage I, surgery may be done on the retroperitoneal/paraaortic lymph nodes (in a separate operation) to accurately determine whether the cancer is in stage I or stage II and to reduce the risk that malignant testicular cancer cells that may have metastasized to lymph nodes in the lower abdomen.  This surgery is called retroperitoneal lymph node dissection (RPLND).  However, this approach, while standard in many places, especially the United States, is out of favor due to costs and the high level of expertise required to perform successful surgery. Sperm banking is frequently carried out prior to the procedure (as with chemotherapy), as there is a risk that RPLND may damage the nerves involved in ejaculation, causing ejaculation to occur internally into the bladder rather than externally.Many patients are instead choosing surveillance, where no further surgery is performed unless tests indicate that the cancer has returned. This approach maintains a high cure rate because of the growing accuracy of surveillance techniques.

Adjuvant treatment
Since testicular cancers can spread, patients are usually offered adjuvant treatment - in the form of chemotherapy or radiotherapy - to kill any cancerous cells that may exist outside of the affected testicle. The type of adjuvant therapy depends largely on the histology of the tumor (i.e. the size and shape of its cells under the microscope) and the stage of progression at the time of surgery (i.e. how far cells have escaped from the testicle, invaded the surrounding tissue, or spread to the rest of the body). If the cancer is not particularly advanced, patients may be offered careful surveillance by periodic CT scans and blood tests, in place of adjuvant treatment.Before 1970, survival rates from testicular cancer were low. Since the introduction of adjuvant chemotherapy, chiefly platinum-based drugs like cisplatin and carboplatin, the outlook has improved substantially. Although 7000 to 8000 new cases of testicular cancer occur in the United States yearly, only 400 men are expected to die of the disease.
In the UK, a similar trend has emerged: since improvements in treatment, survival rates have risen rapidly to cure rates of over 95%.

Radiation therapy
Radiation may be used to treat stage II seminoma cancers, or as adjuvant (preventative) therapy in the case of stage I seminomas, to minimize the likelihood that tiny, non-detectable tumors exist and will spread (in the inguinal and para-aortic lymph nodes).  Radiation is ineffective against and is therefore never used as a primary therapy for nonseminoma.

Chemotherapy
Non-seminoma
Chemotherapy is the standard treatment for non-seminoma when the cancer has spread to other parts of the body (that is, stage 2B or 3).  The standard chemotherapy protocol is three, or sometimes four, rounds of Bleomycin-Etoposide-Cisplatin (BEP). BEP as a first-line treatment was first reported by Professor Michael Peckham in 1983. The landmark trial published in 1987 which established BEP as the optimum treatment was conducted by Dr. Lawrence Einhorn at Indiana University. An alternative, equally effective treatment involves the use of four cycles of Etoposide-Cisplatin (EP).Lymph node surgery may also be performed after chemotherapy to remove masses left behind (stage 2B or more advanced), particularly in the cases of large nonseminomas.

Seminoma
As an adjuvant treatment, use of chemotherapy as an alternative to radiation therapy in the treatment of seminoma is increasing, because radiation therapy appears to have more significant long-term side effects (for example, internal scarring, increased risks of secondary malignancies, etc.).  Two doses, or occasionally a single dose of carboplatin, typically delivered three weeks apart, is proving to be a successful adjuvant treatment, with recurrence rates in the same ranges as those of radiotherapy. The concept of carboplatin as a single-dose therapy was developed by Tim Oliver, Professor of Medical Oncology at Barts and The London School of Medicine and Dentistry. However, very long-term data on the efficacy of adjuvant carboplatin in this setting do not exist.Since seminoma can recur decades after the primary tumor is removed, patients receiving adjuvant chemotherapy should remain vigilant and not assume they are cured 5 years after treatment.

Prognosis
Treatment of testicular cancer is one of the success stories of modern medicine, with sustained response to treatment in more than 90% of cases, regardless of stage. In 2011 overall cure rates of more than 95% were reported, and 80% for metastatic disease—the best response by any solid tumor, with improved survival being attributed primarily to effective chemotherapy.  By 2013 more than 96 per cent of the 2,300 men diagnosed each year in the U.K. were deemed cured, a rise by almost a third since the 1970s, the improvement attributed substantially to the chemotherapy drug cisplatin. In the United States, when the disease is treated while it is still localized, more than 99% of people survive 5 years.

Surveillance
For many patients with stage I cancer, adjuvant (preventative) therapy following surgery may not be appropriate and patients will undergo surveillance instead. The form this surveillance takes, e.g. the type and frequency of investigations and the length time it should continue, will depend on the type of cancer (non-seminoma or seminoma), but the aim is to avoid unnecessary treatments in the many patients who are cured by their surgery, and ensure that any relapses with metastases (secondary cancers) are detected early and cured. This approach ensures that chemotherapy and or radiotherapy is only given to the patients that need it. The number of patients ultimately cured is the same using surveillance as post-operative "adjuvant" treatments, but the patients have to be prepared to follow a prolonged series of visits and tests.For both non-seminomas and seminomas, surveillance tests generally include physical examination, blood tests for tumor markers, chest x-rays and CT scanning.  However, the requirements of a surveillance program differ according to the type of disease since, for seminoma patients, relapses can occur later and blood tests are not as good at indicating relapse.CT scans are performed on the abdomen (and sometimes the pelvis) and also the chest in some hospitals. Chest x-rays are increasingly preferred for the lungs as they give sufficient detail combined with a lower false-positive rate and significantly smaller radiation dose than CT.The frequency of CT scans during surveillance should ensure that relapses are detected at an early stage while minimizing the radiation exposure.For patients treated for stage I non-seminoma, a randomised trial (Medical Research Council TE08) showed that, when combined with the standard surveillance tests described above, 2 CT scans at 3 and 12 months were as good as 5 over 2 years in detecting relapse at an early stage.
For patients treated for stage I seminoma who choose surveillance rather than undergoing adjuvant therapy, there have been no randomized trials to determine the optimum frequency of scans and visits, and the schedules vary very widely across the world, and within individual countries. In the UK there is an ongoing clinical trial called TRISST. This is assessing how often scans should take place and whether magnetic resonance imaging (MRI) can be used instead of CT scans. MRI is being investigated because it does not expose the patient to radiation and so, if it is shown to be as good at detecting relapses, it may be preferable to CT.For more advanced stages of testicular cancer, and for those cases in which radiation therapy or chemotherapy was administered, the extent of monitoring (tests) after treatment will vary on the basis of the circumstances, but normally should be done for five years in uncomplicated cases and for longer in those with higher risks of relapse.

Fertility
A man with one remaining testis may maintain fertile.  However, sperm banking may be appropriate for men who still plan to have children, since fertility may be adversely affected by chemotherapy and/or radiotherapy.  A man who loses both testicles will be infertile after the procedure, though he may elect to bank viable, cancer-free sperm prior to the procedure.

Epidemiology
Globally testicular cancer resulted in 8,300 deaths in 2013 up from 7,000 deaths in 1990. Testicular cancer has the highest prevalence in the U.S </s>