<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 Gulf War syndrome and can you explain it in depth? [/INST] Gulf War syndrome or Gulf War illness is a chronic and multi-symptomatic disorder affecting military veterans of both sides of the 1990–1991 Persian Gulf War.  A wide range of acute and chronic symptoms have been linked to it, including fatigue, muscle pain, cognitive problems, insomnia, rashes and diarrhea. Approximately 250,000 of the 697,000 U.S. veterans who served in the 1991 Gulf War have enduring chronic multi-symptom illness, a condition with serious consequences.The Royal British Legion said research suggested up to 33,000 UK Gulf War veterans could be living with the syndrome, with 1,300 claiming a war pension for conditions connected to their service. In 2007 the Royal British Legion produced a comprehensive report entitled Legacy of Suspicion, which made recommendations about necessary research and compensation. The Royal British Legion is still campaigning for the UK government to properly address symptoms experienced by veterans of the Gulf War.From 1995 to 2005, the health of combat veterans worsened in comparison with nondeployed veterans, with the onset of more new chronic diseases, functional impairment, repeated clinic visits and hospitalizations, chronic fatigue syndrome-like illness, post-traumatic stress disorder, and greater persistence of adverse health incidents.Exposure to pesticides and exposure to pills containing pyridostigmine bromide (used as a pretreatment to protect against nerve agent effects) has been found to be associated with the neurological effects seen in Gulf War syndrome. Other causes that have been investigated are sarin, cyclosarin, and emissions from oil well fires, but their relationship to the illness is not as clear.Studies have consistently indicated that Gulf War syndrome is not the result of combat or other stressors and that Gulf War veterans have lower rates of post-traumatic stress disorder (PTSD) than veterans of other wars.According to a 2013 report by the Iraq and Afghanistan Veterans of America, veterans of the U.S. wars in Iraq and Afghanistan may also have Gulf War syndrome, though later findings identified causes that would not have been present in those wars.In 2022, researchers led by Robert Haley, MD at University of Texas Southwestern Medical Center found that exposure to sarin nerve gas in soldiers who had a particular genetic mutation that prevented them from breaking down the nerve gas is likely to be responsible for the syndrome. The findings and an editorial by two leading epidemiologists were published in Environmental Health Perspectives.

Signs and symptoms
According to an April 2010 U.S. Department of Veterans Affairs (VA) sponsored study conducted by the Institute of Medicine (IOM), part of the U.S. National Academy of Sciences, 250,000 of the 696,842 U.S. servicemen and women in the 1991 Gulf War continue to be affected by chronic multi-symptom illness, which the IOM now refers to as Gulf War illness. The IOM found that it continued to affect these veterans nearly 20 years after the war.
According to the IOM, "It is clear that a significant portion of the soldiers deployed to the Gulf War have experienced troubling constellations of symptoms that are difficult to categorize," said committee chair Stephen L. Hauser, professor and chair, department of neurology, University of California, San Francisco (UCSF). Unfortunately, symptoms that cannot be easily quantified are sometimes incorrectly dismissed as insignificant and receive inadequate attention and funding by the medical and scientific establishment. Veterans who continue to suffer from these symptoms deserve the very best that modern science and medicine can offer to speed the development of effective treatments, cures, and—we hope—prevention. Our report suggests a path forward to accomplish this goal, and we believe that through a concerted national effort and rigorous scientific input, answers can be found.
Questions still exist regarding why certain veterans showed, and still show, medically unexplained symptoms while others did not, why symptoms are diverse in some and specific in others, and why combat exposure is not consistently linked to having or not having symptoms.  The lack of data on veterans pre-deployment and immediate post-deployment health status and lack of measurement and monitoring of the various substances to which veterans may have been exposed make it difficult—and in many cases impossible—to reconstruct what happened to service members during their deployments nearly 20 years after the fact, the committee noted. The report called for a substantial commitment to improving identification and treatment of multisymptom illness in Gulf War veterans focussing on continued monitoring of Gulf War veterans, improved medical care, examination of genetic differences between symptomatic and asymptomatic groups and studies of environment-gene interactions.A variety of signs and symptoms have been associated with GWI:

* This table applies only to coalition forces involved in combat.Birth defects have been suggested as a consequence of Gulf War deployment.  However, a 2006 review of several studies of international coalition veterans children found no strong or consistent evidence of an increase in birth defects, finding a modest increase in birth defects that was within the range of the general population, in addition to being unable to exclude recall bias as an explanation for the results. A 2008 report stated that "it is difficult to draw firm conclusions related to birth defects and pregnancy outcomes in Gulf War veterans", observing that while there have been "significant, but modest, excess rates of birth defects in children of Gulf War veterans", the "overall rates are still within the normal range found in the general population". The same report called for more research on the issue.

Comorbid illnesses
Gulf War veterans have been identified to have an increased risk of multiple sclerosis.A 2017 study by the U.S. Department of Veterans Affairs found that veterans possibly exposed to chemical warfare agents at Khamisiyah experienced different patterns of brain cancer mortality risk compared to the other groups, with veterans possibly exposed having a higher risk of brain cancer in the time period immediately following the Gulf War.

Iraqi veterans
Although an understudied group, opposing Iraqi veterans of the Iraqi Army in the Gulf War also experienced acute and chronic symptoms associated with Gulf War syndrome. A 2011 study in the U.S Army Medical Department Journal reported Iraqi veterans of the Gulf War had a higher prevalence of somatic disorders as compared to Iraqi civilians, with risk greater in troops stationed in Kuwait.In comparison to Allied troops, health symptoms were similar amongst Iraqi veterans:

* Zone 1 = In Kuwait, Zone 3 = 360 km from Kuwait.

Causes
The United States Congress mandated the U.S. Department of Veterans Affairs contract with the National Academy of Sciences (NAS) to provide reports on Gulf War illnesses. Since 1998, the NASs Institute of Medicine (IOM) has authored ten such reports. In addition to the many physical and psychological issues involved in any war zone deployment, Gulf War veterans were exposed to a unique mix of hazards not previously experienced during wartime. These included pyridostigmine bromide pills (given to protect troops from the effects of nerve agents), depleted uranium munitions, and multiple simultaneous vaccinations including anthrax and botulinum toxin vaccines. The oil and smoke that spewed for months from hundreds of burning oil wells presented another exposure hazard not previously encountered in a war zone. Military personnel also had to cope with swarms of insects, requiring the widespread use of pesticides. High-powered microwaves were used to disrupt Iraqi communications, and though it is unknown whether this might have contributed to the syndrome, research has suggested that safety limits for electromagnetic radiation are too lenient.The Research Advisory Committee on Gulf War Veterans Illnesses (RAC), a VA federal advisory committee mandated by Congress in legislation enacted in 1998, found that pre-2005 studies suggested the veterans illnesses are neurological and apparently are linked to exposure to neurotoxins, such as the nerve gas sarin, the anti-nerve gas drug pyridostigmine bromide, and pesticides that affect the nervous system. The RAC concluded in 2004 that, "research studies conducted since the war have consistently indicated that psychiatric illness, combat experience or other deployment-related stressors do not explain Gulf War veterans illnesses in the large majority of ill veterans."The RAC concluded that "exposure to pesticides and/or to PB [pyridostigmine bromide nerve agent protective pills] are causally associated with GWI and the neurological dysfunction in GW veterans. Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene-environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been called "toxic wounds" by veterans. This type of injury requires further study and concentrated treatment research efforts that may also benefit other occupational groups with similar exposure-related illnesses."

Earlier considered potential causes
Depleted uranium
Depleted uranium (DU) was widely used in tank kinetic energy penetrator and autocannon rounds for the first time ever during the Gulf War and has been suggested as a possible cause of Gulf War syndrome. A 2008 review by the U.S. Department of Veterans Affairs found no association between DU exposure and multisymptom illness, concluding that "exposure to DU munitions is not likely a primary cause of Gulf War illness". However, there are suggestions that long-term exposure to high doses of DU may cause other health problems unrelated to GWI.More recent medical literature reviews disagree, stating for example that, "the number of Gulf War veterans who developed the Gulf War syndrome following exposure to high quantities of DU has risen to about one-third of the 800,000 U.S. forces deployed," with 25,000 of those having had a premature death. Since 2011, US combat veterans may claim disability compensation for health problems related to exposure to depleted uranium. The Veterans Administration decides these claims on a case-by-case basis.
A team at the University of Portsmouth led by Professor Randall Parrish tested urine samples of 154 US veterans in 2021, reporting that no soldiers with the syndrome were exposed to significant amounts of depleted uranium and that it "is not and never was in the bodies of those who are ill at sufficient quantities to cause disease".

Pyridostigmine bromide nerve gas antidote
The US military issued pyridostigmine bromide (PB) pills to protect against exposure to nerve gas agents such as sarin and soman. PB was used as a prophylactic against nerve agents; it is not a vaccine. Taken before exposure to nerve agents, PB was thought to increase the efficiency of nerve agent antidotes. PB had been used since 1955 for patients who have myasthenia gravis with doses up to 1,500 mg a day, far in excess of the 90 mg given to soldiers, and was considered safe by the FDA at either level for indefinite use and its use to pre-treat nerve agent exposure had recently been approved.Given both the large body of epidemiological data on myasthenia gravis patients and follow-up studies done on veterans it was concluded that while it was unlikely that health effects reported today by Gulf War veterans are the result of exposure solely to PB, use of PB was causally associated with illness. However, a later review by the Institute of Medicine concluded that the evidence was not strong enough to establish a causal relationship.

Organophosphates
Organophosphate-induced delayed neuropathy (OPIDN, aka organophosphate-induced delayed polyneuropathy) may contribute to the unexplained illnesses of the Gulf War veterans.

Organophosphate pesticides
The use of organophosphate pesticides and insect repellents during the first Gulf War is credited with keeping rates of pest-borne diseases low. Pesticide use is one of only two exposures consistently identified by Gulf War epidemiologic studies to be significantly associated with Gulf War illness. Multisymptom illness profiles similar to Gulf War illness have been associated with low-level pesticide exposures in other human populations. In addition, Gulf War studies have identified dose-response effects, indicating that greater pesticide use is more strongly associated with Gulf War illness than more limited use. Pesticide use during the Gulf War has also been associated with neurocognitive deficits and neuroendocrine alterations in Gulf War veterans in clinical studies conducted following the end of the war. The 2008 report concluded that "all available sources of evidence combine to support a consistent and compelling case that pesticide use during the Gulf War is causally associated with Gulf War illness."

Sarin nerve agent
Many of the symptoms of Gulf War illness are similar to the symptoms of organophosphate, mustard gas, and nerve gas poisoning. Gulf War veterans were exposed to a number of sources of these compounds, including nerve gas and pesticides.Chemical detection units from Czechoslovakia, France, and Britain confirmed chemical agents. French detection units detected chemical agents. Both Czech and French forces reported detections immediately to U.S. forces. U.S. forces detected, confirmed, and reported chemical agents; and U.S. soldiers were awarded medals for detecting chemical agents. The Riegle Report said that chemical alarms went off 18,000 times during the Gulf War. After the air war started on January 16, 1991, coalition forces were chronically exposed to low but nonlethal levels of chemical and biological agents released primarily by direct Iraqi attack via missiles, rockets, artillery, or aircraft munitions and by fallout from allied bombings of Iraqi chemical warfare munitions facilities.In 1997, the US Government released an unclassified report that stated:

"The US Intelligence Community (IC) has assessed that Iraq did not use chemical weapons during the Gulf war. However, based on a comprehensive review of intelligence information and relevant information made available by the United Nations Special Commission (UNSCOM), we conclude that chemical warfare (CW) agent was released as a result of US postwar demolition of rockets with chemical warheads in a bunker (called Bunker 73 by Iraq) and a pit in an area known as Khamisiyah."Over 125,000 U.S. troops and 9,000 U.K. troops were exposed to nerve gas and mustard gas when the Iraqi depot in Khamisiyah was destroyed.Recent studies have confirmed earlier suspicions that exposure to sarin, in combination with other contaminants such as pesticides and PB were related to reports of veteran illness. Estimates range from 100,000 to 300,000 individuals exposed to nerve agents.While low-level exposure to nerve agents has been suggested as the cause of GWI, the 2008 report by the U.S. Department of Veterans Affairs (VA) Research Advisory Committee on Gulf War illnesses (RAC) stated that "evidence is inconsistent or limited in important ways." The VAs 2014 RAC report concluded that, "exposure to the nerve gas agents sarin/cyclosarin has been linked in two more studies to changes in structural magnetic resonance imaging findings that are associated with cognitive decrements, further supporting the conclusion from evidence reviewed in the 2008 report that exposure to these agents is etiologically important to the central nervous system dysfunction that occurs in some subsets of Gulf War veterans."A 2022 study by Dr. Robert W. Haley of the University of Texas Southwestern Medical Center, et al., of 1,016 U.S. Gulf War veterans found evidence of a causal link between GWI and exposure to low levels of sarin, which was released into the air by coalition bombing of Iraqi chemical weapons facilities. Significantly, the study found an increased incidence of GWI not only among veterans who recounted hearing nerve agent alarms, but also among veterans with the RR or QR (as opposed to the QQ) forms of the PON1 gene, which produces an enzyme that deactivates organophosphates (including sarin) through hydrolysis. By contrast, GWI was inversely associated with higher levels of the type Q isozyme, which is more efficient at breaking down sarin than its type R counterpart. The authors "found that the PON1 genotype and hearing nerve agent alarms were independent and the findings robust to both measured and unmeasured confounding, supporting a mechanistic [gene–environment] interaction. ... Moreover, the change in the combined effect from one category to the next was significantly greater than the sum of the independent effects of the environmental exposure and the genotype". Although organophosphate pesticides could have triggered the nerve agent alarms in use at the time and contributed to neurotoxic symptoms similar to GWI, Haley et al. ruled out pesticides as a primary cause of GWI, citing that pesticide use was "ubiquitous long before the approximately 10,000 alarms began sounding at the start of the air campaign when Coalition bombing of Iraqi chemical weapon facilities released the fallout cloud that reached U.S. troop concentrations just as sarin was detected at multiple sites," while "the PON1 R isoenzyme is the more efficient detoxifier of most pesticides."

Less likely causes
According to the VAs 2008 RAC report, "For several Gulf War exposures, an association with Gulf War illness cannot be ruled out. These include low-level exposure to nerve agents, close proximity to oil well fires, receipt of multiple vaccines, and effects of combinations of Gulf War exposures." However, several potential causes of GWI were deemed, "not likely to have caused Gulf War illness for the majority of ill veterans," including "depleted uranium, anthrax vaccine, fuels, solvents, sand and particulates, infectious diseases, and chemical agent resistant coating (CARC)," for which "there is little evidence supporting an association with Gulf War illness or a major role is unlikely based on what is known about exposure patterns during the Gulf War and more recent deployments."The VAs 2014 RAC report reinforced its 2008 report findings: "The research reviewed in this report supports and reinforces the conclusion in the 2008 RACGWVI report that exposures to pesticides and pyridostigmine bromide are causally associated with Gulf War illness. Evidence also continues to demonstrate that Gulf War illness is not the result of psychological stressors during the war." It also found additional evidence since the 2008 report for the role of sarin in GWI, but inadequate evidence regarding exposures to oil well fires, vaccines, and depleted uranium to make new conclusions about them.

Oil well fires
During the war, many oil wells were set on fire in Kuwait by the retreating Iraqi army, and the smoke from those fires was inhaled by large numbers of soldiers, many of whom had acute pulmonary and other chronic effects, including asthma and bronchitis. However, firefighters who were assigned to the oil well fires and encountered the smoke, but who did not take part in combat, have not had GWI symptoms.: 148, 154, 156  The 2008 RAC report states that "evidence [linking oil well fires to GWI] is inconsistent or limited in important ways."

Anthrax vaccine
Iraq had loaded anthrax, botulinum toxin, and aflatoxin into missiles and artillery shells in preparing for the Gulf War and these munitions were deployed to four locations in Iraq. During Operation Desert Storm, 41% of U.S. combat soldiers and 75% of UK combat soldiers were vaccinated against anthrax.: 73  Reactions included local skin irritation, some lasting for weeks or months. While the Food and Drug Administration (FDA) approved the vaccine, it never went through large-scale clinical trials.While recent studies have demonstrated the vaccine is highly reactogenic, there is no clear evidence or epidemiological studies on Gulf War veterans linking the vaccine to Gulf War illness. Combining this with the lack of symptoms from current deployments of individuals who have received the vaccine led the Committee on Gulf War Veterans Illnesses to conclude that the vaccine is not a likely cause of Gulf War illness for most ill veterans. However, the committee report does point out that veterans who received a larger number of various vaccines in advance of deployment have shown higher rates of persistent symptoms since the war.However, research was done by PB Asa, Y Cao, and RF Garry on serum antibodies to squalene in Gulf War Syndrome patients. The results showed "the substantial majority (95%) of overtly ill deployed GWS patients had antibodies to squalene. All (100%) GWS patients immunized for service in Desert Shield/Desert Storm who did not deploy, but had the same signs and symptoms as those who did deploy, had antibodies to squalene. In contrast, none (0%) of the deployed Persian Gulf veterans not showing signs and symptoms of GWS have antibodies to squalene. Neither patients with idiopathic autoimmune disease nor healthy controls had detectable serum antibodies to squalene." Their work of the researchers was profiled by Gary Matsumoto in "Vaccine A".

Combat stress
Research studies conducted since the war have consistently indicated that psychiatric illness, combat experience or other deployment-related stressors do not explain Gulf War veterans illnesses in the large majority of ill veterans, according to a U.S. Department of Veterans Affairs (VA) review committee.An April 2010 Institute of Medicine review found, "the excess of unexplained medical symptoms reported by deployed [1991] Gulf war veterans cannot be reliably ascribed to any known psychiatric disorder", although they also concluded that "the constellation of unexplained symptoms associated with the Gulf War illness complex could result from interplay between both biological and psychological factors."

Pathobiology
Chronic inflammation
The 2008 VA report on Gulf War illness and the Health of Gulf War Veterans suggested a possible link between GWI and chronic, nonspecific inflammation of the central nervous system that cause pain, fatigue and memory issues, possibly due to pathologically persistent increases in cytokines and suggested further research be conducted on this issue.

Diagnosis
Clinical diagnosis of Gulf War illness has been complicated by multiple case definitions. In 2014, the National Academy of Sciences Institute of Medicine (IOM)—contracted by the U.S. Department of Veterans Affairs for the task—released a report concluding that the creation of a new case definition for chronic multisymptom illness in Gulf War veterans was not possible because of insufficient evidence in published studies regarding its onset, duration, severity, frequency of symptoms, exclusionary criteria, and laboratory findings. Instead, the report recommended the use of two case definitions, the "Kansas" definition and the "Centers for Disease Control and Prevention (CDC)" definition, noting: "There is a set of symptoms (fatigue, pain, neurocognitive) that are reported in all the studies that have been reviewed. The CDC definition captures those three symptoms; the Kansas definition also captures them, but it also includes the symptoms reported most frequently by Gulf War veterans."The Kansas case definition is more specific and may be more applicable for research settings, while the CDC case definition is more broad and may be more applicable for clinical settings.

Classification
Medical ailments associated with service in the 1990–1991 Gulf War have been recognized by both the U.S. Department of Defense and the U.S. Department of Veterans Affairs.Before 1998, the terms Gulf War syndrome, Gulf War veterans illness, unexplained illness, and undiagnosed illness were used interchangeably to describe chronic unexplained symptoms in veterans of the 1991 Gulf War. The term chronic multisymptom illness (CMI) was first used following publication of a 1998 study describing chronic unexplained symptoms in Air Force veterans of the 1991 Gulf War.In a 2014 report contracted by the U.S. Department of Veterans Affairs, the National Academy of Sciences Institute of Medicine recommended the use the term Gulf War illness rather than chronic multisymptom illness. Since that time, relevant publications by the National Academy of Science and the U.S. Department of Defense have used only the term Gulf War illness (GWI).The U.S. Department of Veterans Affairs (VA) confusingly still uses an array of both old and new terminology for Gulf War illness. VAs specialty clinical evaluation War Related Illness and Injury Study Centers (WRIISCs) use the recommended term Gulf War illness, as do VAs Office of Research and Development (VA-ORD) and many recent VA research publications. However, VAs Public Health website still uses Gulf War veterans medically unexplained illnesses, chronic multi-symptom illness (CMI), and undiagnosed illnesses, but explains that VA doesnt use the term Gulf War syndrome because of varying symptoms.The Veterans Health Administration (VHA) originally classified individuals with related ailments believed to be connected to their service in the Persian Gulf a special non-ICD-9 code DX111, as well as ICD-9 code V65.5.

Kansas definition
In 1998, the State of Kansas Persian Gulf Veterans Health Initiative sponsored an epidemiological survey led by Dr. Lea Steele of deployment-related symptoms in 2,030 Gulf War veterans. The result was a "clinically based descriptive definition using correlated symptoms" in six symptom groups: fatigue and sleep problems, pain, neurologic and mood, gastrointestinal, respiratory symptoms, and skin (dermatologic) symptoms.To meet the "Kansas" case definition, a veteran of the 1990–91 Gulf War must have symptoms in at least three of the six symptom domains, which during the survey were scored based on severity ("severity"). Symptom onset must have developed during or after deploying to the 1990–91 Gulf War theatre of operations ("onset") and must have been present in the year before interview ("duration"). Participants were excluded if they had a diagnosis of or were being treated for any of several conditions that might otherwise explain their symptoms ("exclusionary criteria"), including cancer, diabetes, heart disease, chronic infectious disease, lupus, multiple sclerosis, stroke, or any serious psychiatric condition.Applying the Kansas case definition to the original Kansas study cohort resulted in a prevalence of Gulf War illness of 34.2% in Gulf War veterans and 8.3% in nondeployed Gulf War era veterans, or an excess rate of GWI of 26.3% in Gulf War veterans.

CDC definition
Also in 1998, a study published by Dr. Keiji Fukuda under the auspices of the U.S. Centers for Disease Control and Prevention (CDC) examined chronic multisymptom illness through a cross-sectional survey of 3,675 ill and healthy U.S. Air Force veterans of the 1990–91 Gulf War, including from a Pennsylvania-based Air National Guard unit and three comparison Air Force units. The CDC case definition was derived from clinical data and statistical analyses.The result was a symptom-category approach to a case definition, with three symptom categories: fatigue, mood–cognition, and musculoskeletal. To meet the case definition, the veteran of the 1990–91 Gulf War must have symptoms in two of the three categories and have experienced the illness for six months or longer ("duration").The original study also including a determination of severity of symptoms ("severity"). "Severe cases were identified if at least one symptom in each of the required categories was rated as severe. Of 1,155 participating Gulf War veterans, 6% had severe CMI, and 39% had mild to moderate CMI; of the 2,520 nondeployed era veterans Of 1,155 participating Gulf War veterans, 6% had severe CMI, and 39% had mild to moderate CMI; of the 2,520 nondeployed era veterans, 0.7% had severe and 14% had mild to moderate CMI."

Treatment
A 2013 report by the Institute of Medicine reviewed the peer-reviewed published medical literature for evidence regarding treatments for symptoms associated with chronic multisymptom illness (CMI) in 1990–91 Gulf War veterans, and in other chronic multisymptom conditions. For the studies the report reviewed that were specifically regarding CMI in 1990–91 Gulf War veterans (Gulf War illness), the report made the following conclusions:
Doxycycline: "Although the study of doxycycline was found to have high strength of evidence and was conducted in a group of 1991 Gulf War veterans who had CMI, it did not demonstrate efficacy; that is, doxycycline did not reduce or eliminate the symptoms of CMI in the study population."
Cognitive Behavioral Therapy (CBT) and Exercise: "These studies evaluated the effects of exercise and CBT in combination and individually. The therapeutic benefit of exercise was unclear in those studies. Group CBT rather than exercise may confer the main therapeutic benefit with respect to physical symptoms."The report concluded: "On the basis of the evidence reviewed, the committee cannot recommend any specific therapy as a set treatment for [Gulf War] veterans who have CMI. The committee believes that a one-size-fits-all approach is not effective for managing [Gulf War] veterans who have CMI and that individualized health care management plans are necessary."By contrast, the U.S. Department of Defense (DoD) noted in a May 2018 publication that the primary focus of its Gulf War illness Research Program (GWIRP) "has been to fund research studies to identify treatment targets and test interventional approaches to alleviate symptoms. While most of these studies remain in progress, several have already shown varying levels of promise as GWI treatments."
According to the May 2018 DoD publication:
Published Results on Treatments
The earliest federally funded multi-center clinical trials were VA- and DoD-funded trials that focused on antibiotic treatment (doxycycline) (Donta, 2004) and cognitive behavioral therapy with exercise (Donta, 2003). Neither intervention provided long-lasting improvement for a substantial number of Veterans.
Preliminary analysis from a placebo-controlled trial showed that 100 mg of Coenzyme Q10 (known as CoQ10 or Ubiquinone) significantly improved general self-reported health and physical functioning, including among 20 symptoms, each of which was present in at least half of the study participants, with the exception of sleep. These improvements included reducing commonly reported symptoms of fatigue, dysphoric mood, and pain (Golomb, 2014). These results are currently being expanded in a GWIRP-funded trial of a "mitochondrial cocktail" for GWI of CoQ10 plus a number of nutrients chosen to support cellular energy production and defend against oxidative stress. The treatment is also being investigated in a larger, VA- sponsored Phase III trial of Ubiquinol, the reduced form of CoQ10.
In a randomized, sham-controlled VA-funded trial of a nasal CPAP mask (Amin, 2011-b), symptomatic GW Veterans with sleep-disordered breathing receiving the CPAP therapy showed significant improvements in fatigue scores, cognitive function, sleep quality, and measures of physical and mental health (Amin, 2011a).
Preliminary data from a GWIRP-funded acupuncture treatment study showed that Veterans reported significant reductions in pain and both primary and secondary health complaints, with results being more positive in the bi-weekly versus weekly treatment group (Conboy, 2012). Current studies funded by the GWIRP and the VA are also investigating yoga as a treatment for GWI.
An amino acid supplement containing L-carnosine was found to reduce irritable bowel syndrome-associated diarrhea in a randomized, controlled GWIRP-funded trial in GW Veterans (Baraniuk, 2013). Veterans receiving L-carnosine showed a significant improvement in performance in a cognitive task, but no improvement in fatigue, pain, hyperalgesia, or activity levels.
Results from a 26 week GWIRP-funded trial comparing standard care to nasal irrigation with either saline or a xylitol solution revealed that both irrigation protocols reduced GWI respiratory (chronic rhinosinusitis) and fatigue symptoms (Hayer, 2015).
Administration of the glucocorticoid receptor antagonist mifepristone to GW Veterans in a GWIRP-funded randomized trial resulted in an improvement in verbal learning, but no improvement in self-reported physical health or other self-reported measures of mental health (Golier, 2016).Ongoing Intervention Studies
The GWIRP is currently funding many early-phase clinical trials aimed at GWI. Interventions include direct electrical nerve stimulation, repurposing FDA-approved pharmaceuticals, and dietary protocols and/or nutraceuticals. Both ongoing and closed GWIRP-supported clinical treatment trials and pilot studies can be found at [1].
A Clinical Consortium Award was offered [in FY2017] to support a group of institutions, coordinated through an Operations Center that will conceive, design, develop, and conduct collaborative Phase I and II clinical evaluations of promising therapeutic agents for the management or treatment of GWI. These mechanisms were designed to build on the achievements of the previously established consortia and to further promote collaboration and resource sharing.
The U.S Congress has made significant and continuing investment in DoDs Gulf War illness treatment research, with $129 million appropriated for the GWIRP between federal fiscal years (FY) 2006 and 2016. The funding has risen from $5 million in FY2006, to $20 million each year from FY2013 through FY2017, and to $21 million for FY2018.

Prognosis
According to the May 2018 DoD publication cited above, "Research suggests that the GWI symptomology experienced by Veterans has not improved over the last 25 years, with few experiencing improvement or recovery ... . Many [Gulf War] Veterans will soon begin to experience the common co-morbidities associated with aging. The effect that aging will have on this unique and vulnerable population remains a matter of significant concern, and population-based research to obtain a better understanding of mortality, morbidity, and symptomology over time is needed."

Prevalence
The 2008 and 2014 VA (RAC) reports and the 2010 IOM report found that the chronic multisymptom illness in Gulf War veterans—Gulf War illness—is more prevalent in Gulf War veterans than their non-deployed counterparts or veterans of previous conflicts. While a 2009 study found the pattern of comorbidities similar for actively deployed and nondeployed Australian military personnel, the large body of U.S. research reviewed in the VA and IOM reports showed the opposite in U.S. troops. The VAs 2014 RAC report found Gulf War illness in "an excess of 26–32 percent of Gulf War veterans compared to nondeployed era veterans" in pre-2008 studies, and "an overall multisymptom illness prevalence of 37 percent in Gulf War veterans and an excess prevalence of 25 percent" in a later, larger VA study.According to a May 2018 report by the U.S. Department of Defense, "GWI is estimated to have affected 175,000 to 250,000 of the nearly 700,000 troops deployed to the 1990–1991 GW theater of operations. Twenty-seven of the 28 Coalition members participating in the GW conflict have reported GWI in their troops. Epidemiologic studies indicate that rates of GWI vary in different subgroups of GW Veterans. GWI affects Veterans who served in the U.S. Army and Marines Corps at higher rates than those who served in the Navy and Air Force, and U.S. enlisted personnel are affected more than officers. Studies also indicate that GWI rates differ according to where Veterans were located during deployment, with the highest rates among troops who served in forward areas."

Research
Epidemiologic studies have looked at many suspected causal factors for Gulf War illness as seen in veteran populations. Below is a summary of epidemiologic studies of veterans displaying multisymptom illness and their exposure to suspect conditions from the 2008 U.S. Department of Veterans Affairs report.A fuller understanding of immune function in ill Gulf War veterans is needed, particularly in veteran subgroups with different clinical characteristics and exposure histories. It is also important to determine the extent to which identified immune perturbations may be associated with altered neurological and endocrine processes that are associated with immune regulation. Very limited cancer data have been reported for U.S. Gulf War veterans in general, and no published research on cases occurring after 1999. Because of the extended latency periods associated with most cancers, it is important that cancer information is brought up to date and that cancer rates be assessed in Gulf War veterans on an ongoing basis. In addition, cancer rates should be evaluated in relation to identifiable exposure and location subgroups.

Controversies
An early argument in the years following the Gulf War was that similar syndromes have been seen as an after effect of other conflicts — for example, "shell shock" after World War I, and post-traumatic stress disorder (PTSD) after the Vietnam War. Cited as evidence for this argument was a review of the medical records of 15,000 American Civil War soldiers showing that "those who lost at least 5% of their company had a 51% increased risk of later development of cardiac, gastrointestinal, or nervous disease."Early Gulf War research also failed to accurately account for the prevalence, duration, and health impact of Gulf War illness. For example, a November 1996 article in the New England Journal of Medicine found no difference in death rates, hospitalization rates, or self-reported symptoms between Persian Gulf veterans and non-Persian Gulf veterans. This article was a compilation of dozens of individual studies involving tens of thousands of veterans. The study did find a statistically significant elevation in the number of traffic accidents Gulf War veterans had. An April 1998 article in Emerging Infectious Diseases similarly found no increased rate of hospitalization and better health on average for veterans of the Persian Gulf War in comparison to those who stayed home.In contrast to those early studies, in January 2006, a study led by Melvin Blanchard published in the Journal of Epidemiology, part of the "National Health Survey of Gulf War-Era Veterans and Their Families", found that veterans deployed in the Persian Gulf War had nearly twice the prevalence of chronic multisymptom illness, a cluster of symptoms similar to a set of conditions often at that time called Gulf War Syndrome.

On November 17, 2008, the Department of Veterans Affairs (VA) Research Advisory Committee on Gulf War Veterans Illnesses (RAC), a Congressionally mandated federal advisory committee composed of VA-appointed clinicians, researchers, and representative Gulf War veterans, issued a major report announcing scientific findings, in part, that "Gulf War illness is real", that GWI is a distinct physical condition, and that it is not psychological in nature. The 454 page report reviewed 1,840 published studies to form its conclusions identifying the high prevalence of Gulf War illness, suggesting likely causes rooted in toxic exposures while ruling out combat stress as a cause, and opining that treatments likely could be found. It recommended that Congress increase funding for treatment-focused Gulf War illness research to at least $60 million per year.In March 2013, a hearing was held before the Subcommittee on Oversight and Investigations of the Committee on Veterans Affairs, U.S. House of Representatives, to determine not whether Gulf War illness exists, but rather how it is identified, diagnosed and treated, and how the tools put in place to aid these efforts have been used.By 2016, the National Academy of Sciences, Engineering, and Medicine (NASEM) concluded there was sufficient evidence of a positive association between deployment to the 1990–1991 Gulf War and Gulf War illness.

Jones controversy
Louis Jones Jr., the perpetrator of the 1995 murder of Tracie McBride, stated that the Gulf War syndrome caused him to commit the crime and he sought clemency, hoping to avoid the death penalty given to him by a federal court </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 Hemophagocytic lymphohistiocytosis and can you explain it in depth? [/INST] Hemophagocytic lymphohistiocytosis (HLH), also known as haemophagocytic lymphohistiocytosis (British spelling), and hemophagocytic or haemophagocytic syndrome, is an uncommon hematologic disorder seen more often in children than in adults. It is a life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages, characterised by proliferation of morphologically benign lymphocytes and macrophages that secrete high amounts of inflammatory cytokines. It is classified as one of the cytokine storm syndromes. There are inherited and non-inherited (acquired) causes of hemophagocytic lymphohistiocytosis (HLH).

Signs and symptoms
The onset of HLH occurs before the age of one year in approximately 70 percent of cases. Familial HLH should be suspected if siblings are diagnosed with HLH or if symptoms recur when therapy has been stopped. Familial HLH is an autosomal recessive disease, hence each sibling of a child with familial HLH has a twenty-five–percent chance of developing the disease, a fifty-percent chance of carrying the defective gene (which is very rarely associated with any risk of disease), and a twenty-five–percent chance of not being affected and not carrying the gene defect.Patients with HLH, especially when untreated, may need intensive therapy. Therefore, HLH should be included in the differential diagnosis of intensive care unit patients with cytopenia and hyperferritinemia. Patients in the earlier stages of HLH are frequently hospitalized at internal medicine wards.HLH clinically manifests with fever, enlargement of the liver and spleen, enlarged lymph nodes, yellow discoloration of the skin and eyes, and a rash. Laboratory findings may include elevated triglyceride levels, low fibrinogen levels, transaminitis, and elevated ferritin levels (among others).

Causes
Primary HLH is caused by loss of function, (i.e. inactivating) mutations in genes that code for proteins cytotoxic T cells and NK cells use to kill targeted cells, such as those infected with pathogens like the Epstein-Barr virus (EBV) or the Dengue virus. These mutations include those in the following genes: UNC13D, STX11, RAB27A, STXBP2, LYST, PRF1 1, SH2D1A, BIRC4, ITK, CD27, and MAGT1.Secondary HLH (sHLH) is associated with, and thought to be promoted by, malignant and non-malignant diseases that likewise weaken the ability of the immune system to attack EBV-infected cells. Malignant disorders associated with secondary HLH include T-cell lymphoma, B-cell lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, and myelodysplastic syndrome. Non-malignant disorders associated with secondary HLH include: autoimmune disorders such as juvenile idiopathic arthritis, juvenile Kawasaki disease, systemic lupus erythematosus, the juvenile onset and adult onset forms of Stills disease, and rheumatoid arthritis; immunodeficiency disorders such as severe combined immunodeficiency, DiGeorge syndrome, Wiskott–Aldrich syndrome, ataxia–telangiectasia, and dyskeratosis congenita); and infections caused by EBV, cytomegalovirus, HIV/AIDS, bacteria, protozoa, fungi and SARS-CoV-2. Secondary HLH may also result from iatrogenic causes such as bone marrow or other organ transplantations; chemotherapy; or therapy with immunosuppressing agents;About 33% of all HLH cases, ~75% of Asian HLH cases, and nearly 100% of HLH cases caused by mutations in SH2D1A (see X-linked lymphoproliferative disease type 1) are associated with, and thought triggered or promoted by, EBV infection. These cases of HLH are classified as belonging to the class of Epstein–Barr_virus–associated_lymphoproliferative_diseases and termed EBV+ HLH.

Genetics
Five genetic subtypes (FHL1, FHL2, FHL3, FHL4, and FHL5) are described, with an estimated overall prevalence of one in 50,000 and equal gender distribution. Molecular genetic testing for four of the causative genes, PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5), is available on a clinical basis. Symptoms of FHL are usually evident within the first few months of life and may even develop in utero. However, symptomatic presentation throughout childhood and even into young adulthood has been observed in some cases.The five subtypes of FHL are each associated with a specific gene:

FHL1: HPLH1
FHL2: PRF1 (Perforin)
FHL3: UNC13D (Munc13-4)
FHL4: STX11  (Syntaxin 11)
FHL5: STXBP2 (Syntaxin binding protein 2)/UNC18-2Nearly half of the cases of type 2 familial hemophagocytic lymphohistiocytosis are due to bi-allelic PRF1 mutations.

Pathophysiology
The underlying causes, either inherited or acquired, lead to an unchecked immune response when exposed to triggers. Impaired NK-cell cytotoxicity is the hallmark of HLH. All genetic defects for familial HLH are related to granule-dependent cytotoxicity. This inability to remove infected and antigen-presenting cells and terminate the immune response leads to uncontrolled proliferation and activation of the immune system with release of excessive cytokines. These cells then infiltrate organs, releasing more cytokines, which gives the clinical picture. The fever is caused by IL-1, IL-6 and TNF-alpha; the cytopenia is due to the suppressive effect on hematopoiesis by TNF-alpha and TNF-gamma. TNF-alpha and TNF-gamma may also lead to inhibition of lipoprotein lipase or stimulate triglyceride synthesis. Activated macrophages secrete ferritin and plasminogen activator leading to hyperfibrinolysis.

Diagnosis
The blood count typically shows decreased numbers of blood cells—including a decreased number of circulating red blood cells, white blood cells, and platelets. The bone marrow may show hemophagocytosis. The liver function tests are usually elevated. A low level of the protein albumin in the blood is common.The serum C reactive protein, erythrocyte sedimentation rate, and ferritin level are markedly elevated. In children, a ferritin above 10000 is very sensitive and specific for the diagnosis of HLH, however, the diagnostic utility for ferritin is less for adult HLH patients.The serum fibrinogen level is usually low and the D-dimer level is elevated.
The sphingomyelinase is elevated.Bone marrow biopsy shows histiocytosis.

Classification
Primary HLH, also known as familial haemophagocytic lymphohistiocytosis (FHL) or familial erythrophagocytic lymphohistiocytosis, is a heterogeneous autosomal recessive disorder found to be more prevalent with parental consanguinity.Secondary haemophagocytic lymphohistiocytosis (acquired haemophagocytic lymphohistiocytosis) occurs after strong immunologic activation, such as that which can occur with systemic infection, immunodeficiency, or underlying malignancy.Both forms are characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and haematologic alterations and death in the absence of treatment.A subtype of primary HLH where the inflammation is limited to the central nervous system has been described.

Diagnostic criteria
The current (2008) diagnostic criteria for HLH are1. A molecular diagnosis consistent with HLH. These include the identification of pathologic mutations of PRF1, UNC13D, or STX11.
OR
2. Fulfillment of five out of the eight criteria below:

Fever (defined as a temperature >100.3 °F, >38 °C)
Enlargement of the spleen
Decreased blood cell counts affecting at least two of three lineages in the peripheral blood:
Haemoglobin <9 g/100 ml (in infants <4 weeks: haemoglobin <10 g/100 ml) (anemia)
Platelets <100×109/L (thrombocytopenia)
Neutrophils <1×109/L (neutropenia)
High blood levels of triglycerides (fasting, greater than or equal to 265 mg/100 ml) and/or decreased amounts of fibrinogen in the blood (≤ 150 mg/100 ml)
Ferritin ≥ 500 ng/ml
Haemophagocytosis in the bone marrow, spleen or lymph nodes
Low or absent natural killer cell activity
Soluble CD25 (soluble IL-2 receptor) >2400 U/ml (or per local reference laboratory)In addition, in the case of familial HLH, no evidence of malignancy should be apparent.
Not all five out of eight criteria are required for diagnosis of HLH in adults, and a high index of suspicion is required for diagnosis as delay results in increased mortality. The diagnostic criteria were developed in pediatric populations and have not been validated for adult HLH patients.  Attempts to improve diagnosis of HLH have included use of the HScore, which can be used to estimate an individuals risk of HLH.  In adults, soluble IL-2 receptor has been found to be a very sensitive marker for HLH, demonstrating 100% sensitivity for ruling out HLH below a cutoff of 2400 U/mL and optimal cutoff for ruling in at 2515 U/mL (sensitivity, 100%; specificity, 72.5%), with 93% specificity at >10 000 U/mL.

Differential diagnosis
The differential diagnosis of HLH includes secondary HLH and macrophage-activation syndrome or other primary immunodeficiencies that present with hemophagocytic lymphohistiocytosis, such as X-linked lymphoproliferative disease.Other conditions that may be confused with this condition include autoimmune lymphoproliferative syndrome. As a syndrome of intense inflammation it needs to be differentiated from sepsis, which may be extremely challenging.The diagnosis of acquired, or secondary, HLH is usually made in association with infection by viruses, bacteria, fungi, or parasites or in association with lymphoma, autoimmune disease, or metabolic disease. Acquired HLH may have decreased, normal, or increased NK cell activity.

Griscelli syndrome
A major differential diagnosis of HLH is Griscelli syndrome (type 2). This is a rare autosomal recessive disorder characterized by partial albinism, hepatosplenomegaly, pancytopenia, hepatitis, immunologic abnormalities, and lymphohistiocytosis. Most cases have been diagnosed between 4 months and 7 years of age, with a mean age of about 17 months.Three types of Griscelli syndrome are recognised: type 1 has neurologic symptoms and mutations in MYO5A. Prognosis depends on the severity of neurologic manifestations. Type 2 has mutations in RAB27A and haemophagocytic syndrome, with abnormal T-cell and macrophage activation. This type has a grave prognosis if untreated </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 Carnitine palmitoyltransferase I deficiency and can you explain it in depth? [/INST] Carnitine palmitoyltransferase I deficiency is a rare metabolic disorder that prevents the body from converting certain fats called long-chain fatty acids into energy, particularly during periods without food. It is caused by a mutation in CPT1A on chromosome 11.Carnitine, a natural substance acquired mostly through the diet, is used by cells to process fats and produce energy </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 Osteoclast and can you explain it in depth? [/INST] An osteoclast (from Ancient Greek  ὀστέον (osteon) bone, and  κλαστός (clastos) broken) is a type of bone cell that breaks down bone tissue.  This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated protein and mineral at a molecular level by secreting acid and a collagenase, a process known as bone resorption. This process also helps regulate the level of blood calcium.
Osteoclasts are found on those surfaces of bone which are undergoing resorption. On such surfaces, the osteoclasts are seen to be located in shallow depressions called resorption bays (Howships lacunae). The resorption bays are created by erosive action of osteoclasts on the underlying bone. The border of the lower part of an osteoclast exhibits finger-like processes due to presence of deep infoldings of the cell membrane; this border is called ruffled border. The ruffled border lies in contact with the bone surface within a resorption bay. The periphery of the ruffled border is surrounded by a ring-like zone of cytoplasm which is devoid of cell organelles but is rich in actin filaments. This zone is called clear zone or sealing zone. The actin filaments enable the cell membrane surrounding the sealing zone to be anchored firmly to the bony wall of Howships lacunae. In this way, a closed subosteoclastic compartment is created between the ruffled border and the bone that is undergoing resorption. The osteoclasts secrete hydrogen ions, collagenase, cathepsin K and hydrolytic enzymes into this compartment. Resorption of bone matrix by the osteoclasts involves two steps: (1) dissolution of inorganic components (minerals), and (2) digestion of organic component of the bone matrix. The osteoclasts pump hydrogen ions into subosteoclastic compartment and thus create an acidic microenvironment, which increases solubility of bone mineral, resulting in the release and re-entry of bone minerals into the cytoplasm of osteoclasts to be delivered to nearby capillaries. After the removal of minerals, collagenase and gelatinase are secreted into the subosteoclastic compartment. These enzymes digest and degrade collagen and other organic components of decalcified bone matrix. The degradation products are phagocytosed by osteoclasts at the ruffled border. Because of their phagocytic properties, osteoclasts are considered to be a component of the mononuclear phagocyte system (MPS). The activity of osteoclasts is controlled by hormones and cytokines. Calcitonin, a hormone of thyroid gland, suppresses the osteoclastic activity. The osteoclasts do not have receptors for parathyroid hormone (PTH). However, PTH stimulates the osteoblasts to secrete  the cytokine called osteoclast-stimulating factor, which is a potent stimulator of the osteoclastic activity.An odontoclast (/odon·to·clast/; o-don´to-klast) is an osteoclast associated with absorption of the roots of deciduous teeth.

Structure
An osteoclast is a large multinucleated cell and human osteoclasts on bone typically have five nuclei and are 150–200 µm in diameter. When osteoclast-inducing cytokines are used to convert macrophages to osteoclasts, very large cells that may reach 100 µm in diameter occur. These may have dozens of nuclei, and typically express major osteoclast proteins but have significant differences from cells in living bone because of the not-natural substrate.  The size of the multinucleated assembled osteoclast allows it to focus the ion transport, protein secretory and vesicular transport capabilities of many macrophages on a localized area of bone.

Location
In bone, osteoclasts are found in pits in the bone surface which are called resorption bays, or Howships lacunae. Osteoclasts are characterized by a cytoplasm with a homogeneous, "foamy" appearance. This appearance is due to a high concentration of vesicles and vacuoles. These vacuoles include lysosomes filled with acid phosphatase. This permits characterization of osteoclasts by their staining for high expression of tartrate resistant acid phosphatase (TRAP) and cathepsin K. Osteoclast rough endoplasmic reticulum is sparse, and the Golgi complex is extensive.At a site of active bone resorption, the osteoclast forms a specialized cell membrane, the "ruffled border", that opposes the surface of the bone tissue.  This extensively folded or ruffled border facilitates bone removal by dramatically increasing the cell surface for secretion and uptake of the resorption compartment contents and is a morphologic characteristic of an osteoclast that is actively resorbing bone.

Development
Since their discovery in 1873 there has been considerable debate about their origin. Three theories were dominant: from 1949 to 1970 the connective tissue origin was popular, which stated that osteoclasts and osteoblasts are of the same lineage, and osteoblasts fuse together to form osteoclasts. After years of controversy it is now clear that these cells develop from the self fusion of macrophages. It was in the beginning of 1980 that the monocyte phagocytic system was recognized as precursor of osteoclasts. Osteoclast formation requires the presence of RANKL (receptor activator of nuclear factor κβ ligand) and M-CSF (Macrophage colony-stimulating factor). These membrane-bound proteins are produced by neighbouring stromal cells and osteoblasts, thus requiring direct contact between these cells and osteoclast precursors.
M-CSF acts through its receptor on the osteoclast, c-fms (colony-stimulating factor 1 receptor), a transmembrane tyrosine kinase-receptor, leading to secondary messenger activation of tyrosine kinase Src. Both of these molecules are necessary for osteoclastogenesis and are widely involved in the differentiation of monocyte/macrophage derived cells.
RANKL is a member of the tumour necrosis family (TNF), and is essential in osteoclastogenesis. RANKL knockout mice exhibit a phenotype of osteopetrosis and defects of tooth eruption, along with an absence or deficiency of osteoclasts. RANKL activates NF-κβ (nuclear factor-κβ) and NFATc1 (nuclear factor of activated t cells, cytoplasmic, calcineurin-dependent 1) through RANK. NF-κβ activation is stimulated almost immediately after RANKL-RANK interaction occurs and is not upregulated. NFATc1 stimulation, however, begins ~24–48 hours after binding occurs and its expression has been shown to be RANKL dependent.
Osteoclast differentiation is inhibited by osteoprotegerin (OPG), which is produced by osteoblasts and binds to RANKL thereby preventing interaction with RANK. It may be important to note that while osteoclasts are derived from the hematopoietic lineage, osteoblasts are derived from mesenchymal stem cells.

Function
Once activated, osteoclasts move to areas of microfracture in the bone by chemotaxis. Osteoclasts lie in small cavities called Howships lacunae, formed from the digestion of the underlying bone. The sealing zone is the attachment of the osteoclasts plasma membrane to the underlying bone. Sealing zones are bounded by belts of specialized adhesion structures called podosomes. Attachment to the bone matrix is facilitated by integrin receptors, such as αvβ3, via the specific amino acid motif Arg-Gly-Asp in bone matrix proteins, such as osteopontin. The osteoclast releases hydrogen ions through the action of carbonic anhydrase (H2O + CO2 → HCO3− + H+) through the ruffled border into the resorptive cavity, acidifying and aiding dissolution of the mineralized bone matrix into Ca2+, H3PO4, H2CO3, water and other substances. Dysfunction of the carbonic anhydrase has been documented to cause some forms of osteopetrosis.  Hydrogen ions are pumped against a high concentration gradient by proton pumps, specifically a unique vacuolar-ATPase. This enzyme has been targeted in the prevention of osteoporosis. In addition, several hydrolytic enzymes, such as members of the cathepsin and matrix metalloprotease (MMP) groups, are released to digest the organic components of the matrix. These enzymes are released into the compartment by lysosomes. Of these hydrolytic enzymes, cathepsin K is of most importance.

Cathepsin K and other cathepsins
Cathepsin K is a collagenolytic papain-like cysteine protease that is mainly expressed in osteoclasts, and is secreted into the resorptive pit. Cathepsin K is the major protease involved in the degradation of type I collagen and other noncollagenous proteins. Mutations in the cathepsin K gene are associated with pycnodysostosis, a hereditary osteopetrotic disease, characterised by a lack of functional cathepsin K expression. Knockout studies of cathepsin K in mice lead to an osteopetrotic phenotype, which, is partially compensated by increased expression of proteases other that cathepsin K and enhanced osteoclastogenesis.
Cathepsin K has an optimal enzymatic activity in acidic conditions. It is synthesized as a proenzyme with a molecular weight of 37kDa, and upon activation by autocatalytic cleavage, is transformed into the mature, active form with a molecular weight of ~27kDa.
Upon polarization of the osteoclast over the site of resorption, cathepsin K is secreted from the ruffled border into the resorptive pit.  Cathepsin K transmigrates across the ruffled border by intercellular vesicles and is then released by the functional secretory domain. Within these intercellular vesicles, cathepsin K, along with reactive oxygen species generated by TRAP, further degrades the bone extracellular matrix.
Several other cathepsins are expressed in osteoclasts including cathepsins B, C, D, E, G, and L.  The function of these cysteine and aspartic proteases is generally unknown within bone, and they are expressed at much lower levels than cathepsin K.
Studies on cathepsin L knockout mice have been mixed, with a report of reduced trabecular bone in homozygous and heterozygous cathepsin L knockout mice compared to wild-type and another report finding no skeletal abnormalities.

Matrix metalloproteinases
The matrix metalloproteinases (MMPs) comprise a family of more than 20 zinc-dependent endopeptidases. The role of matrix metalloproteinases (MMPs) in osteoclast biology is ill-defined, but in other tissue they have been linked with tumor promoting activities, such as activation of growth factors and are required for tumor metastasis and angiogenesis.
MMP9 is associated with the bone microenvironment. It is expressed by osteoclasts, and is known to be required for osteoclast migration and is a powerful gelatinase. Transgenic mice lacking MMP-9 develop defects in bone development, intraosseous angiogenesis, and fracture repair.
MMP-13 is believed to be involved in bone resorption and in osteoclast differentiation, as knockout mice revealed decreased osteoclast numbers, osteopetrosis, and decreased bone resorption.
MMPs expressed by the osteoclast include MMP-9, -10, -12, and -14. apart from MMP-9, little is known about their relevance to the osteoclast, however, high levels of MMP-14 are found at the sealing zone.

Osteoclast physiology
In the 1980s and 90s the physiology of typical osteoclasts was studied in detail.  With the isolation of the ruffled border, ion transport across it was studied directly in biochemical detail. Energy-dependent acid transport was verified and the postulated proton pump purified. With the successful culture of osteoclasts, it became apparent that they are organized to support the massive transport of protons for acidification of the resorption compartment and solubilization of the bone mineral.  This includes ruffled border Cl− permeability to control membrane potential and basolateral Cl−/HCO3− exchange to maintain cytosolic pH in physiologically acceptable ranges.The effectiveness of its ion secretion depends upon the osteoclast forming an effective seal around the resorption compartment </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 Gallstone and can you explain it in depth? [/INST] A gallstone is a stone formed within the gallbladder from precipitated bile components. The term cholelithiasis may refer to the presence of gallstones or to any disease caused by gallstones, and choledocholithiasis refers to the presence of migrated gallstones within bile ducts.
Most people with gallstones (about 80%) are asymptomatic. However, when a gallstone obstructs the bile duct and causes acute cholestasis, a reflexive smooth muscle spasm often occurs, resulting in an intense cramp-like visceral pain in the right upper part of the abdomen known as a biliary colic (or "gallbladder attack"). This happens in 1–4% of those with gallstones each year. Complications from gallstones may include inflammation of the gallbladder (cholecystitis), inflammation of the pancreas (pancreatitis), obstructive jaundice, and infection in bile ducts (cholangitis). Symptoms of these complications may include pain that lasts longer than five hours, fever, yellowish skin, vomiting, dark urine, and pale stools.Risk factors for gallstones include birth control pills, pregnancy, a family history of gallstones, obesity, diabetes, liver disease, or rapid weight loss. The bile components that form gallstones include cholesterol, bile salts, and bilirubin. Gallstones formed mainly from cholesterol are termed cholesterol stones, and those formed mainly from bilirubin are termed pigment stones. Gallstones may be suspected based on symptoms. Diagnosis is then typically confirmed by ultrasound. Complications may be detected using blood tests.The risk of gallstones may be decreased by maintaining a healthy weight with exercise and a healthy diet. If there are no symptoms, treatment is usually not needed. In those who are having gallbladder attacks, surgery to remove the gallbladder is typically recommended. This can be carried out either through several small incisions or through a single larger incision, usually under general anesthesia. In rare cases when surgery is not possible, medication can be used to dissolve the stones or lithotripsy can be used to break them down.In developed countries, 10–15% of adults experience gallstones. Gallbladder and biliary-related diseases occurred in about 104 million people (1.6% of people) in 2013 and resulted in 106,000 deaths. Gallstones are more common among women than men and occur more commonly after the age of 40. Gallstones occur more frequently among certain ethnic groups than others. For example, 48% of Native Americans experience gallstones, whereas gallstone rates in many parts of Africa are as low as 3%. Once the gallbladder is removed, outcomes are generally positive.

Definition
Gallstone disease refers to the condition where gallstones are either in the gallbladder or common bile duct. The presence of stones in the gallbladder is referred to as cholelithiasis, from the Greek chol- (bile) + lith- (stone) + -iasis (process). The presence of gallstones in the common bile duct is called choledocholithiasis, from the Greek chol- (bile) + docho- (duct) + lith- (stone) + iasis- (process). Choledocholithiasis is frequently associated with obstruction of the bile ducts, which can lead to cholangitis, from the Greek: chol- (bile) + ang- (vessel) + itis- (inflammation), a serious infection of the bile ducts. Gallstones within the ampulla of Vater can obstruct the exocrine system of the pancreas and can result in pancreatitis.

Signs and symptoms
Gallstones, regardless of size or number, are often asymptomatic. These "silent stones" do not require treatment and can remain asymptomatic even years after they form.A characteristic symptom of a gallstone attack is the presence of colic-like pain in the upper-right side of the abdomen, often accompanied by nausea and vomiting. Pain from symptomatic gallstones may range from mild to severe and can steadily increase over a period lasting from 30 minutes to several hours. Other symptoms may include fever, as well as referred pain between the shoulder blades or below the right shoulder. If one or more gallstones block the bile ducts and cause bilirubin to leak into the bloodstream and surrounding tissue, jaundice and itching may also occur. In this case, liver enzyme levels are likely to be raised.Often, gallbladder attacks occur after eating a heavy meal. Attacks are most common in the evening or at night.

Other complications
In rare cases, gallstones that cause severe inflammation can erode through the gallbladder into adherent bowel, potentially causing an obstruction termed gallstone ileus.Other complications can include ascending cholangitis, which occurs when a bacterial infection causes purulent inflammation in the biliary tree and liver, and acute pancreatitis caused by blockage of the bile ducts that prevents active enzymes from being secreted into the bowel, instead damaging the pancreas. Rarely, gallbladder cancer may occur as a complication.

Risk factors
Gallstone risk increases for females (especially before menopause) and for people near or above 40 years; the condition is more prevalent among both North and South Americans and people of European descent than among other ethnicities. A lack of melatonin could significantly contribute to gallbladder stones, as melatonin inhibits cholesterol secretion from the gallbladder, enhances the conversion of cholesterol to bile, and is an antioxidant, which is able to reduce oxidative stress to the gallbladder. Gilbert syndrome has been linked to an increased risk of gallstones. Researchers believe that gallstones may be caused by a combination of factors, including inherited body chemistry, body weight, gallbladder motility (movement), and low-calorie diet. The absence of such risk factors does not, however, preclude the formation of gallstones.
Nutritional factors that may increase risk of gallstones include constipation; eating fewer meals per day; low intake of the nutrients folate, magnesium, calcium, and vitamin C; low fluid consumption; and, at least for men, a high intake of carbohydrate, a high glycemic load, and high glycemic index diet. Wine and whole-grained bread may decrease the risk of gallstones.Rapid weight loss increases risk of gallstones. The weight loss drug orlistat is known to increase the risk of gallstones.Cholecystokinin deficiency caused by celiac disease increases risk of gallstone formation, especially when diagnosis of celiac disease is delayed.Pigment gallstones are most commonly seen in the developing world. Risk factors for pigment stones include hemolytic anemias (such as from sickle-cell disease and hereditary spherocytosis), cirrhosis, and biliary tract infections. People with erythropoietic protoporphyria (EPP) are at increased risk to develop gallstones. Additionally, prolonged use of proton pump inhibitors has been shown to decrease gallbladder function, potentially leading to gallstone formation.Cholesterol modifying medications can affect gallstone formation. Statins inhibit cholesterol synthesis and there is evidence that their use may decrease the risk of getting gallstones. Fibrates increase cholesterol concentration in bile and their use has been associated with an increased risk of gallstones. Bile acid malabsorption may also be a risk.

Pathophysiology
Cholesterol gallstones develop when bile contains too much cholesterol and not enough bile salts. Besides a high concentration of cholesterol, two other factors are important in causing gallstones. The first is how often and how well the gallbladder contracts; incomplete and infrequent emptying of the gallbladder may cause the bile to become overconcentrated and contribute to gallstone formation. This can be caused by high resistance to the flow of bile out of the gallbladder due to the complicated internal geometry of the cystic duct. The second factor is the presence of proteins in the liver and bile that either promote or inhibit cholesterol crystallization into gallstones. In addition, increased levels of the hormone estrogen, as a result of pregnancy or hormone therapy, or the use of combined (estrogen-containing) forms of hormonal contraception, may increase cholesterol levels in bile and also decrease gallbladder motility, resulting in gallstone formation.

Composition
The composition of gallstones is affected by age, diet and ethnicity. On the basis of their composition, gallstones can be divided into the following types: cholesterol stones, pigment stones, and mixed stones. An ideal classification system is yet to be defined.

Cholesterol stones
Cholesterol stones vary from light yellow to dark green or brown or chalk white and are oval, usually solitary, between 2 and 3 cm long, each often having a tiny, dark, central spot. To be classified as such, they must be at least 80% cholesterol by weight (or 70%, according to the Japanese classification system). Between 35% and 90% of stones are cholesterol stones.

Pigment stones
Bilirubin ("pigment", "black pigment") stones are small, dark (often appearing black), and usually numerous. They are composed primarily of bilirubin (insoluble bilirubin pigment polymer) and calcium (calcium phosphate) salts that are found in bile. They contain less than 20% of cholesterol (or 30%, according to the Japanese classification system). Between 2% and 30% of stones are bilirubin stones.

Mixed stones
Mixed (brown pigment stones) typically contain 20–80% cholesterol (or 30–70%, according to the Japanese classification system). Other common constituents are calcium carbonate, palmitate phosphate, bilirubin and other bile pigments (calcium bilirubinate, calcium palmitate and calcium stearate). Because of their calcium content, they are often radiographically visible. They typically arise secondary to infection of the biliary tract which results in the release of β-glucuronidase (by injured hepatocytes and bacteria) which hydrolyzes bilirubin glucuronides and increases the amount of unconjugated bilirubin in bile. Between 4% and 20% of stones are mixed.Gallstones can vary in size and shape from as small as a grain of sand to as large as a golf ball. The gallbladder may contain a single large stone or many smaller ones. Pseudoliths, sometimes referred to as sludge, are thick secretions that may be present within the gallbladder, either alone or in conjunction with fully formed gallstones.

Diagnosis
Diagnosis is typically confirmed by abdominal ultrasound. Other imaging techniques used are ERCP and MRCP. Gallstone complications may be detected on blood tests.On abdominal ultrasound, sinking gallstones usually have posterior acoustic shadowing. In floating gallstones, reverberation echoes (or comet-tail artifact) is seen instead in a clinical condition called adenomyomatosis. Another sign is wall-echo-shadow (WES) triad (or double-arc shadow) which is also characteristic of gallstones.A positive Murphys sign is a common finding on physical examination during a gallbladder attack.

Prevention
Maintaining a healthy weight by getting sufficient exercise and eating a healthy diet that is high in fiber may help prevent gallstone formation.Ursodeoxycholic acid (UDCA) appears to prevent formation of gallstones during weight loss. A high fat diet during weight loss also appears to prevent gallstones.

Treatment
Lithotripsy
Extracorporeal shock wave lithotripsy is a non-invasive method to manage gallstones that uses high-energy sound waves to disintegrate them first applied in January 1985.
Side effects of extracorporeal shock wave lithotripsy include biliary pancreatitis and liver haematoma.

Surgical
Cholecystectomy (gallbladder removal) has a 99% chance of eliminating the recurrence of cholelithiasis. The lack of a gallbladder has no negative consequences in most people, however 10 to 15% of people develop postcholecystectomy syndrome, which may cause nausea, indigestion, diarrhea, and episodes of abdominal pain.There are two surgical options for cholecystectomy:

Open cholecystectomy is performed via an abdominal incision (laparotomy) below the lower right ribs. Recovery typically requires 3–5 days of hospitalization, with a return to normal diet a week after release and to normal activity several weeks after release.
Laparoscopic cholecystectomy, introduced in the 1980s, is performed via three to four small puncture holes for a camera and instruments. Post-operative care typically includes a same-day release or a one-night hospital stay, followed by a few days of home rest and pain medication. Perforation of the gall bladder is not uncommon—it has been reported in the range of 10% to 40% </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 Adenoiditis and can you explain it in depth? [/INST] Adenoiditis is the inflammation of the adenoid tissue usually caused by an infection. Adenoiditis is treated using medication (antibiotics and/or steroids) or surgical intervention.
Adenoiditis may produce cold-like symptoms. However, adenoiditis symptoms often persist for ten or more days, and often include pus-like discharge from nose.
The infection cause is usually viral. However, if the adenoiditis is caused by a bacterial infection, antibiotics may be prescribed for treatment. A steroidal nasal spray may also be prescribed in order to reduce nasal congestion </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 Keratosis pilaris and can you explain it in depth? [/INST] Keratosis pilaris (KP; also follicular keratosis, lichen pilaris, or colloquially chicken skin) is a common, autosomal-dominant, genetic condition of the skins hair follicles characterized by the appearance of possibly itchy, small, gooseflesh-like bumps, with varying degrees of reddening or inflammation. It most often appears on the outer sides of the upper arms (the forearms can also be affected), thighs, face, back, and buttocks; KP can also occur on the hands, and tops of legs, sides, or any body part except glabrous (hairless) skin (like the palms or soles of feet). Often the lesions can appear on the face, which may be mistaken for acne or folliculitis.
The several types of KP have been associated with pregnancy, type 1 diabetes mellitus, obesity, dry skin, allergic diseases (e.g., atopic dermatitis), and rarely cancer. Many rarer types of the disorder are part of inherited genetic syndromes.The cause of KP is not completely understood. As of 2018, KP is thought to be due to abnormalities in the process of depositing the protein keratin in hair follicles, abnormalities in the hair shaft, or both. KP is usually diagnosed by a medical professional based on the appearance of the skin, but dermoscopy can be used, as well, if the diagnosis is unclear. Variants of the ABCA12 gene have been associated with KP.KP is the most common disorder of the hair follicle in children. How common KP is in adults is unclear, with estimates ranging from 0.75 to 34% of the population. No single approach has been found to completely cure KP, but treatments can improve the cosmetic appearance of the condition. Treatment includes the application of topical preparations of moisturizers and medications such as glycolic acid, lactic acid, salicylic acid, urea, or retinoids to the skin. Fractional carbon dioxide lasers and Nd:YAG laser therapies are also effective.

Signs and symptoms
KP results in small, rough bumps on the surface of the skin. They are skin-colored bumps the size of a grain of sand, many of which are surrounded by a slight pink color in light-skinned people and dark spots in dark-skinned people. Most people with KP do not have symptoms, but the bumps in the skin can occasionally be itchy. Irritation due to scratching KP bumps can result in redness and inflammation.
Though people with KP experience the condition year-round, the problem can become exacerbated, with the bumps likely to look and feel more pronounced in color and texture, during the colder months, when moisture levels in the air are lower. The symptoms may also worsen during pregnancy or after childbirth. Increased sun exposure might mitigate the symptoms of KP.

Pathophysiology
KP occurs when the human body produces excess amounts of the skin protein keratin, resulting in the formation of small, raised bumps in the skin, often with surrounding redness. The excess keratin, which is the same color as the persons natural skin tone, surrounds and entraps the hair follicles in the pore. This causes the formation of hard plugs (a process known as hyperkeratinization). Many KP bumps contain an ingrown hair that has coiled. This is a result of the keratinized skins "capping off" the hair follicle, preventing the hair from exiting. The hair grows encapsulated inside the follicle. KP is more common in patients affected by atopic diseases such as allergic rhinitis and atopic dermatitis.
KP subtypes are occasionally part of genetically inherited syndromes associated with intellectual disability, neuro-cardio-facial-cutaneous syndromes, RASopathies, ectodermal dysplasias, and certain myopathies.

Diagnosis
Physicians can often diagnose KP simply by examining the skin without specialized tests, but a dermatologist can use dermoscopy to confirm the diagnosis and assess if a person with KP is responding to treatment. Physicians often consider family history and the presence of symptoms when making the diagnosis. Those with this condition are generally encouraged to contact a physician if the bumps are bothersome and do not improve with over-the-counter lotions.

Differential diagnosis
Several medications that can cause a skin eruption similar to KP include cyclosporine, BRAF inhibitors, and tyrosine kinase inhibitors.

Classification
The several different types of KP include KP rubra (red, inflamed bumps, which can be on arms, head, legs), KP alba (rough, bumpy skin with no irritation), KP rubra faceii (reddish rash on the cheeks), KP atrophicans, keratosis follicularis spinulosa decalvans, atrophoderma vermiculatum, KP atrophicans faciei, erythromelanosis follicularis faciei et colli, and papular profuse precocious KP.KP is commonly described in association with other dry-skin conditions, such as ichthyosis vulgaris, dry skin, and atopic dermatitis, including those of asthma and allergies. KP does not bear any known, long-term health implications, nor is it associated with increased mortality or morbidity </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 Piedraia hortae and can you explain it in depth? [/INST] Piedraia hortae is a superficial fungus that exists in the soils of tropical and subtropical environments and affects both sexes of all ages. The fungus grows very slowly, forming dark hyphae, which contain chlamydoconidia cells and black colonies when grown on agar. Piedraia hortae is a dermatophyte and causes a superficial fungal infection known as black piedra, which causes the formation of black nodules on the hair shaft and leads to progressive weakening of the hair. The infection usually infects hairs on the scalp and beard, but other varieties tend to grow on pubic hairs. The infection is usually treated with cutting or shaving of the hair and followed by the application of anti-fungal and topical agents. The fungus is used for cosmetic purposes to darken hair in some societies as a symbol of attractiveness.

Morphology
When grown on agar at 25 °C (77 °F) Piedraia hortae grows very slowly to form black-greenish, limited and pointed colonies. Piedraia hortae taken from infected hairs have dark brown nodules, which are made up of ascostroma. The nodules have a gritty feel, organized in a stromatic fashion and have a high concentration of chitin and melanoid pigments. The colonies produce a red pigment and remain smooth and covered with short aerial hyphae. Microscopically, P. hortae produces short, dark hyphae containing thick-walled resting cells. The ascomata consist of irregularly shaped pseudothecia that are black in colour. Each ascoma contains a single ascus containing eight ascospores. The ascospores are dark, curved and become very narrow at the ends forming whip-like appendages. Affected hairs develop stone-like black nodules affixed to the hair shaft that cause weakness of the hair. Infected hairs treated with potassium hydroxide fluoresce under ultraviolet light despite that the fungus itself does not normally fluoresce. Fluorescence of the piedra indicates secondary contamination by bacteria. Identification is easily achieved by microscopic examination of the hair nodules, and can be confirmed by sequence analysis of the nuclear ribosomal internal transcribed spacer region.

Pathology
Piedraia hortae causes the formation of nodules on the hair shaft, a clinical superficial disease commonly known as black piedra. Black piedra is usually seen in tropical regions and it usually targets humans  of all ages and targets the scalp, moustache and occasionally pubic hair. The source of the infection is usually in soils, poor hygiene, long hair, cultural use of veils and the application of plant oils to wet hair favours the growth of the infection. Black piedra is a superficial fungal infection, which means that it is restricted to the stratum corneum and causes no inflammation. The infection of the hair shaft results in the formation of nodules on the scalp, moustache and pubic hair. The nodules are hard and gritty, which produce a metallic sound when the hair is combed. The nodules colonize the hair shaft, which causes progressive weakness of the hair and leads to breakage of the hair in severe cases, which can lead to hair loss and baldness. The fungus also has the potential to destroy the cuticular layers of the hair and move into the cortex. Piedraia hortae survives in the scalp is due to the slow rate of the keratin degradation near the cortex and the compact formation of the nodules and the hyphae are tightly packed in black piedra cases. The initial invasion of human hair by P. hortae is achieved by using an eroding hyphae, which force their way beneath or between the cuticular layer. The force applied between or beneath the hair cuticle arises from the growth of the fungus itself. The breakdown of keratin is mainly due to enzymatic processes and corresponds to the abundance of localized mitochondria. The breakdown of keratin begins with the cementing material and progresses to the cortex of the hair shaft. In the cortex two types of degradative patterns are produced which are either parallel or vertical to the axis hair shaft. The parallel pattern arises from hyphal separation of the external cortical layers. The vertical pattern is produced by direct hyphal penetration which creates channels that increase in size as the cortex degrades.

Treatment
The infection cannot easily be removed mechanically, although further proliferation of infection can be achieved by avoidance of moisture. Removal generally involves cutting or shaving of the hair, but chemical treatments may be similarly useful. For women some individuals use a fine comb to remove as much of the infection as possible and then they cut or shave their hair. This is then followed by the application of a sublimate solution in 60% alcohol solution to the scalp. Historical treatments have used alcoholic tinctures of heavy metals, such as mercury bichloride. The application of antifungal shampoos such as pyrithione zinc, formaldehyde and salicylic acid is effective against black piedra. Oral therapy with itraconazole or terbinafine also causes nodules to break down over time. Removal of affected hair and treatment with topical agents is also effective and results in very low recurrences rates. However, even in the absence of treatment, spontaneous remission may occur.Terbinafine has been used in the treatment.

Cosmetic uses
Black piedra is sometimes cultivated for cosmetic purposes due to social factors that favour a specific hair colour, which makes them more attractive in their society. Several Indian tribes located from Panama have been known to use several methods in order to darken the hair of albino individuals within their community. One of these methods is the cultivation of black piedra for an extensive period of time in the individuals hair </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 Extravasation of urine 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 Mannosidosis and can you explain it in depth? [/INST]  </s>