<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 Neisseria gonorrhoeae and can you explain it in depth? [/INST] Neisseria gonorrhoeae, also known as gonococcus (singular), or gonococci (plural), is a species of Gram-negative diplococci bacteria isolated by Albert Neisser in 1879. It causes the sexually transmitted genitourinary infection gonorrhea as well as other forms of gonococcal disease including disseminated gonococcemia, septic arthritis, and gonococcal ophthalmia neonatorum.
It is oxidase positive and aerobic, and it survives phagocytosis and grows inside neutrophils. Culturing it requires carbon dioxide supplementation and enriched agar (chocolate agar) with various antibiotics (Thayer–Martin). It exhibits antigenic variation through genetic recombination of its pili and surface proteins that interact with the immune system.Sexual transmission is through vaginal, anal, or oral sex. Sexual transmission may be prevented through the use of barrier protection. Perinatal transmission may occur during childbirth, and may be prevented by antibiotic treatment of the mother before birth and the application of antibiotic eye gel on the eyes of the newborn. After an episode of gonococcal infection, infected persons do not develop immunity to future infections. Reinfection is possible due to N. gonorrhoeaes ability to evade the immune system by varying its surface proteins.N. gonorrhoeae can cause infection of the genitals, throat, and eyes. Asymptomatic infection is common in males and females. Untreated infection may spread to the rest of the body (disseminated gonorrhea infection), especially the joints (septic arthritis). Untreated infection in women may cause pelvic inflammatory disease and possible infertility due to the resulting scarring. Diagnosis is through culture, Gram stain, or nucleic acid tests, such as polymerase chain reaction, of a urine sample, urethral swab, or cervical swab. Chlamydia co-testing and testing for other STIs is recommended due to high rates of co-infection.

Microbiology
Neisseria species are fastidious, Gram-negative cocci that require nutrient supplementation to grow in laboratory cultures. Neisseria spp. are facultatively intracellular and typically appear in pairs (diplococci), resembling the shape of coffee beans. Neisseria is non-spore-forming, capable of moving using twitching motility, and an obligate aerobe (requires oxygen to grow). Of the 11 species of Neisseria that colonize humans, only two are pathogens. N. gonorrhoeae is the causative agent of gonorrhea and N. meningitidis is one cause of bacterial meningitis.

Culture and identification
N. gonorrhoeae is usually isolated on Thayer–Martin agar (or VPN) agar in an atmosphere enriched with 3-7% carbon dioxide. Thayer–Martin agar is a chocolate agar plate (heated blood agar) containing nutrients and antimicrobials (vancomycin, colistin, nystatin, and trimethoprim). This agar preparation facilitates the growth of Neisseria species while inhibiting the growth of contaminating bacteria and fungi. Martin Lewis and New York City agar are other types of selective chocolate agar commonly used for Neisseria growth. N. gonorrhoeae is oxidase positive (possessing cytochrome c oxidase) and catalase positive (able to convert hydrogen peroxide to oxygen). When incubated with the carbohydrates lactose, maltose, sucrose, and glucose, N. gonorrhoeae will oxidize only the glucose.

Surface molecules
On its surface, N. gonorrhoeae bears hair-like pili, surface proteins with various functions, and sugars called lipooligosaccharides.  The pili mediate adherence, movement, and DNA exchange. The Opa proteins interact with the immune system, as do the porins. Lipooligosaccharide (LOS) is an endotoxin that provokes an immune response. All are antigenic and all exhibit antigenic variation (see below). The pili exhibit the most variation.  The pili, Opa proteins, porins, and even the LOS have mechanisms to inhibit the immune response, making asymptomatic infection possible.Dynamic polymeric protein filaments called type IV pili allow N. gonorrhoeae to adhere to and move along surfaces. To enter the host the bacteria uses the pili to adhere to and penetrate mucosal surfaces. The pili are a necessary virulence factor for N. gonorrhoeae; without them, the bacterium is unable to cause infection. To move, individual bacteria use their pili like a grappling hook: first, they are extended from the cell surface and attach to a substrate. Subsequent pilus retraction drags the cell forward. The resulting movement is referred to as twitching motility. N. gonorrhoeae is able to pull 100,000 times its own weight, and the pili used to do so are amongst the strongest biological motors known to date, exerting one nanonewton. The PilF and PilT ATPase proteins are responsible for powering the extension and retraction of the type IV pilus, respectively. The adhesive functions of the gonococcal pilus play a role in microcolony aggregation and biofilm formation.
Surface proteins called Opa proteins can be used to bind to receptors on immune cells and prevent an immune response. At least 12 Opa proteins are known and the many permutations of surface proteins make recognizing N. gonorrhoeae and mounting a defense by immune cells more difficult.Lipooligosaccharide (LOS) is a low-weight version of lipopolysaccharide present on the surfaces of most other Gram-negative bacteria. It is a sugar (saccharide) side chain attached to lipid A (thus "lipo-") in the outer membrane coating the cell wall of the bacteria. The root "oligo" refers to the fact that it is a few sugars shorter than the typical lipopolysaccharide. As an endotoxin, LOS provokes inflammation. The shedding of LOS by the bacteria is responsible for local injury in, for example, pelvic inflammatory disease. Although its main function is as an endotoxin, LOS may disguise itself with host sialic acid and block initiation of the complement cascade.

Antigenic variation
N. gonorrhoeae evades the immune system through a process called antigenic variation. This process allows N. gonorrhoeae to recombine its genes and alter the antigenic determinants (sites where antibodies bind), such as the Type IV pili, that adorn its surface. Simply stated, the chemical composition of molecules is changed due to changes at the genetic level. N. gonorrhoeae is able to vary the composition of its pili, and LOS; of these, the pili exhibit the most antigenic variation due to chromosomal rearrangement. The PilS gene is an example of this ability to rearrange as its combination with the PilE gene is estimated to produce over 100 variants of the PilE protein. These changes allow for adjustment to the differences in the local environment at the site of infection, evasion of recognition by targeted antibodies, and contribute to the lack of an effective vaccine.In addition to the ability to rearrange the genes it already has, it is also naturally competent to acquire new DNA (via plasmids), via its type IV pilus, specifically proteins Pil Q and Pil T. These processes allow N. gonorrhoeae to acquire/spread new genes, disguise itself with different surface proteins, and prevent the development of immunological memory – an ability which has led to antibiotic resistance and has also impeded vaccine development.

Phase variation
Phase variation is similar to antigenic variation, but instead of changes at the genetic level altering the composition of molecules, these genetic changes result in the turning on or off of a gene. Phase variation most often arises from a frameshift in the expressed gene. The Opacity, or Opa, proteins of N. gonorrhoeae rely strictly on phase variation. Every time the bacteria replicate, they may switch multiple Opa proteins on or off through slipped-strand mispairing. That is, the bacteria introduce frameshift mutations that bring genes in or out of frame. The result is that different Opa genes are translated every time. Pili are varied by antigenic variation, but also phase variation. Frameshifts occur in both the pilE and pilC genes, effectively turning off the expression of pili in situations when they are not needed, such as after colonization when N. gonorrhoeae survives within cells as opposed to on their surfaces.

Survival of gonococci
After gonococci invade and transcytose the host epithelial cells, they land in the submucosa, where neutrophils promptly consume them. The pili and Opa proteins on the surface may interfere with phagocytosis, but most gonococci end up in neutrophils. The exudates from infected individuals contain many neutrophils with ingested gonococci. Neutrophils release an oxidative burst of reactive oxygen species in their phagosomes to kill the gonococci. However, a significant fraction of the gonococci can resist killing through the action of their catalase which breaks down reactive oxygen species and is able to reproduce within the neutrophil phagosomes.Stohl and Seifert showed that the bacterial RecA protein, which mediates repair of DNA damage, plays an important role in gonococcal survival. Michod et al. have suggested that N. gonorrhoeae may replace DNA damaged in neutrophil phagosomes with DNA from neighboring gonococci. The process in which recipient gonococci integrate DNA from neighboring gonococci into their genome is called transformation.

Genome
The genomes of several strains of N. gonorrhoeae have been sequenced. Most of them are about 2.1 Mb in size and encode 2,100 to 2,600 proteins (although most seem to be in the lower range). For instance, strain NCCP11945 consists of one circular chromosome (2,232,025 bp) encoding 2,662 predicted open reading frames (ORFs) and one plasmid (4,153 bp) encoding 12 predicted ORFs. The estimated coding density over the entire genome is 87%, and the average G+C content is 52.4%, values that are similar to those of strain FA1090. The NCCP11945 genome encodes 54 tRNAs and four copies of 16S-23S-5S rRNA operons.

Horizontal gene transfer
In 2011, researchers at Northwestern University found evidence of a human DNA fragment in a N. gonorrhoeae genome, the first example of horizontal gene transfer from humans to a bacterial pathogen.

Disease
Symptoms of infection with N. gonorrhoeae differ depending on the site of infection and many infections are asymptomatic independent of sex. In symptomatic men, the primary symptom of genitourinary infection is urethritis – burning with urination (dysuria), increased urge to urinate, and a pus-like (purulent) discharge from the penis. The discharge may be foul smelling. If untreated, scarring of the urethra may result in difficulty urinating. Infection may spread from the urethra in the penis to nearby structures, including the testicles (epididymitis/orchitis), or to the prostate (prostatitis). Men who have had a gonorrhea infection have a significantly increased risk of having prostate cancer. In symptomatic women, the primary symptoms of genitourinary infection are increased vaginal discharge, burning with urination (dysuria), increased urge to urinate, pain with intercourse, or menstrual abnormalities. Pelvic inflammatory disease results if N. gonorrhoeae ascends into the pelvic peritoneum (via the cervix, endometrium, and fallopian tubes). The resulting inflammation and scarring of the fallopian tubes can lead to infertility and increased risk of ectopic pregnancy. Pelvic inflammatory disease develops in 10 to 20% of the females infected with N. gonorrhoeae. It is important to note that depending on the route of transmission, N. gonorrhoeae may cause infection of the throat (pharyngitis) or infection of the anus/rectum (proctitis).In perinatal infection, the primary manifestation is infection of the eye (neonatal conjunctivitis or ophthalmia neonatorum) when the newborn is exposed to N. gonorrhoeae in the birth canal.  The eye infection can lead to corneal scarring or perforation, ultimately resulting in blindness. If the newborn is exposed during birth, conjunctivitis occurs within 2–5 days after birth and is severe. Gonococcal ophthalmia neonatorum, once common in newborns, is prevented by the application of erythromycin (antibiotic) gel to the eyes of babies at birth as a public health measure. Silver nitrate is no longer used in the United States.Disseminated gonococcal infections can occur when N. gonorrhoeae enters the bloodstream, often spreading to the joints and causing a rash (dermatitis-arthritis syndrome). Dermatitis-arthritis syndrome results in joint pain (arthritis), tendon inflammation (tenosynovitis), and painless non-pruritic (non-itchy) dermatitis. Disseminated infection and pelvic inflammatory disease in women tend to begin after menses due to reflux during menses, facilitating spread. In rare cases, disseminated infection may cause infection of the meninges of the brain and spinal cord (meningitis) or infection of the heart valves (endocarditis).

Transmission
N. gonorrhoeae is transmitted through vaginal, oral, or anal sex; nonsexual transmission is unlikely in adult infection. It can also be transmitted to the newborn during passage through the birth canal if the mother has untreated genitourinary infection. Given the high rate of asymptomatic infection, all pregnant women should be tested for gonorrhea infection. However, communal baths, towels or fabric, rectal thermometers and caregivers hands have been implicated as means of transmission in the pediatric setting. Kissing has also been implicated as a theoretical means of transmission in the gay male population, based on a newer study.Traditionally, the bacterium was thought to move attached to spermatozoa, but this hypothesis did not explain female to male transmission of the disease. A recent study suggests that rather than "surf" on wiggling sperm, N. gonorrhoeae bacteria use pili to anchor onto proteins in the sperm and move through coital liquid.

Infection
For N. gonorrhoeae, the first step after successful transmission is adherence to the epithelial cells found at the mucosal site that is infected. The bacterium relies on type IV pili that attach and retract, pulling N. gonorrhoeae toward the epithelial membrane where its surface proteins, such as opacity proteins, can interact directly. After adherence, N. gonorrhoeae replicates itself and forms microcolonies. While colonizing, N. gonorrhoeae has the potential to transcytose across the epithelial barrier and work its way in to the bloodstream. During growth and colonization, N. gonorrhoeae stimulates the release of cytokines and chemokines from host immune cells that are pro-inflammatory. These pro-inflammatory molecules result in the recruitment of macrophages and neutrophils. These phagocytic cells typically take in foreign pathogens and destroy them, but N. gonorrhoeae has evolved many mechanisms that allow it to survive within these immune cells and thwart the attempts at elimination.

Prevention
Transmission is reduced by using latex barriers (e.g. condoms or dental dams) during sex and by limiting sexual partners. Condoms and dental dams should be used during oral and anal sex, as well. Spermicides, vaginal foams, and douches are not effective for prevention of transmission.

Treatment
The current treatment recommended by the CDC is an injected single dose of ceftriaxone (a third-generation cephalosporin). Sexual partners (defined by the CDC as sexual contact within the past 60 days) should also be notified, tested, and treated. It is important that if symptoms persist after receiving treatment of N. gonorrhoeae infection, a reevaluation should be pursued.

Antibiotic resistance
Antibiotic resistance in gonorrhea has been noted beginning in the 1940s. Gonorrhea was treated with penicillin, but doses had to be progressively increased to remain effective. By the 1970s, penicillin- and tetracycline-resistant gonorrhea emerged in the Pacific Basin. These resistant strains then spread to Hawaii, California, the rest of the United States, Australia and Europe. Fluoroquinolones were the next line of defense, but soon resistance to this antibiotic emerged, as well. Since 2007, standard treatment has been third-generation cephalosporins, such as ceftriaxone, which are considered to be our "last line of defense".Recently, a high-level ceftriaxone-resistant strain of gonorrhea called H041 was discovered in Japan. Lab tests found it to be resistant to high concentrations of ceftriaxone, as well as most of the other antibiotics tested. Within N. gonorrhoeae, genes exist that confer resistance to every single antibiotic used to cure gonorrhea, but thus far they do not coexist within a single gonococcus. However, because of N. gonorrhoeaes high affinity for horizontal gene transfer, antibiotic-resistant gonorrhea is seen as an emerging public health threat.

Serum resistance
As a Gram negative bacteria, N. gonorrhoeae requires defense mechanisms to protect itself against the complement system (or complement cascade), whose components are found with human serum. There are three different pathways that activate this system however, they all result in the activation of complement protein 3 (C3). A cleaved portion of this protein, C3b, is deposited on pathogenic surfaces and results in opsonization as well as the downstream activation of the membrane attack complex. N. gonorrhoeae has several mechanisms to avoid this action. As a whole, these mechanisms are referred to as serum resistance.

History
Name origin
Neisseria gonorrhoeae is named for Albert Neisser, who isolated it as the causative agent of the disease gonorrhea in 1878. Galen (130 AD) coined the term "gonorrhea" from the Greek gonos which means "seed" and rhoe which means "flow". Thus, gonorrhea means "flow of seed", a description referring to the white penile discharge, assumed to be semen, seen in male infection.

Discovery
In 1878, Albert Neisser isolated and visualized N. gonorrhoeae diplococci in samples of pus from 35 men and women with the classic symptoms of genitourinary infection with gonorrhea – two of whom also had infections of the eyes </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 Cheilitis and can you explain it in depth? [/INST] Cheilitis is a medical condition characterized by inflammation of the lips. The inflammation may include the perioral skin (the skin around the mouth), the vermilion border, or the labial mucosa. The skin and the vermilion border are more commonly involved, as the mucosa is less affected by inflammatory and allergic reactions.Cheilitis is a general term, and there are many recognized types and different causes. According to its onset and course, cheilitis can be either acute or chronic. Most cheilitis is caused by exogenous factors such as dryness (chapping) and acute sun exposure. Allergic tests may identify allergens that cause cheilitis.

Chapped lips
Chapped lips (also known as cheilitis simplex or common cheilitis) is characterized by the cracking, fissuring, and peeling of the skin of the lips, and is one of the most common types of cheilitis. While both lips may be affected, the lower lip is the most common site. There may also be burning or the formation of large, painful cracks when the lips are stretched. Chronic cheilitis simplex can progress to crusting and bleeding.

Counterintuitively, constant licking of the lips causes drying and irritation, and eventually the mucosa splits or cracks. The lips have a greater tendency to dry out in cold, dry weather. Digestive enzymes present in the saliva may also irritate the lips, and the evaporation of the water in saliva saps moisture from them.

Some children have a habit of sucking and chewing on the lower lip, producing a combination of cheilitis and a sharply demarcated perioral erythema.Treatment is usually successful with barrier lubricants, such as lip salve or Vaseline. Medical grade (USP) lanolin accelerates repair of the lips, and is used in some lip repair products.
Sometimes the term "cheilitis simplex" is used interchangeably with cheilitis in general; however, exfoliative cheilitis is also sometimes stated to be the equivalent of chapped lips.

Actinic cheilitis
Also termed "solar cheilosis", actinic cheilitis is the result of chronic over-exposure to ultraviolet radiation in sunlight. It usually occurs on the lower lip, which is dry, scaling, and wrinkled grey-white in appearance. It is especially common in people with light skin types who live in sunny climates (e.g., Australians of European ancestry), and in persons who spend a lot of time outdoors. There is a small risk that actinic cheilitis can develop into squamous cell carcinoma in the long term, but lip cancer is usually noticed early and hence has a good prognosis compared to oral cancer generally.

Angular cheilitis
Angular cheilitis (angular stomatitis, also known as cheilosis) is inflammation of one or both of the corners (angles) of the mouth. It is a fairly common condition, and often affects elderly people.
There are many possible causes, including nutritional deficiencies (iron, B vitamins, folate), contact allergies, infections (Candida albicans, Staphylococcus aureus or β-hemolytic streptococci) and edentulism (often with overclosure of the mouth and concomitant denture-related stomatitis), and others.

Eczematous cheilitis
Also termed "lip dermatitis", eczematous cheilitis is a diverse group of disorders which often have an unknown cause. Chronic eczematous reactions account for the majority of chronic cheilitis cases.It is divided into endogenous (due to an inherent characteristic of the individual), and exogenous (where it is caused by an external agent). The main cause of endogenous eczematous cheilitis is atopic cheilitis (atopic dermatitis), and the main causes of exogenous eczematous cheilitis is irritant contact cheilitis (e.g., caused by a lip-licking habit) and allergic contact cheilitis. The latter is characterized by a dryness, fissuring, edema, and crusting. It affects females more commonly than males, in a ratio of about 9:1.

The most common causes of allergic contact cheilitis is lip cosmetics, including lipsticks and lip balm, followed by toothpastes. A lipstick allergy can be difficult to diagnose in some cases as it is possible that cheilitis can develop without the person even wearing lipstick. Instead, small exposure such as kissing someone who is wearing lipstick is enough to cause the condition.Allergy to Balsam of Peru can manifest as cheilitis.  Allergies to metal, wood, or other components can cause cheilitis reactions in musicians, especially players of woodwind and brass instruments, e.g., the so-called "clarinetists cheilitis", or "flutists cheilitis".  "Pigmented contact cheilitis" is one type of allergic cheilitis in which a brown-black discoloration of the lips develops. Patch testing is used to identify the substance triggering allergic contact cheilitis.

Infectious cheilitis
Infectious cheilitis refers to cheilitis caused by infectious disease. The terms "Candidal cheilitis" and "bacterial cheilitis" are sometimes used, denoting the involvement of Candida organisms and bacterial species respectively. The term "cheilocandidiasis" describes exfoliative (flaking) lesions of the lips and the skin around the lips, and is caused by a superficial candidal infection due to chronic lip licking. Impetigo (caused by Streptococcus pyogenes and/or Staphylococcus aureus), can manifest as an exfoliative cheilitis-like appearance.Herpes labialis (cold sore) is a common cause of infectious cheilitis. A lesion caused by recurrence of a latent herpes simplex infection can occur in the corner of the mouth, and be mistaken for other causes of angular cheilitis. In fact this is herpes labialis, and is sometimes termed "angular herpes simplex".

Granulomatous cheilitis
Orofacial granulomatosis is enlargement of lips due to the formation of non-caseating granulomatous inflammation, which obstruct lymphatic drainage of the orofacial soft tissues, causing lymphedema. Essentially, granulomatous cheilitis refers to the lip swelling that accompanies this condition. "Median cheilitis" may be seen, which is fissuring in the midline of the lips due to the enlargement of the lips. Angular cheilitis may also be associated with orofacial granulomatosis.
A related condition is Melkersson–Rosenthal syndrome, a triad of facial palsy, chronic lip edema, and fissured tongue. "Mieschers cheilitis", and "granulomatous macrocheilitis", are synonyms of granulomatous cheilitis.

Drug-related cheilitis
Common causes of drug-related cheilitis include Etretinate, Indinavir, Protease inhibitors, Vitamin A and Isotretinoin (a retinoid drug). Uncommon causes include Atorvastatin, Busulphan, Clofazimine, Clomipramine, Cyancobalamin, Gold, Methyldopa, Psoralens, Streptomycin, Sulfasalazine and Tetracycline. A condition called "drug-induced ulcer of the lip" is described as being characterized by painful or tender, well-defined ulcerations of the lip without induration. It is the result of oral administration of drugs, and the condition resolves when the drugs are stopped.

Exfoliative cheilitis
Also termed "cheilitis exfoliativa" or "tic de levres", is an uncommon inflammatory condition of the vermilion zone of the lips, which become painful and crusted. There  is continuous production and desquamation (shedding) of thick, brown scales of keratin. The keratin layer of the epidermis of the lips experiences a faster growth and death rate than normal and desquamates. When these scales are removed, a lip of normal appearance is revealed beneath, although  there may be associated erythema and edema. The condition has not yet been attributed to any particular cause. Rarely are infections to blame. In some individuals, there is an association with stress, anxiety, depression or personality disorders. In one report, 87% of individuals had some form of psychiatric disturbance, and 47% had thyroid dysfunction, which in turn can cause psychiatric conditions like depression.Some cases of exfoliative cheilitis are thought to represent factitious damage, termed "factitious cheilitis" or "artifactual cheilitis", and are related to repetitive lip picking or licking habits. This appears as crusting and ulceration caused by repetitive chewing and sucking of the lips. Some consider habitual lip licking or picking to be a form of nervous tic. This habit is sometimes termed perlèche (derived from the French word pourlècher meaning "to lick ones lips"). Factitious cheilitis is significantly more common in young females.Exfoliative cheilitis has also been linked to HIV/AIDS. Management consists mostly of keeping the lips moist and the application of topical corticosteroids ranging from hydrocortisone to clobetasol. There have also been reports of using topical tacrolimus ointment.

Cheilitis glandularis
Chelitis glandularis is a rare inflammatory condition of the minor salivary glands, usually in the lower lip, which appears swollen and everted. There may also be ulceration, crusting, abscesses, and sinus tracts. It is an acquired disorder, but the cause is uncertain </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 Ossification of the posterior longitudinal ligament 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 Hypertrophic scar and can you explain it in depth? [/INST] A hypertrophic scar is a cutaneous condition characterized by deposits of excessive amounts of collagen which gives rise to a raised scar, but not to the degree observed with keloids. Like keloids, they form most often at the sites of pimples, body piercings, cuts and burns. They often contain nerves and blood vessels. They generally develop after thermal or traumatic injury that involves the deep layers of the dermis and express high levels of TGF-β.

Cause
Mechanical tension on a wound has been identified as a leading cause for hypertrophic scar formation.When a normal wound heals, the body produces new collagen fibers at a rate which balances the breakdown of old collagen. Hypertrophic scars are red and thick and may be itchy or painful </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Familial dysalbuminemic hyperthyroxinemia 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 Neutrophilia 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 Facial eczema and can you explain it in depth? [/INST] Facial eczema is a mycotoxic disease that affects the liver of several animals, mainly sheep and cattle, but can also infect other ungulates. It is caused by ingesting sporidesmins released by the fungus Pithomyces chartarum. Its visible symptoms are characterized by red skin that turns black and crusty before peeling off, as well as inflammation that can cause swelling of the udder, teats, ears and face. The disease is not always visible. Other symptoms include weight loss, weakness and death.

P. chartarum
It grows mostly in New Zealand but also occurs in Australia, France, South Africa, and South America. The fungus grows on dead plants, especially on perennial ryegrass near the ground (25mm height). It most commonly grows between January and May, as it requires warm, humid conditions, as well as moisture at ground level. Areas of spore growth can include urine patches and areas sheltered by hedges. The fungus grows in clusters and is normally invisible to human eye. It produces millions of spores with the toxic substance sporidesmin. Fresh spores are particularly toxic. Contaminated pasture loses its toxicity after 2 weeks.

Pathophysiology
The incubation period is 7-20 days after poison intake. Sporidesmin is hepatotoxic and leads to hepatogenous photosensitization and phylloerythrin accumulation in the bloodstream. It damages the bile ducts and then the liver. The worst case is liver necrosis. This causes – as a secondary effect – photosensitization, this means the inflammation of unpigmented areas and exposed skin (ears, teat, face) and photodynamic dermatitis. Only 5% of affected animals show the respective clinical signs.

Symptoms
Sheep
Infected sheep experience sunburn at face, ears, teats and vulva. It is the primary symptom of the poisoning caused by sporidesmin. The sunburn is caused by the fact that the lower tissue is swollen. The skin gets crusty, dark and then peels, </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 Cyclosporiasis and can you explain it in depth? [/INST] Cyclosporiasis is a disease caused by infection with Cyclospora cayetanensis, a pathogenic protozoan transmitted by feces or feces-contaminated food and water. Outbreaks have been reported due to contaminated fruits and vegetables. It is not spread from person to person, but can be a hazard for travelers as a cause of diarrhea.

Cause
Cyclosporiasis primarily affects humans and other primates. When an oocyst of Cyclospora cayetanensis enters the small intestine, it invades the mucosa, where it incubates for about one week. After incubation, the infected person begins to experience severe watery diarrhea, bloating, fever, stomach cramps, and muscle aches.The parasite particularly affects the jejunum of the small intestine. Of nine patients in Nepal who were diagnosed with cyclosporiasis, all had inflammation of the lamina propria along with an increase of plasma in the lamina propria. Oocysts were also observed in duodenal aspirates.Oocysts are often present in the environment as a result of using contaminated water or human feces as fertilizer.

Diagnosis
Diagnosis can be difficult due to the lack of recognizable oocysts in the feces. PCR-based DNA tests and acid-fast staining can help with identification.

Prevention
There is no vaccine to prevent cyclosporiasis in humans at present, but one is available for reduction of fetal losses in sheep.

Treatment
The infection is often treated with trimethoprim/sulfamethoxazole, also known as Bactrim or co-trimoxazole, because traditional anti-protozoal drugs are not sufficient. To prevent transmission, food should be cooked thoroughly and drinking water from streams should be avoided.

Epidemiology
The first recorded cases of cyclosporiasis in humans were as recent as 1977, 1978, and 1979. They were reported by Ashford, a British parasitologist who discovered three cases while working in Papua New Guinea. Ashford found that the parasite had very late sporulation, from 8–11 days, making the illness difficult to diagnose. When examining feces, the unsporulated oocysts can easily be mistaken for fungal spores, and thus can be easily overlooked.In 2007, Indian researchers published a case report that found an association between Cyclospora infection and Bells palsy. This was the first reported case of Bell’s palsy following chronic Cyclospora infection. In addition to other extra-intestinal reports, cyclosporiasis might be involved in either reversible neuronal damage or other unknown mechanisms to lead to Guillain-Barré syndrome or Bells palsy.
In 2010, a report of Cyclospora transmission via swimming in the Kathmandu Valley was published in the Journal of Institute of Medicine. The researchers found that openly defecated human stool samples around the swimmers living quarters and near the swimming pool were positive for Cyclospora. However, they did not find the parasite in dog stool, bird stool, cattle dung, vegetable samples, or water samples. They concluded that pool water contaminated via environmental pollution might have caused the infection, as the parasite can resist chlorination in water.Cyclosporiasis infections have been well reported in Nepal. In one study, Tirth Raj Ghimire, Purna Nath Mishra, and Jeevan Bahadur Sherchan collected samples of vegetables, sewage, and water from ponds, rivers, wells, and municipal taps in the Kathmandu Valley from 2002 to 2004. They found Cyclospora in radish, cauliflower, cabbage, and mustard leaves, as well as sewage and river water. This first epidemiological study determined the seasonal character of cyclosporiasis outbreaks in Nepal  during the rainy season, from May to September.

Cyclosporiasis in AIDS patients
At the beginning of the AIDS epidemic in the early 1980s, cyclosporiasis was identified as one of the most important opportunistic infections among AIDS patients.In 2005, Ghimire and Mishra reported a case of cyclosporiasis in a patient with low hemoglobin and suggested that this coccidian might be involved in reducing hemoglobin due to lack of immune system </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 Progressive outer retinal necrosis and can you explain it in depth? [/INST] Progressive outer retinal necrosis (PORN) syndrome is a form of chorio-retinitis, an infection in the retina, the back of the eye. The disease is most commonly caused by the Varicella zoster virus and is found almost exclusively in patients with HIV/AIDS (acquired immunodeficiency syndrome). Progressive outer retinal necrosis is the second most common opportunistic retinal infection in North America among people with AIDS. The reason this disease process is considered opportunistic is precisely because it only presents in patients with AIDS, a disease that attacks and weakens the immune system, making space for other infections, like Varicella zoster virus (VZV) and Herpes simplex virus (HSV), to attack the body.

The syndrome, PORN, falls under the umbrella of Necrotizing Herpetic Retinopathy, along with Acute Retinal Necrosis (ARN). Although fairly similar processes, the two forms of retinopathy have different presenting symptoms. Acute Retinal Necrosis, or ARN, is damage more central in the retinal portion of the eye with dead or necrotic areas well defined. ARN also presents with inflammation within the eye and is often painful. Progressive outer retinal necrosis (PORN) is a chorioretinitis presenting with multiple lesions in the peripheral retina. Unlike ARN, this disease process has no signs of intraocular inflammation, the hallmark feature, or vascular involvement.

Presentation (Signs and Symptoms)
The presentation of the disease is dependent on the patients AIDS prognosis </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 Prune belly syndrome and can you explain it in depth? [/INST] Prune belly syndrome is a rare, genetic birth defect affecting about 1 in 40,000 births. About 97% of those affected are male. Prune belly syndrome is a congenital disorder of the urinary system, characterized by a triad of symptoms. The syndrome is named for the mass of wrinkled skin that is often (but not always) present on the abdomen of those with the disorder.

Signs and symptoms
Prune-belly triad consists of signs such as: Cryptorchidism, abdominal wall defects and genitourinary defects:
A partial or complete lack of abdominal wall muscles. There may be wrinkly folds of skin covering the abdomen.
Cryptorchidism (undescended testicles) in males
Urinary tract abnormality such as unusually large ureters, distended bladder, accumulation and backflow of urine from the bladder to the ureters and the kidneys (vesicoureteral reflux)Other signs include:

Frequent urinary tract infections due to the inability to properly expel urine.
Ventricular septal defect
Malrotation of the gut
Club foot
Later in life, a common symptom is post-ejaculatory discomfort.  Most likely a bladder spasm, it lasts about two hours.
Musculoskeletal abnormalities include pectus excavatum, scoliosis, and congenital joint dislocations including the hip. Diagnosis of prune belly syndrome necessitates a thorough orthopaedic evaluation because of the high prevalence of associated musculoskeletal abnormalities.
Pulmonary hypoplasia, pneumonia, and atelectasis involving lung lobes

Complications
Prune belly syndrome can result in distention and enlargement of internal organs such as the bladder and intestines. Surgery is often required but will not return the organs to a normal size. Bladder reductions have shown that the bladder will again stretch to its previous size due to lack of muscle. Complications may also arise from enlarged/malformed kidneys, which may result in kidney failure and the childs going on dialysis or requiring a kidney transplant. Many individuals with prune belly syndrome have good physical and mental health, despite all the concerns </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 Eosinophilic gastroenteritis and can you explain it in depth? [/INST] Eosinophilic gastroenteritis (EG or EGE) is a rare and heterogeneous condition characterized by patchy or diffuse eosinophilic infiltration of gastrointestinal (GI) tissue, first described by Kaijser in 1937. Presentation may vary depending on location as well as depth and extent of bowel wall involvement and usually runs a chronic relapsing course. It can be classified into mucosal, muscular and serosal types based on the depth of involvement. Any part of the GI tract can be affected, and isolated biliary tract involvement has also been reported.
The stomach is the organ most commonly affected, followed by the small intestine and the colon.

Signs and symptoms
EG typically presents with a combination of chronic nonspecific GI symptoms which include abdominal pain, diarrhea, occasional nausea and vomiting, weight loss and abdominal distension. Approximately 80% have symptoms for several years; a high degree of clinical suspicion is often required to establish the diagnosis, as the disease is extremely rare. It doesnt come all of a sudden but takes about 3–4 years to develop depending upon the age of the patient. Occasionally, the disease may manifest itself as an acute abdomen or bowel obstruction.
Mucosal EG (25–100%) is the most common variety, which presents with features of malabsorption and protein losing enteropathy. Failure to thrive and anaemia may also be present. Lower gastrointestinal bleeding may imply colonic involvement.
Muscular EG (13–70%) present with obstruction of gastric outlet or small intestine; sometimes as an obstructing caecal mass or intussusception.
Subserosal EG (4.5% to 9% in Japan and 13% in the US) presents with ascites which is usually exudative in nature, abundant peripheral eosinophilia, and has favourable responses to corticosteroids.
Other documented features are cholangitis, pancreatitis, eosinophilic splenitis, acute appendicitis and giant refractory duodenal ulcer.

Pathophysiology
Peripheral blood eosinophilia and elevated serum IgE are usual but not universal. The damage to the gastrointestinal tract wall is caused by eosinophilic infiltration and degranulation.As a part of host defense mechanism, eosinophils are normally present in gastrointestinal mucosa, though the finding in deeper tissue is almost always pathologic. What triggers such dense infiltration in EG is not clear. It is possible that different pathogenetic mechanisms of disease is involved in several subgroups of patients. Food allergy and variable IgE response to food substances has been observed in some patients which implies role of hypersensitive response in pathogenesis. Many patients indeed have history of other atopic conditions like eczema, asthma, etc.Eosinophil recruitment into inflammatory tissue is a complex process, regulated by a number of inflammatory cytokines. In EG cytokines IL-3, IL-5 and granulocyte macrophage colony stimulating factor (GM-CSF) may be behind the recruitment and activation. They have been observed immunohistochemically in diseased intestinal wall.
In addition eotaxin has been shown to have an integral role in regulating the homing of eosinophils into the lamina propria of stomach and small intestine.
In the allergic subtype of disease, it is thought that food allergens cross the intestinal mucosa and trigger an inflammatory response that includes mast cell degranulation and recruitment of eosinophils.

Diagnosis
Talley et al </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 Intestinal neuronal dysplasia 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 Metabolic myopathy and can you explain it in depth? [/INST] Metabolic myopathies are myopathies that result from defects in biochemical metabolism that primarily affect muscle. They are generally genetic defects that interfere with muscles ability to create energy. At the cellular level, metabolic myopathies lack some kind of enzyme that prevent the chemical reactions necessary to create adenosine triphosphate (ATP). This prevents the muscle cells from being able to function properly and disrupts communication between joints and bones. Some people with a metabolic myopathy never develop symptoms due to the bodys ability to produce enough ATP through alternative pathways. In the event more ATP is needed from the affected pathway, the lack of it becomes an issue and symptoms develop. People with a metabolic myopathy often experience symptoms such as progressive muscle weakness, fatigue, pain and cramping after exercise, and considerable breakdown of muscle tissue. The degree of symptoms varies greatly from person to person and is dependent on the severity of enzymatic defect. In extreme cases it can lead to Rhabdomyolysis.

Types
Metabolic myopathies are generally caused by an inherited genetic mutation. This mutation has an autosomal recessive inheritance pattern making it fairly rare to inherit, but it can also be caused by a random genetic mutation. Metabolic myopathies are named after the pathway in which the defective enzyme or a lack of enzymes is present </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 Ornithine translocase deficiency and can you explain it in depth? [/INST] Ornithine translocase deficiency, also called hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, is a rare autosomal recessive urea cycle disorder affecting the enzyme ornithine translocase, which causes ammonia to accumulate in the blood, a condition called hyperammonemia.
Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

Pathophysiology
Mutations in SLC25A15 cause ornithine translocase deficiency. Ornithine translocase deficiency belongs to a class of metabolic disorders referred to as urea cycle disorders. The urea cycle is a sequence of reactions that occurs in liver cells. This cycle processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys. The SLC25A15 gene provides instructions for making a protein called a mitochondrial ornithine transporter. This protein is needed to move a molecule called ornithine within the mitochondria (the energy-producing centers in cells). Specifically, this protein transports ornithine across the inner membrane of mitochondria to the region called the mitochondrial matrix, where it participates in the urea cycle. Mutations in the SLC25A15 gene result in a mitochondrial ornithine transporter that is unstable or the wrong shape, and which cannot bring ornithine to the mitochondrial matrix. This failure of ornithine transport causes an interruption of the urea cycle and the accumulation of ammonia, resulting in the signs and symptoms of ornithine translocase deficiency.This disorder is inherited in an autosomal recessive pattern, which means the defective gene is located on an autosome, and two copies of the gene - one from each parent - are required to be born with the disorder </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 Central diabetes insipidus and can you explain it in depth? [/INST] Central diabetes insipidus, also called neurogenic diabetes insipidus, is a type of diabetes insipidus due to a lack of vasopressin (ADH) production in the brain.  Vasopressin acts to increase the volume of blood (intravascularly), and decrease the volume of urine produced. Therefore, a lack of it causes increased urine production and volume depletion.
It is also known as neurohypophyseal diabetes insipidus, referring to the posterior pituitary (neurohypophysis), which is supplied by the hypothalamus in the brain. This condition has only polyuria in common with diabetes. Although not mutually exclusive, with most typical cases, the name diabetes insipidus is a misleading misnomer </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 Gastritis and can you explain it in depth? [/INST] Gastritis is inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain (see dyspepsia). Other possible symptoms include nausea and vomiting, bloating, loss of appetite and heartburn. Complications may include stomach bleeding, stomach ulcers, and stomach tumors. When due to autoimmune problems, low red blood cells due to not enough vitamin B12 may occur, a condition known as pernicious anemia.Common causes include infection with Helicobacter pylori and use of nonsteroidal anti-inflammatory drugs (NSAIDs). Less common causes include alcohol, smoking, cocaine, severe illness, autoimmune problems, radiation therapy and Crohns disease. Endoscopy, a type of X-ray known as an upper gastrointestinal series, blood tests, and stool tests may help with diagnosis. The symptoms of gastritis may be a presentation of a myocardial infarction. Other conditions with similar symptoms include inflammation of the pancreas, gallbladder problems, and peptic ulcer disease.Prevention is by avoiding things that cause the disease. Treatment includes medications such as antacids, H2 blockers, or proton pump inhibitors. During an acute attack drinking viscous lidocaine may help. If gastritis is due to NSAIDs these may be stopped. If H. pylori is present it may be treated with a combination of antibiotics such as amoxicillin and clarithromycin. For those with pernicious anemia, vitamin B12 supplements are recommended either by mouth or by injection. People are usually advised to avoid foods that bother them.Gastritis is believed to affect about half of people worldwide. In 2013 there were approximately 90 million new cases of the condition. As people get older the disease becomes more common. It, along with a similar condition in the first part of the intestines known as duodenitis, resulted in 50,000 deaths in 2015. H. pylori was first discovered in 1981 by Barry Marshall and Robin Warren.

Signs and symptoms
Many people with gastritis experience no symptoms at all. However, upper central abdominal pain is the most common symptom; the pain may be dull, vague, burning, aching, gnawing, sore, or sharp. Pain is usually located in the upper central portion of the abdomen, but it may occur anywhere from the upper left portion of the abdomen around to the back.
Other signs and symptoms may include the following:

Nausea
Vomiting (may be clear, green or yellow, blood-streaked or completely bloody depending on the severity of the stomach inflammation)
Belching (does not usually relieve stomach pain if present)
Bloating
Early satiety
Loss of appetite
Unexplained weight loss

Causes
There are two categories of gastritis depending on the cause of the disease. There is erosive gastritis, for which the common causes are stress, alcohol, some drugs, such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and Crohns disease.  And, there is non-erosive gastritis, for which the most common cause is a Helicobacter pylori infection.

Helicobacter pylori
Helicobacter pylori colonizes the stomachs of more than half of the worlds population, and the infection continues to play a key role in the pathogenesis of a number of gastroduodenal diseases. Colonization of the gastric mucosa with Helicobacter pylori results in the development of chronic gastritis in infected individuals and, in a subset of patients, chronic gastritis progresses to complications (e.g., ulcer disease, stomach cancers, and some distinct extragastric disorders). However, more than 80% of individuals infected with the bacterium are asymptomatic and it has been postulated that it may play an important role in the natural stomach ecology.

Critical illness
Gastritis may also develop after major surgery or traumatic injury ("Cushing ulcer"), burns ("Curling ulcer"), or severe infections. Gastritis may also occur in those who have had weight loss surgery resulting in the banding or reconstruction of the digestive tract.

Diet
Evidence does not support a role for specific foods, including spicy foods and coffee, in the development of peptic ulcers. People are usually advised to avoid foods that bother them. There is little specific advice on diet published by authoritative sources. The website of the National Health Service of the United Kingdom advises "avoiding foods that can irritate the stomach, such as spicy, acidic or fried foods", and suggests that "you may want to talk to a GP about this".

Pathophysiology
Acute
Acute erosive gastritis typically involves discrete foci of surface necrosis due to damage to mucosal defenses. NSAIDs inhibit cyclooxygenase-1, or COX-1, an enzyme responsible for the biosynthesis of eicosanoids in the stomach, which increases the possibility of peptic ulcers forming.  Also, NSAIDs, such as aspirin, reduce a substance that protects the stomach called prostaglandin. These drugs used in a short period are not typically dangerous. However, regular use can lead to gastritis. Additionally, severe physiologic stress ("stress ulcers") from sepsis, hypoxia, trauma, or surgery is also a common etiology for acute erosive gastritis. This form of gastritis can occur in more than 5% of hospitalized patients.Also, note that alcohol consumption does not cause chronic gastritis.  It does, however, erode the mucosal lining of the stomach; low doses of alcohol stimulate hydrochloric acid secretion. High doses of alcohol do not stimulate secretion of acid.

Chronic
Chronic gastritis refers to a wide range of problems of the gastric tissues.  The immune system makes proteins and antibodies that fight infections in the body to maintain a homeostatic condition.  In some disorders the body targets the stomach as if it were a foreign protein or pathogen; it makes antibodies against, severely damages, and may even destroy the stomach or its lining.  In some cases bile, normally used to aid digestion in the small intestine, will enter through the pyloric valve of the stomach if it has been removed during surgery or does not work properly, also leading to gastritis.  Gastritis may also be caused by other medical conditions, including HIV/AIDS, Crohns disease, certain connective tissue disorders, and liver or kidney failure. Since 1992, chronic gastritis lesions are classified according to the Sydney system.

Metaplasia
Mucous gland metaplasia, the reversible replacement of differentiated cells, occurs in the setting of severe damage of the gastric glands, which then waste away (atrophic gastritis) and are progressively replaced by mucous glands. Gastric ulcers may develop; it is unclear if they are the causes or the consequences.  Intestinal metaplasia typically begins in response to chronic mucosal injury in the antrum and may extend to the body. Gastric mucosa cells change to resemble intestinal mucosa and may even assume absorptive characteristics. Intestinal metaplasia is classified histologically as complete or incomplete. With complete metaplasia, gastric mucosa is completely transformed into small-bowel mucosa, both histologically and functionally, with the ability to absorb nutrients and secrete peptides. In incomplete metaplasia, the epithelium assumes a histologic appearance closer to that of the large intestine and frequently exhibits dysplasia.

Diagnosis
Often, a diagnosis can be made based on  patients description of their symptoms. Other methods which may be used to verify gastritis include:

Blood tests:
Blood cell count
Presence of H. pylori
Liver, kidney, gallbladder, or pancreas functions
Urinalysis
Stool sample, to look for blood in the stool
X-rays
Endoscopy, to check for stomach lining inflammation and mucous erosion
Stomach biopsy, to test for gastritis and other conditionsThe OLGA staging frame of chronic gastritis on histopathology. Atrophy is scored as the percentage of atrophic glands and scored on a four-tiered scale. No atrophy (0%) = score 0; mild atrophy (1–30%) = score 1; moderate atrophy (31–60%) = score 2; 9 severe atrophy (>60%) = score 3. These scores (0–3) are used in the OLGA staging assessment in each 10 compartment:

Treatment
Antacids are a common treatment for mild to medium gastritis. When antacids do not provide enough relief, medications such as H2 blockers and proton-pump inhibitors that help reduce the amount of acid are often prescribed.Cytoprotective agents are designed to help protect the tissues that line the stomach and small intestine. They include the medications sucralfate and misoprostol. If NSAIDs are being taken regularly, one of these medications to protect the stomach may also be taken. Another cytoprotective agent is bismuth subsalicylateSeveral regimens are used to treat H. pylori infection. Most use a combination of two antibiotics and a proton pump inhibitor. Sometimes bismuth is added to the regimen.

History
In 1,000 A.D, Avicenna first gave the description of stomach cancer. In 1728, German physician Georg Ernst Stahl first coined the term "gastritis". Italian anatomical pathologist Giovanni Battista Morgagni further described the characteristics of gastric inflammation </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 Urticarial vasculitis and can you explain it in depth? [/INST] Urticarial vasculitis (also known as "chronic urticaria as a manifestation of venulitis", "hypocomplementemic urticarial vasculitis syndrome", "hypocomplementemic vasculitis" and "unusual lupus-like syndrome") is a skin condition characterized by fixed urticarial lesions that appear histologically as a vasculitis.: 834

Mechanism
Antibodies are usually raised against foreign proteins, such as those made by a replicating virus or invading bacterium. Virus or bacteria with antibodies opsonized or "stuck" to them highlight them to other cells of the immune system for clearance.
Antibodies against self proteins are known as autoantibodies, and are not found in healthy individuals. These autoantibodies can be used to detect certain diseases.

C1q
C1q is an integral component within the complement pathway – a complicated cascade of protein interactions, culminating in an immune response against a broad variety of pathogens. The anti-C1q antibodies found in patients with hypocomplementemic urticarial vasculitis activate C1q, which instigates activation of the entire complement pathway. Consequently, levels of all complement proteins become low.

Impaired classical complement pathway
The complement pathway is composed of several subset pathways: the lectin/mannose pathway, alternative pathway and the classical pathway. All pathways culminate in the production of a C3 convertase, which catalyses C3 into its constitutive parts (better detailed here – classical complement pathway).In brief, the crucial role of C1q in the pathway is its importance as the first protein to start the complement cascade (which ends in the destruction of the invading bacteria or virus), and its ability to link the two important arms of the immune system – the innate immune system: a broad defence system; and the adaptive immune system: the strong immune response capable of remembering previous infections, allowing fast response against recurrent infections, meaning that people with a normal immune system dont continually catch the same cold or same strain of flu repeatedly.Case studies of individuals with HUV have also highlighted other potential complicating factors which it seems the anti-C1q antibodies play a role in. This can mean in some cases the deposition of large immune complexes in the kidney which cannot be cleared by the usual cells of the immune system (e.g. macrophages which are unable to bind the Fc portion of the C1q antibody), leading to further complications </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Pancreatic fistula and can you explain it in depth? [/INST] A pancreatic fistula is an abnormal communication between the pancreas and other organs due to leakage of pancreatic secretions from damaged pancreatic ducts. An external pancreatic fistula is one that communicates with the skin, and is also known as a pancreaticocutaneous fistula, whereas an internal pancreatic fistula communicates with other internal organs or spaces. Pancreatic fistulas can be caused by pancreatic disease, trauma, or surgery.

Signs and symptoms
Marked recent weight loss is a major clinical manifestation, and unresponsiveness of the ascites to diuretics is an additional diagnostic clue.

Pathogenesis
Internal pancreatic fistulas are most commonly caused by disruption of the pancreatic duct due to chronic pancreatitis. The chronic pancreatitis is usually alcoholic in origin in adults, and traumatic in origin in children.  They may also be caused by leakage from a pancreatic pseudocyst.
Anterior disruption of a pseudocyst or a pancreatic duct leads to leakage of pancreatic secretions into the free peritoneal cavity, leading to pancreatic ascites </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 Histidinemia and can you explain it in depth? [/INST] Histidinemia is a rare autosomal recessive metabolic disorder caused by a deficiency of the enzyme histidase. Histidase is needed for the metabolism of the amino acid histidine.  Although originally thought to be linked to multiple developmental disorders histidinemia is now accepted as a relatively benign disorder, leading to a reduction in the prevalence of neonatal screening procedures.

Presentation
Histidinemia is considered benign as most patients remain asymptomatic, early correlational evidence from the first decade of histidinemia research lead to the theory that histidinemia was associated with multiple developmental symptoms including hyperactivity, speech impediment, developmental delay, learning difficulties, and sometimes mental retardation </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 Hepatosplenomegaly 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 Benzodiazepine dependence and can you explain it in depth? [/INST] Benzodiazepine dependence defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of substance use, according to the DSM-IV. In the case of benzodiazepine dependence, however, the continued use seems to be associated with the avoidance of unpleasant withdrawal reaction rather than from the pleasurable effects of the drug. Benzodiazepine dependence develops with long-term use, even at low therapeutic doses, without the described dependence behavior.Addiction consists of people misusing or craving the drug not to relieve withdrawal symptoms, but to experience its euphoric or intoxicating effects. It is necessary to distinguish between addiction to and abuse of benzodiazepines and physical dependence on them. The increased GABA inhibition on the neural systems caused by benzodiazepines is counteracted by the bodys development of tolerance to the drugs effects; the development of tolerance occurs as a result of neuroadaptations, which result in decreased GABA activity and increased excitability of the glutamate system; these adaptations occur as a result of the body trying to overcome the central nervous system depressant effects of the drug to restore homeostasis. When benzodiazepines are stopped, these neuroadaptations are "unmasked" leading to hyper-excitability of the nervous system and the appearance of withdrawal symptoms.Therapeutic dose dependence is the largest category of people dependent on benzodiazepines. These individuals typically do not escalate their doses to high levels and generally use their medication as intended by their prescriber. Smaller groups include patients escalating their dosage to higher levels and drug misusers as well. Tolerance develops within days or weeks to the anticonvulsant, hypnotic, muscle relaxant and after 4 months there is little evidence that benzodiazepines retain their anxiolytic properties. Some authors, however, disagree and feel that benzodiazepines retain their anxiolytic properties. Long-term benzodiazepine treatment may remain necessary in certain clinical conditions.Numbers of benzodiazepine prescriptions have been declining, due primarily to concerns of dependence. In the short term, benzodiazepines can be effective drugs for acute anxiety or insomnia. With longer-term use, other therapies, both pharmacological and psychotherapeutic, become more effective. This is in part due to the greater effectiveness over time of other forms of therapy, and also due to the eventual development of pharmacological benzodiazepine tolerance.

Signs and symptoms
The signs and symptoms of benzodiazepine dependence include feeling unable to cope without the drug, unsuccessful
attempts to cut down or stop benzodiazepine use, tolerance to the effects of benzodiazepines, and withdrawal symptoms when not taking the drug. Some withdrawal symptoms that may appear include anxiety, depressed mood, depersonalisation, derealisation, sleep disturbance, hypersensitivity to touch and pain, tremor, shakiness, muscular aches, pains, twitches, and headache. Benzodiazepine dependence and withdrawal have been associated with suicide and self-harming behaviors, especially in young people. The Department of Health substance misuse guidelines recommend monitoring for mood disorder in those dependent on or withdrawing from benzodiazepines.Benzodiazepine dependence is a frequent complication for those prescribed for or using for longer than four weeks, with physical dependence and withdrawal symptoms being the most common problem, but also occasionally drug-seeking behavior. Withdrawal symptoms include anxiety, perceptual disturbances, distortion of all the senses, dysphoria, and, in rare cases, psychosis and epileptic seizures.

Elderly
Long-term use and benzodiazepine dependence is a serious problem in the elderly. Failure to treat benzodiazepine dependence in the elderly can cause serious medical complications. The elderly have less cognitive reserve and are more sensitive to the short (e.g., in between dose withdrawal) and protracted withdrawal effects of benzodiazepines, as well as the side-effects both from short-term and long-term use. This can lead to excessive contact with their doctor. Research has found that withdrawing elderly people from benzodiazepines leads to a significant reduction in doctor visits per year, it is presumed, due to an elimination of drug side-effects and withdrawal effects.Tobacco and alcohol are the most common substances that elderly individuals develop dependence on or misuse. The next-most-common substance that elderly people develop a drug dependence to or misuse is benzodiazepines. Drug-induced cognitive problems can have serious consequences for elderly people and can lead to confusional states and "pseudo-dementia". About 10% of elderly patients referred to memory clinics actually have a drug-induced cause that most often is benzodiazepines. Benzodiazepines have also been linked to an increased risk of road traffic accidents and falls in the elderly. The long-term effects of benzodiazepines are still not fully understood. Long-term benzodiazepine use is associated with attentional and visuospatial functional impairments. Withdrawal from benzodiazepines can lead to improved alertness and decreased forgetfulness in the elderly. Withdrawal led to statistically significant improvements in memory function and performance-related skills in those having withdrawn successfully from benzodiazepines, whereas those having remained on benzodiazepines experienced worsening symptoms. People having withdrawn from benzodiazepines also felt their sleep was more refreshing, making statements such as "I feel sharper when I wake up" or "I feel better, more awake", or "It used to take me an hour to fully wake up." This suggests that benzodiazepines may actually make insomnia worse in the elderly.

Cause
Tolerance occurs to the muscle-relaxant, anticonvulsant, and sleep-inducing effects of benzodiazepines, and upon cessation a benzodiazepine withdrawal syndrome occurs. This can lead to benzodiazepines being taken for longer than originally intended, as people continue to take the drugs over a long period of time to suppress withdrawal symptoms. Some people use benzodiazepines at very high doses and devote a lot of time to doing so, satisfying the diagnostic criteria in DSM V for substance use disorder. Another group of people include those on low to moderate therapeutic doses of benzodiazepines who do not use their benzodiazepines differently than recommended by their prescriber but develop a physical tolerance and benzodiazepine dependence. A considerable number of individuals using benzodiazepines for insomnia escalate their dosage, sometimes above therapeutically-prescribed dose levels. Tolerance to the anxiolytic effect of benzodiazepines has been clearly demonstrated in rats. In humans, there is little evidence that benzodiazepines retain their anti-anxiety effects beyond four months of continuous treatment; there is evidence that suggests that long-term use of benzodiazepines may actually worsen anxiety, which in turn may lead to dosage escalation, with one study finding 25% of patients escalated their dosage. Some authors, however, consider benzodiazepines to be effective long-term; however, it is more likely that the drugs are acting to prevent rebound anxiety withdrawal effects which can be mistaken as continued drug efficacy. Tolerance to the anticonvulsant and muscle-relaxing effects of benzodiazepines occurs within a few weeks in most patients.

Risk factors
The risk factors for benzodiazepine dependence are long-term use beyond four weeks, use of high doses, use of potent short-acting benzodiazepines, dependent personalities, and proclivity for substance use. Use of short-acting benzodiazepines leads to repeated withdrawal effects that are alleviated by the next dose, which reinforce in the individual the dependence. A physical dependence develops more quickly with higher potency benzodiazepines such as alprazolam (Xanax) than with lower potency benzodiazepines such as chlordiazepoxide (Librium).Symptom severity is worse with the use of high doses, or with benzodiazepines of high potency or short half-life. Other cross-tolerant sedative hypnotics, such as barbiturates or alcohol, increase the risk of benzodiazepine dependence. Similar to opioids use for pain, therapeutic use of benzodiazepines rarely leads to a substance use disorder.

Mechanism
Tolerance and physical dependence
Tolerance develops rapidly to the sleep-inducing effects of benzodiazepines. The anticonvulsant and muscle-relaxant effects last for a few weeks before tolerance develops in most individuals. Tolerance results in a desensitization of GABA receptors and an increased sensitization of the excitatory neurotransmitter system, such as NMDA glutamate receptors. These changes occur as a result of the body trying to overcome the drugs effects. Other changes that occur are the reduction of the number of GABA receptors (downregulation) as well as possibly long-term changes in gene transcription coding of brain cells. The differing speed at which tolerance occurs to the therapeutic effects of benzodiazepines can be explained by the speed of changes in the range of neurotransmitter systems and subsystems that are altered by chronic benzodiazepine use. The various neurotransmitter systems and subsystems may reverse tolerance at different speeds, thus explaining the prolonged nature of some withdrawal symptoms. As a result of a physical dependence that develops due to tolerance, a characteristic benzodiazepine withdrawal syndrome often occurs after removal of the drug or a reduction in dosage. Changes in the expression of neuropeptides such as corticotropin-releasing hormone and neuropeptide Y may play a role in benzodiazepine dependence. Individuals taking daily benzodiazepine drugs have a reduced sensitivity to further additional doses of benzodiazepines. Tolerance to benzodiazepines can be demonstrated by injecting diazepam into long-term users. In normal subjects, increases in growth hormone occurs, whereas, in benzodiazepine-tolerant individuals, this effect is blunted.Animal studies have shown that repeated withdrawal from benzodiazepines leads to increasingly severe withdrawal symptoms, including an increased risk of seizures; this phenomenon is known as kindling. Kindling phenomena are well established for repeated ethanol (alcohol) withdrawal; alcohol has a very similar mechanism of tolerance and withdrawal to benzodiazepines, involving the GABAA, NMDA, and AMPA receptors.The shift of benzodiazepine receptors to an inverse agonist state after chronic treatment leads the brain to be more sensitive to excitatory drugs or stimuli. Excessive glutamate activity can result in excitotoxicity, which may result in neurodegeneration. The glutamate receptor subtype NMDA is well known for its role in causing excito-neurotoxicity. The glutamate receptor subtype AMPA is believed to play an important role in neuronal kindling as well as excitotoxicity during withdrawal from alcohol as well as benzodiazepines. It is highly possible that NMDA receptors are involved in the tolerance to some effects of benzodiazepines.Animal studies have found that glutamergic changes as a result of benzodiazepine use are responsible for a delayed withdrawal syndrome, which in mice peaks 3 days after cessation of benzodiazepines. This was demonstrated by the ability to avoid the withdrawal syndrome by the administration of AMPA antagonists. It is believed that different glutamate subreceptors, e.g., NMDA and AMPA, are responsible for different stages/time points of the withdrawal syndrome. NMDA receptors are upregulated in the brain as a result of benzodiazepine tolerance. AMPA receptors are also involved in benzodiazepine tolerance and withdrawal. A decrease in benzodiazepine binding sites in the brain may also occur as part of benzodiazepine tolerance.

Cross tolerance
Benzodiazepines share a similar mechanism of action with various sedative compounds that act by enhancing the GABAA receptor. Cross tolerance means that one drug will alleviate the withdrawal effects of another. It also means that tolerance of one drug will result in tolerance of another similarly-acting drug. Benzodiazepines are often used for this reason to detoxify alcohol-dependent patients and can have life-saving properties in preventing or treating severe life-threatening withdrawal syndromes from alcohol, such as delirium tremens. However, although benzodiazepines can be very useful in the acute detoxification of alcoholics, benzodiazepines in themselves act as positive reinforcers in alcoholics, by increasing the desire for alcohol. Low doses of benzodiazepines were found to significantly increase the level of alcohol consumed in alcoholics. Alcoholics dependent on benzodiazepines should not be abruptly withdrawn but be very slowly withdrawn from benzodiazepines, as over-rapid withdrawal is likely to produce severe anxiety or panic, which is well known for being a relapse risk factor in recovering alcoholics.There is cross tolerance between alcohol, the benzodiazepines, the barbiturates, the nonbenzodiazepine drugs, and corticosteroids, which all act by enhancing the GABAA receptors function via modulating the chloride ion channel function of the GABAA receptor.Neuroactive steroids, e.g., progesterone and its active metabolite allopregnanolone, are positive modulators of the GABAA receptor and are cross tolerant with benzodiazepines. The active metabolite of progesterone has been found to enhance the binding of benzodiazepines to the benzodiazepine binding sites on the GABAA receptor. The cross-tolerance between GABAA receptor positive modulators, including benzodiazepines, occurs because of the similar mechanism of action and the subunit changes that occur from chronic use from one or more of these compounds in expressed receptor isoforms. Abrupt withdrawal from any of these compounds, e.g., barbiturates, benzodiazepines, alcohol, corticosteroids, neuroactive steroids, and nonbenzodiazepines, precipitate similar withdrawal effects characterized by central nervous system hyper-excitability, resulting in symptoms such as increased seizure susceptibility and anxiety. While many of the neuroactive steroids do not produce full tolerance to their therapeutic effects, cross-tolerance to benzodiazepines still occurs as had been demonstrated between the neuroactive steroid ganaxolone and diazepam. Alterations of levels of neuroactive steroids in the body during the menstrual cycle, menopause, pregnancy, and stressful circumstances can lead to a reduction in the effectiveness of benzodiazepines and a reduced therapeutic effect. During withdrawal of neuroactive steroids, benzodiazepines become less effective.

Physiology of withdrawal
Withdrawal symptoms are a normal response in individuals having chronically used benzodiazepines, and an adverse effect and result of drug tolerance. Symptoms typically emerge when dosage of the drug is reduced. GABA is the second-most-common neurotransmitter in the central nervous system (the most common being glutamate) and by far the most abundant inhibitory neurotransmitter; roughly one-quarter to one-third of synapses use GABA. The use of benzodiazepines has a profound effect on almost every aspect of brain and body function, either directly or indirectly.Benzodiazepines cause a decrease in norepinephrine (noradrenaline), serotonin, acetylcholine, and dopamine. These neurotransmitters are needed for normal memory, mood, muscle tone and coordination, emotional responses, endocrine gland secretions, heart rate, and blood pressure control. With chronic benzodiazepine use, tolerance develops rapidly to most of its effects, so that, when benzodiazepines are withdrawn, various neurotransmitter systems go into overdrive due to the lack of inhibitory GABA-ergic activity. Withdrawal symptoms then emerge as a result, and persist until the nervous system physically reverses the adaptions (physical dependence) that have occurred in the CNS.Withdrawal symptoms typically consist of a mirror image of the drugs effects: Sedative effects and suppression of REM and SWS stages of sleep can be replaced by insomnia, nightmares, and hypnogogic hallucinations; its antianxiety effects are replaced with anxiety and panic; muscle-relaxant effects are replaced with muscular spasms or cramps; and anticonvulsant effects are replaced with seizures, especially in cold turkey or overly-rapid withdrawal.Benzodiazepine withdrawal represents in part excitotoxicity to brain neurons. Rebound activity of the hypothalamic-pituitary-adrenocortical axis also plays an important role in the severity of benzodiazepine withdrawal. Tolerance and the resultant withdrawal syndrome may be due to alterations in gene expression, which results in long-term changes in the function of the GABAergic neuronal system.During withdrawal from full or partial agonists, changes occur in benzodiazepine receptor with upregulation of some receptor subtypes and downregulation of other receptor subtypes.

Withdrawal
Long-term use of benzodiazepines leads to increasing physical and mental health problems, and as a result, discontinuation is recommended for many long-term users. The withdrawal syndrome from benzodiazepines can range from a mild and short-lasting syndrome to a prolonged and severe syndrome. Withdrawal symptoms can lead to continued use of benzodiazepines for many years, long after the original reason for taking benzodiazepines has passed. Many patients know that the benzodiazepines no longer work for them but are unable to discontinue benzodiazepines because of withdrawal symptoms.Withdrawal symptoms can emerge despite slow reduction but can be reduced by a slower rate of withdrawal. As a result, withdrawal rates have been recommended to be customized to each individual patient. The time needed to withdrawal can vary from a couple of months to a year or more and often depends on length of use, dosage taken, lifestyle, health, and social and environmental stress factors.Diazepam is often recommended due to its long elimination half-life and also because of its availability in low potency doses. The non-benzodiazepine Z drugs such as zolpidem, zaleplon, and zopiclone should not be used as a replacement for benzodiazepines, as they have a similar mechanism of action and can induce a similar dependence. The pharmacological mechanism of benzodiazepine tolerance and dependence is the internalization (removal) of receptor site in the brain and changes in gene transcription codes in the brain.With long-term use and during withdrawal of benzodiazepines, treatment-emergent depression and emotional blunting may emerge and sometimes also suicidal ideation. There is evidence that the higher the dose used the more likely it is benzodiazepine use will induce these feelings. Reducing the dose or discontinuing benzodiazepines may be indicated in such cases. Withdrawal symptoms can persist for quite some time after discontinuing benzodiazepines. Some common protracted withdrawal symptoms include anxiety, depression, insomnia, and physical symptoms such as gastrointestinal, neurologic, and musculoskeletal effects. The protracted withdrawal state may still occur despite slow titration of dosage. It is believed that the protracted withdrawal effects are due to persisting neuroadaptations.

Diagnosis
For a diagnosis of benzodiazepine dependence to be made, the ICD-10 requires that at least 3 of the below criteria are met and that they have been present for at least a month, or, if less than a month, that they appeared repeatedly during a 12-month period.
Behavioral, cognitive, and physiological phenomena that are associated with the repeated use and that typically include a strong desire to take the drug.
Difficulty controlling use
Continued use despite harmful consequences
Preference given to drug use rather than to other activities and obligations
Increased tolerance to effects of the drug and sometimes a physical withdrawal state.These diagnostic criteria are good for research purposes, but, in everyday clinical practice, they should be interpreted according to clinical judgement. In clinical practice, benzodiazepine dependence should be suspected in those having used benzodiazepines for longer than a month, in particular, if they are from a high-risk group. The main factors associated with an increased incidence of benzodiazepine dependence include:
Dose
Duration
Concomitant use of antidepressantsBenzodiazepine dependence should be suspected also in individuals having substance use disorders including alcohol, and should be suspected in individuals obtaining their own supplies of benzodiazepines. Benzodiazepine dependence is almost certain in individuals who are members of a tranquilizer self-help group.Research has found that about 40 percent of people with a diagnosis of benzodiazepine dependence are not aware that they are dependent on benzodiazepines, whereas about 11 percent of people judged not to be dependent believe that they are.
When assessing a person for benzodiazepine dependence, asking specific questions rather than questions based on concepts is recommended by experts as the best approach of getting a more accurate diagnosis. For example, asking persons if they "think about the medication at times of the day other than when they take the drug" would provide a more meaningful answer than asking "do you think you are psychologically dependent?". The Benzodiazepine Dependence Self Report Questionnaire is one questionnaire used to assess and diagnose benzodiazepine dependence.

Definition
Benzodiazepine dependence is the condition resulting from repeated use of benzodiazepine drugs. It can include both a physical dependence as well as a psychological dependence and is typified by a withdrawal syndrome upon a fall in blood plasma levels of benzodiazepines, e.g., during dose reduction or abrupt withdrawal.

Prevention
Due to the risk of developing tolerance, dependence, and adverse health effects, such as cognitive impairment, benzodiazepines are indicated for short-term use only - a few weeks, followed by a gradual dose reduction.

The Committee on the Review of Medicines (UK)
The Committee on the Review of Medicines carried out a review into benzodiazepines due to significant concerns of tolerance, drug dependence, benzodiazepine withdrawal problems, and other adverse effects and published the results in the British Medical Journal in March 1980. The committee found that benzodiazepines do not have any antidepressant or analgesic properties and are, therefore, unsuitable treatments for conditions such as depression, tension headaches, and dysmenorrhea. Benzodiazepines are also not beneficial in the treatment of psychosis. The committee also recommended against benzodiazepines for use in the treatment of anxiety or insomnia in children.The committee was in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse (USA) that there is little evidence that long-term use of benzodiazepine hypnotics are beneficial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tend to lose their sleep-promoting properties within 3–14 days of continuous use, and, in the treatment of anxiety, the committee found that there was little convincing evidence that benzodiazepines retains efficacy in the treatment of anxiety after 4 months of continuous use due to the development of tolerance.The committee found that the regular use of benzodiazepines causes the development of dependence characterized by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome including symptoms such as anxiety, apprehension, tremors, insomnia, nausea, and vomiting upon cessation of benzodiazepine use. Withdrawal symptoms tend to develop within 24 hours upon cessation of short-acting benzodiazepines, and 3–10 days after cessation of longer-acting benzodiazepines. Withdrawal effects could even occur after treatment lasting only 2 weeks at therapeutic dose levels; however, withdrawal effects tend to occur with habitual use beyond 2 weeks and are more likely the higher the dose. The withdrawal symptoms may appear to be similar to the original condition.The committee recommended that all benzodiazepine treatment be withdrawn gradually and recommended that benzodiazepine treatment be used only in carefully selected patients and that therapy be limited to short-term use only. It was noted in the review that alcohol can potentiate the central nervous system-depressant effects of benzodiazepines and should be avoided. The central nervous system-depressant effects of benzodiazepines may make driving or operating machinery dangerous, and the elderly are more prone to these adverse effects. High single doses or repeated low doses have been reported to produce hypotonia, poor sucking, and hypothermia in the neonate, and irregularities in the fetal heart. The committee recommended that benzodiazepines be avoided in lactation.The committee recommended that withdrawal from benzodiazepines be gradual, as abrupt withdrawal from high doses of benzodiazepines may cause confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. Abrupt withdrawal from lower doses may cause depression, nervousness, rebound insomnia, irritability, sweating, and diarrhea.

Treatment
Benzodiazepines are regarded as a highly addictive drug class. A psychological and physical dependence can develop in as short as a few weeks but may take years to develop in other individuals. Patients wanting to withdraw from benzodiazepines typically receive little advice or support, and such withdrawal should be by small increments over a period of months.Benzodiazepines are usually prescribed only short-term, as there is little justification for their prescribing long-term. Some doctors however, disagree and believe long-term use beyond 4 weeks is sometimes justified, although there is little data to support this viewpoint. Such viewpoints are a minority in the medical literature.There is no evidence that "drug holidays" or periods of abstinence reduced the risk of dependence; there is evidence from animal studies that such an approach does not prevent dependence from happening. Use of short-acting benzodiazepines is associated with interdose withdrawal symptoms. Kindling has clinical relevance with regard to benzodiazepines; for example, there is an increasing shift to use of benzodiazepines with a shorter half-life and intermittent use, which can result in interdose withdrawal and rebound effects.

Cognitive behavioral therapy
Cognitive behavioral therapy has been found to be more effective for the long-term management of insomnia than sedative hypnotic drugs. No formal withdrawal programs for benzodiazepines exists with local providers in the UK. Meta-analysis of published data on psychological treatments for insomnia show a success rate between 70 and 80%. A large-scale trial utilizing cognitive behavioral therapy in chronic users of sedative hypnotics including nitrazepam, temazepam, and zopiclone found CBT to be a significantly more effective long-term treatment for chronic insomnia than sedative hypnotic drugs. Persisting improvements in sleep quality, sleep onset latency, increased total sleep, improvements in sleep efficiency, significant improvements in vitality, physical and mental health at 3-, 6-, and 12-month follow-ups were found in those receiving CBT. A marked reduction in total sedative hypnotic drug use was found in those receiving CBT, with 33% reporting zero hypnotic drug use. Age has been found not to be a barrier to successful outcome of CBT. It was concluded that CBT for the management of chronic insomnia is a flexible, practical, and cost-effective treatment, and it was also concluded that CBT leads to a reduction of benzodiazepine drug intake in a significant number of patients.Chronic use of hypnotic medications is not recommended due to their adverse effects on health and the risk of dependence. A gradual taper is usual clinical course in getting people off of benzodiazepines, but, even with gradual reduction, a large proportion of people fail to stop taking benzodiazepines. The elderly are particularly sensitive to the adverse effects of hypnotic medications. A clinical trial in elderly people dependent on benzodiazepine hypnotics showed that the addition of CBT to a gradual benzodiazepine reduction program increased the success rate of discontinuing benzodiazepine hypnotic drugs from 38% to 77% and at the 12-month follow-up from 24% to 70%. The paper concluded that CBT is an effective tool for reducing hypnotic use in the elderly and reducing the adverse health effects that are associated with hypnotics such as drug dependence, cognitive impairments, and increased road traffic accidents.A study of patients undergoing benzodiazepine withdrawal who had a diagnosis of generalized anxiety disorder showed that those having received CBT had a very high success rate of discontinuing benzodiazepines compared to those not having receive CBT. This success rate was maintained at the 12-month follow-up. Furthermore, it was found that, in patients having discontinued benzodiazepines, they no longer met the diagnosis of general anxiety disorder, and that the number of patients no longer meeting the diagnosis of general anxiety disorder was higher in the group having received CBT. Thus, CBT can be an effective tool to add to a gradual benzodiazepine dosage reduction program leading to improved and sustained mental health benefits (Disputed).

Letter to patients
Sending a letter to patients warning of the adverse effects of long-term use of benzodiazepines and recommending dosage reduction has been found to be successful and a cost-effective strategy in reducing benzodiazepine consumption in general practice. Within a year of the letters going out, there was found to be a 17% fall in the number of benzodiazepines being prescribed, with 5% of patients having totally discontinued benzodiazepines. A study in the Netherlands reported a higher success rate by sending a letter to patients who are benzodiazepine-dependent. The results of the Dutch study reported 11.3% of patients discontinuing benzodiazepines completely within a year.

Flumazenil
Flumazenil delivered via slow subcutaneous infusion represents a safe procedure for those withdrawing from long-term, high dose benzodiazepine dependency. It has a low risk of seizures even amongst those who have experienced convulsions when previously attempting benzodiazepine withdrawal.

Epidemiology
Research studies have come to different conclusions on the number of therapeutic dose users who develop a physical dependence and withdrawal syndrome. Researches estimate 20-100% (thats a wide range) of patients, taking benzodiazepines at therapeutic dosages for the long term, are physically dependent and will experience withdrawal symptoms.Benzodiazepines can be addictive and induce dependence even at low doses, with 23% becoming addicted within 3 months of use. Benzodiazepine addiction is considered a public health problem. Approximately 68.5% of prescriptions of benzodiazepines originate from local health centers, with psychiatry and general hospitals accounting for 10% each. A survey of general practitioners reported that the reason for initiating benzodiazepines was due to an empathy for the patients suffering and a lack of other therapeutic options rather than patients demanding them. However, long-term use was more commonly at the insistence of the patient, it is presumed, because physical dependence or addiction had developed.Approximately twice as many women as men are prescribed benzodiazepines. It is believed that this is largely because men typically turned to alcohol to cope with stress and women to prescription drugs. Biased perception of women by male doctors may also play a role in increased prescribing rates to women; however, increased anxiety features in women does not account for the wide gap alone between men and women.Based on findings in the US from the Treatment Episode Data Set (TEDS), an annual compilation of patient characteristics in substance use disorder treatment facilities in the United States, admissions due to "primary tranquilizer" (including, but not limited to, benzodiazepine-type) drug use increased 79% from 1992 to 2002.A study published in the British Journal of General Practice in July 2017 found that in a sample taken from a survey conducted in 2014–2015 in Bradford a mean of 0.69% of registered patients had been prescribed benzodiazepines for more than a year. This would suggest that there were around 300,000 long-term users of diazepine in the UK.

History
Previously, physical dependence on benzodiazepines was largely thought to occur only in people on high-therapeutic-dose ranges. Low- or normal-dose dependence was not suspected until the 1970s, and it was not until the early 1980s that it was confirmed. Low-dose dependence has now been clearly demonstrated in both animal studies and human studies, and is a recognized clinical disadvantage of benzodiazepines </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 Gamma globulin 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 Carbamate poisoning 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 Bednars aphthae 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 Upington disease and can you explain it in depth? [/INST]  </s>