<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 Streptococcus agalactiae and can you explain it in depth? [/INST] Streptococcus agalactiae (also known as group B streptococcus or GBS) is a gram-positive coccus (round bacterium) with a tendency to form chains (as reflected by the genus name Streptococcus). It is a beta-hemolytic, catalase-negative, and facultative anaerobe.S. agalactiae is the most common human pathogen of streptococci belonging to group B of the Rebecca Lancefield classification of streptococci. GBS are surrounded by a bacterial capsule composed of polysaccharides (exopolysacharide). The species is subclassified into ten serotypes (Ia, Ib, II–IX) depending on the immunologic reactivity of their polysaccharide capsule.The plural term group B streptococci (referring to the serotypes) and the singular term group B streptococcus (referring to the single species) are both commonly encountered (even though S. halichoeri and S. pseudoporcinus are also group B Streptococci).
In general, GBS is a harmless commensal bacterium being part of the human microbiota colonizing the gastrointestinal and genitourinary tract of up to 30% of healthy human adults (asymptomatic carriers). Nevertheless, GBS  can cause severe invasive infections especially in newborns, the elderly, and people with compromised immune systems.
S. agalactiae is also a common veterinary pathogen, because it can cause bovine mastitis (inflammation of the udder) in dairy cows. The species name agalactiae meaning "of no milk", alludes to this.

Laboratory identification
GBS grows readily on blood agar plates as colonies surrounded by a narrow zone of β-hemolysis. GBS is characterized by the presence in the cell wall of the antigen group B of Lancefield classification (Lancefield grouping) that can be detected directly in intact bacteria using latex agglutination tests. The CAMP test is also another important test for identification of GBS. The CAMP factor produced by GBS acts synergistically with the staphylococcal β-hemolysin inducing enhanced hemolysis of sheep or bovine erythrocytes. GBS is also able to hydrolyze hippurate and this test can also be used to identify presumptively GBS.
Hemolytic GBS strains produce an orange-brick-red non-isoprenoid polyene (ornithine rhamnolipid) pigment (granadaene) when cultivated on granada medium that allows its straightforward identification.
GBS can also be identified using MALDI-TOF (Matrix Assisted Laser Desorption/Ionization-Time of Flight) instruments.
GBS colonies can additionally be identified tentatively after their appearance in chromogenic agar media, nevertheless GBS-like colonies that develop in chromogenic media should be confirmed as GBS using additional reliable tests (e.g.latex agglutination or the CAMP test) to avoid potential mis-identification.
A summary of the laboratory techniques for GBS identification is depicted in Ref 7.

GBS colonization
GBS is a normal component of the intestinal and vaginal microbiota in some women, GBS is an asymptomatic (presenting no symptoms) colonizer of the gastrointestinal tract and vagina in up to 30% of otherwise healthy adults, including pregnant women. GBS colonization may be permanent, intermittent or temporary. In different studies, GBS vaginal colonization rate ranges from 0% to 36%, most studies reporting colonization rates in sexually active women over 20%. It has been estimated that maternal GBS colonization worldwide is 18%, with regional variation from 11% to 35%.
These variations in the reported prevalence of asymptomatic GBS colonization could be related to the detection methods used, and differences in populations sampled.

Virulence
As other virulent bacteria, GBS harbors an important number of virulence factors (virulence factors are molecules produced by bacteria that boosts their capacity to infect and damage human tissues), the most important being the capsular polysaccharide (rich in sialic acid)
and a pore-forming toxin, β-hemolysin.
Today it is considered that GBS pigment and hemolysin are identical or closely related molecules.

GBS infection in newborns
GBS colonization usually does not cause problems in healthy women, nevertheless during pregnancy it can sometimes cause serious illness for the mother and the newborn. GBS is the leading cause of bacterial neonatal infection in the baby during gestation and after delivery with significant mortality rates in premature infants. GBS infections in the mother can cause chorioamnionitis (a severe infection of the placental tissues) infrequently, postpartum infections (after birth) and it had been related with prematurity and fetal death. GBS urinary tract infections (UTI) may also induce labor and cause premature delivery.
In the western world, GBS (in the absence of effective prevention measures) is the major cause of several bacterial infections of the newborn neonatal infection sepsis, pneumonia, and meningitis, which can lead to death or long-term sequelae.GBS neonatal infection typically originates in the lower reproductive tract of infected mothers.
GBS infections in newborns are separated into two clinical syndromes, early-onset disease (EOD) and late-onset disease (LOD).
EOD manifests from 0 to 7 living days in the newborn, most of the cases of EOD being apparent within 24h of birth. The most common clinical syndromes of EOD are sepsis without apparent focus, pneumonia, and less frequently meningitis. EOD is acquired vertically (vertical transmission),  through exposure of the fetus or the baby to GBS from the vagina of a colonized woman, either intrautero or during birth after rupture of membranes. Infants can be infected during passage through the birth canal, nevertheless newborns that acquire GBS through this route can become only colonized, and these colonized infants habitually do not develop EOD. Roughly 50% of newborns to GBS colonized mothers are also GBS colonized and (without prevention measures) 1–2% of these newborns will develop EOD. In the past, the incidence of EOD ranged from 0.7 to 3.7 per thousand live births in the US and from 0.2 to 3.25 per thousand in Europe. In 2008, after widespread use of antenatal screening and intrapartum antibiotic prophylaxis (IAP), the CDC reported an incidence of 0.28 cases of EOD per thousand live births in the US.Multistate surveillance 2006-2015 shows a decline in EOD from 0.37 to 0.23 per 1000 live births in the US but LOD remains steady at 0.31 per 1000 live births.It has been indicated that where there was a policy of providing IAP for GBS colonized mothers the overall risk of EOGBS is 0.3%. Since 2006 to 2015 the incidence of GBS EOD decreased from 0.37 to 0.23 per thousand live births in the US.Though maternal GBS colonization is the key determinant for EOD, other factors also increase the risk. These factors include onset of labor before 37 weeks of gestation (premature birth), prolonged rupture of membranes (≥18h before delivery), intra-partum fever (>38 °C,  >100.4 °F), amniotic infections (chorioamnionitis), young maternal age, and low levels of GBS anticapsular polysaccharide antibodies in the mother. Nevertheless, most babies who develop EOD are born to GBS colonized mothers without any additional risk factor. A previous sibling with EOD is also an important risk factor for development of the infection in subsequent deliveries, probably reflecting a lack of GBS polysaccharides protective antibodies in the mother.
Heavy GBS vaginal colonization is also associated with a higher risk for EOD.
Overall, the case–fatality rates from EOD have declined, from 50% observed in studies from the 1970s to 2 to 10% in recent years, mainly as a consequence of improvements in therapy and management. Fatal neonatal infections by GBS are more frequent among premature infants.GBS LOD affects infants from 7 days to 3 months of age and is more likely to cause bacteremia or meningitis. LOD can be acquired from the mother or from environmental sources. Hearing loss and mental impairment can be a long-term sequela of GBS meningitis. In contrast with EOD, the incidence of LOD has remained unchanged at 0.26 per 1000 live births in the US. S. agalactiae neonatal meningitis does not present with the hallmark sign of adult meningitis, a stiff neck; rather, it presents with nonspecific symptoms, such as fever, vomiting and irritability, and can consequently lead to a late diagnosis.

Prevention of neonatal infection
The only reliable way to prevent EOD currently is intrapartum antibiotic prophylaxis (IAP), that is to say administration of antibiotics during delivery.  It has been proved that intravenous penicillin or ampicillin administered for at least 4 hours before delivery to GBS colonized women is very effective at preventing vertical transmission of GBS from mother to baby and EOD. Intravenous penicillin remains the agent of choice for IAP, with intravenous ampicillin as an acceptable alternative. For penicillin allergic women, the laboratory requisitions for ordering antepartum GBS screening cultures should indicate clearly the presence of penicillin allergy.Cefazolin, clindamycin, and vancomycin are used to prevent EOD in infants born to penicillin-allergic mothers.
Intravenous vancomycin is recommended for IAP in women colonized with a clindamycin-resistant Group B Streptococcus strain and a severe penicillin allergy.There are two ways to identify female candidates to receive intrapartum antibiotic prophylaxis: a risk-based approach or a culture-based screening approach. The culture-based screening approach identifies candidates to receive IAP using lower vaginal and rectal cultures obtained between 36 and 37 weeks gestation (32–34 weeks of gestation for women with twins) and IAP is administered to all GBS colonized women. The risk-based strategy identifies candidates to receive IAP by the aforementioned risk factors known to increase the probability of EOD without considering if the mother is or is not a GBS carrier.IAP is also recommended for women with intrapartum risk factors if their GBS carrier status is not known at the time of delivery, for women with GBS bacteriuria during their pregnancy, and for women who have had an infant with EOD previously.
The risk-based approach for IAP is in general less effective than the culture-based approach because in most of the cases EOD develops among newborns, which are born to mothers without risk factors.In 2010, the Centers for Disease Control and Prevention (CDC), in collaboration with several professional groups, issued its revised GBS prevention guidelines.In 2018, the task of revising and updating the GBS prophylaxis guidelines was transferred from the CDC   to ACOG (American College of Obstetricians and Gynecologists), the American Academy of Pediatrics and to the American Society for Microbiology. The ACOG committee issued an update document on Prevention of Group B Streptococcal Early-Onset Disease in Newborns in 2019. This document does not introduce important changes from the CDC guidelines. The key measures necessary for preventing neonatal GBS early onset disease continue to be universal prenatal screening by culture of GBS from swabs collected from the lower vagina and rectum, correct collection and microbiological processing of the samples, and proper implementation of intrapartum antibiotic prophylaxis. The ACOG now recommends performing universal GBS screening between 36 and 37 weeks of gestation.
This new recommendation provides a five-week window  for valid culture results that includes births that occur up to a gestational age of at least 41 weeks.
The culture-based screening approach is followed in most developed countries such as the United States,  France, Spain, Belgium, Canada, Argentina, and Australia. The risk-based strategy is followed in the United Kingdom, and the Netherlands.

Screening for GBS colonization
Though the GBS colonization status of women can change during pregnancy, cultures to detect GBS carried out ≤5 weeks before delivery predict quite accurately the GBS carrier status at delivery.
In contrast, if the prenatal culture is performed more than five weeks before delivery it is unreliable for predicting accurately the GBS carrier status at delivery.The clinical specimens recommended for culture of GBS at 36–37 weeks’ gestation, this recommendation provides a 5-week window for valid culture results that includes births that occur up to a gestational age of at least 41 weeks  (32–34 weeks of gestation for women with twins) are swabs collected the lower vagina (near the introitus) and then from the rectum (through the anal sphincter) without use of a speculum. Vaginal-rectal samples should be collected using a flocked swab preferably, since flocked swabs releases samples and microorganisms more effectively than fiber swabs. Following the recommendations of the Centers for Disease Control and Prevention of United States  (CDC) these swabs should be placed into a non-nutritive transport medium and later inoculated into a selective enrichment broth, Todd Hewitt broth with selective antibiotics  (enrichment culture). After incubation the enrichment broth is subcultured to blood agar plates and GBS like colonies are identified by the CAMP test or using latex agglutination with GBS antisera. After incubation the enrichment broth can also be subcultured to granada medium agar  where GBS grows as pink-red colonies or to chromogenic agars, where GBS grows as colored colonies. GBS-like colonies that develop in chromogenic media should be confirmed as GBS using additional reliable tests to avoid mis-identification.Nucleic acid amplification tests (NAAT) such as polymerase chain reaction (PCR) and DNA hybridization probes have been developed for identifying GBS directly from recto-vaginal samples, but they still cannot replace antenatal culture for the most accurate detection of GBS carriers.
 Intrapartum NAAT without enrichment has a high false negative rate and the use of intrapartum NAAT without enrichment to rule out the need for IAP.

Vaccination
Though IAP for EOD prevention is associated with a large decline in the incidence of the disease, there is, however, no effective strategy for preventing late-onset neonatal GBS disease.Vaccination is considered an ideal solution to prevent not only EOD and LOD but also GBS infections in adults at risk. Nevertheless, though research and clinical trials for the development of an effective vaccine to prevent GBS infections are underway, no vaccine was available in 2020.
The capsular polysaccharide of GBS is not only an important GBS virulence factor but it is also an excellent candidate for the development of an effective vaccine. Protein-based vaccines are also in development.

GBS infection in adults
GBS is also an important infectious agent able to cause invasive infections in adults </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 Protrusio acetabuli and can you explain it in depth? [/INST] Protrusio acetabuli is an uncommon defect of the acetabulum, the socket that receives the femoral head to make the hip joint. The hip bone of the pelvic bone/girdle is composed of three bones, the ilium, the ischium and the pubis </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 Opisthorchiasis and can you explain it in depth? [/INST] Opisthorchiasis is a parasitic disease caused by certain species of genus Opisthorchis (specifically, Opisthorchis viverrini and Opisthorchis felineus). Chronic infection may lead to cholangiocarcinoma, a cancer of the bile ducts.
Medical care and loss of wages caused by Opisthorchis viverrini in Laos and in Thailand costs about $120 million annually. In Asia, infection by Opisthorchis viverrini and  other liver flukes affects the poorest people. Along with other foodborne trematode infections such as clonorchiasis, fascioliasis and paragonimiasis, opisthorchiasis is listed among the World Health Organizations list of neglected tropical diseases.

Signs and symptoms
Symptoms of opisthorchiasis are indistinguishable from clonorchiasis. About 80% of infected people have no symptoms, though they can have eosinophilia. Asymptomatic infection can occur when there are less than 1000 eggs in one gram of feces. Infection is considered heavy when there are 10,000-30,000 eggs in one gram of feces. Symptoms of heavier infections may include diarrhea, epigastric and right upper quadrant pain, lack of appetite, fatigue, yellowing of the eyes and skin and mild fever.These parasites are long-lived and cause heavy chronic infections that may lead to accumulation of fluid in the legs (edema) and in the peritoneal cavity (ascites), enlarged non-functional gallbladder and also ascending cholangitis, which can lead to periductal fibrosis, cholecystitis and cholelithiasis, obstructive jaundice, hepatomegaly and/or portal hypertension.

Chronic opisthorchiasis and cholangiocarcinoma
Both experimental and epidemiological evidence strongly implicates Opisthorchis viverrini infections in the etiology of a malignant cancer of the bile ducts (cholangiocarcinoma) in humans which has a very poor prognosis.  Clonorchis sinensis and Opisthorchis viverrini are both categorized by the International Agency for Research on Cancer (IARC) as Group 1 carcinogens.In humans, the onset of cholangiocarcinoma occurs with chronic opisthorchiasis, associated with hepatobiliary damage, inflammation, periductal fibrosis and/or cellular responses to antigens from the infecting fluke. These conditions predispose to cholangiocarcinoma, possibly through an enhanced susceptibility of DNA to damage by carcinogens. Chronic hepatobiliary damage is reported to be multi-factorial and considered to arise from a continued mechanical irritation of the epithelium by the flukes present, particularly via their suckers, metabolites and excreted/secreted antigens as well as immunopathological processes. In silico analyses using techniques of genomics and bioinformatics is unraveling information on molecular mechanisms that may be relevant to the development of cholangiocarcinoma.In regions where Opisthorchis viverrini is highly endemic, the incidence of cholangiocarcinoma is unprecedented. For instance, cholangiocarcinoma represents 15% of primary liver cancer worldwide, but in Thailands Khon Kaen province, this figure escalates to 90%, the highest recorded incidence of this cancer in the world. Of all cancers recorded worldwide in 2002, 0.02% were cholangiocarcinoma caused by Opisthorchis viverrini. Cancer of the bile ducts caused by opisthorchiasis occurs in the ages 25–44 years in Thailand. A few cases have appeared in later life among U.S. veterans of the Vietnam War, who consumed poorly cooked fish from streams in endemic areas near the border of Laos and Vietnam.

Diagnosis
The medical diagnosis is usually established by finding eggs of Opisthorchis viverrini in feces using the Kato technique.
Alternatively, an antigen of Opisthorchis viverrini can be detected by ELISA test. A polymerase chain reaction test that can be performed on faeces has been developed and evaluated in a rural community in central Thailand.

Prevention
Cholangiocarcinoma is typically incurable at diagnosis. Because of this, intervention strategies are focused on the prevention or treatment of liver fluke infection. Prevention can be accomplished through education (by persuading people not to consume raw or undercooked fish), but the ancient cultural custom to consume raw, undercooked or freshly pickled fish persists in endemic areas. One community health program, known as the Integrated Opisthorchiasis Control Program, has achieved success in the Lawa Lakes region south of Khon Kaen.Cooking or deep-freezing (-20 °C for 7 days) of food made of fish is an effective method of prevention. Methods for prevention of Opisthorchis viverrini in aquaculture fish ponds have also been proposed.

Treatment
Treatment of opisthorchiasis is usually accomplished with praziquantel. A single dose of praziquantel of 40 mg/kg is effective against opisthorchiasis (and also against schistosomiasis). Despite the efficacy of this compound, the lack of acquired immunity to infection predisposes humans to reinfection in endemic regions. In addition, under experimental conditions, the treatment of Opisthorchis viverrini-infected hamsters with praziquantel induced a dispersion of parasite antigens, resulting in adverse immunopathological changes following re-infection with Opisthorchis viverrini, a process which has been proposed to initiate and/or promote the development of cholangiocarcinoma in humans. Albendazole can be used as an alternative.A randomized controlled trial published in 2011 showed that tribendimidine, a broad-spectrum anthelmintic, appears to be at least as efficacious as praziquantel </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 Low milk supply and can you explain it in depth? [/INST] In breastfeeding women, low milk supply, also known as lactation insufficiency, insufficient milk syndrome,  agalactia, agalactorrhea, hypogalactia or hypogalactorrhea, is the production of breast milk in daily volumes that do not fully meet the nutritional needs of her infant.
Breast milk supply augments in response to the babys demand for milk, and decreases when milk is allowed to remain in the breasts. Low milk supply is usually caused by allowing milk to remain in the breasts for long periods of time, or insufficiently draining the breasts during feeds. It is usually preventable, unless caused by medical conditions that have been estimated to affect five to fifteen percent of women.Several common misconceptions often lead mothers to believe they have insufficient milk when they are in fact producing enough. Actual low milk supply is likely if the baby is latching and swallowing well at the breast, is nevertheless not growing well or is showing signs of dehydration or malnutrition, and does not have a medical condition that would explain the lack of growth. The main method for increasing milk supply is improved breastfeeding practices and/or expressing milk through pumping or hand expression. The medication domperidone increases milk supply for some women. For mothers who cannot breastfeed exclusively, breastfeeding as much as possible, with supplementary formula feeding as necessary, offers many benefits over formula alone.

Causes
Low milk supply can be either primary (caused by medical conditions or anatomical issues in the mother), secondary (caused by not thoroughly and regularly removing milk from the breasts) or both. Secondary causes are far more common than primary ones. One study found that 15% of healthy first-time mothers had low milk supply 2–3 weeks after birth, with secondary causes accounting for at least two-thirds of those cases.Breastfeeding management issues that can interfere with regular milk drainage from the breast include poor latch, unnecessary use of supplemental formula, timed or scheduled feedings (as opposed to on-demand feedings), and overuse of pacifiers. Medical conditions in the infant that result in weak or unco-ordinated sucking can cause low milk supply by inhibiting the transfer of milk to the baby. These conditions include tongue-tie, congenital heart defects,  prematurity, and Down syndrome.Primary causes of low milk supply include:

insufficient glandular tissue, also known as primary lactation failure. Breasts with insufficient glandular tissue often have a tubular shape, with a large space between the breasts, and often do not grow during pregnancy.
retained placenta
Sheehans syndrome
prior breast surgery (especially breast reduction)
prior nipple piercing
polycystic ovary syndrome (PCOS)
hypothyroidism
hypoprolactinemia
theca lutein cysts
hypertension
pregnancySmoking more than 15 cigarettes per day is associated with reduced milk production. Many medications are known to significantly suppress milk production, including pseudoephedrine, diuretics, and contraceptives that contain estrogen. It is suspected that some herbs, particularly sage and peppermint, suppress milk production.

Mechanism
The physiological mechanisms that regulate breast milk supply are poorly understood. High levels of prolactin are necessary for lactation, however there is no direct correlation between baseline levels of prolactin and quantity of milk production. One aspect of supply regulation that has been identified is that breast milk contains a peptide called feedback inhibitor of lactation (FIL).  When milk is present in the breast, FIL inhibits the secretion of milk.
After a mothers milk comes in, a reduction in supply is inevitable unless milk is removed regularly and thoroughly from the breasts.Surgery or injury to the breast can decrease supply by disrupting milk ducts that carry milk from the alveoli, where milk is produced, to the nipple. Retained placenta results in high levels of progesterone, a hormone that inhibits lactation.

Diagnosis
A womans belief that her milk supply is insufficient is one of the most common reasons for discontinuing breastfeeding. In many of those cases, the womans milk supply is actually normal. After a few weeks or months of breastfeeding, changes that are commonly mistaken for signs of low milk supply include breasts feeling softer (this is normal after 1–3 months), more frequent demands by the infant to feed, feeds becoming shorter over time, baby colic, the perception that the baby is more satisfied after being fed infant formula, and a slowdown in growth after three months.To evaluate whether milk supply is actually insufficient, qualitative parameters should be used such as the following:

By 3–5 days, of age, the infant should be stooling 3–4 times per day and urinating 3—5 times per day. By 5–7 days of age, there should be 3—6 stools per day and 4—6 urines.
The infant should be alert, have good muscle tone, and show no signs of dehydration.
The infant should be consistently gaining weight and growing. In newborns, a loss of more than 5 to 7 percent of birth weight warrants investigation. The use of IV fluids in labour tends to artificially increase the birth weight of the baby, and subsequently inflate the babys weight loss. Newborns should regain their birth weight by two weeks of age, and gain at least 150 g per week.If an infant is not showing these signs of growing well, other possible causes include:

Poor milk transfer due to tongue-tie, or cleft palate.
Medical conditions in the infant, such as malabsorption of nutrients.

Definition
A mother is considered to have low milk supply if she produces less breast milk than her infant requires. The term is used only after a mothers milk "comes in", which usually occurs around 30–40 hours after delivery of a full-term infant. Low milk supply is distinct from the scenario in which the mothers milk comes in later than normal but is thereafter produced in sufficient quantities; this is known as delayed onset of lactation (delayed lactogenesis II).

Prevention
The first week after birth is a critical window for establishing milk supply. The Ten Steps of the Baby Friendly Hospital Initiative describe some maternity hospital practices that promote the development of a good milk supply, such as rooming in (allowing mothers and infants to remain together 24 hours a day) and having trained staff available to help mothers with breastfeeding. Supplemental formula or donor milk should be given only when medically necessary.
There is increasing evidence that suggests that early skin-to-skin contact between mother and baby stimulates breastfeeding behavior in the baby. Newborns who are immediately placed on their mothers skin have a natural instinct to latch on to the breast and start nursing, typically within one hour of birth. Immediate skin-to-skin contact may provide a form of imprinting that makes subsequent feeding significantly easier.  Interrupting the process, such as removing the baby to weigh him/her, may complicate subsequent feeding.Frequent suckling in the first days of life is correlated with higher milk production. Infants should be fed when they show signs of hunger. It is common for breastfed babies to feed during the night for the first six months. Usually feedings last 10–15 minutes in the early days.If the infant is unable to breastfeed, it is recommended that pumping or hand expression of milk begin within two hours of delivery, and be done at least eight times every 24 hours.

Management
Attempts to increase milk supply should begin promptly as the longer low supply continues, the more difficult it is to reverse. The primary method for increasing milk supply is to increase the frequency and the thoroughness of milk drainage from the breasts, and to increase breast stimulation.For mothers of healthy term infants who are able to nurse, very strong evidence supports improving breastfeeding practices as a primary treatment. Increasing skin-to-skin contact between mother and baby, and allowing unrestricted breastfeeding, aid in stimulating the milk ejection reflex and promote frequent feeds. If the babys latch is not optimal, improving the latch will help the baby drink more milk. Making the mother comfortable, particularly by resolving nipple pain, is essential. Breast self-massage is recommended to stimulate the milk ejection reflex and to physically promote the flow of milk. Some experts recommend using a breast pump after each breastfeeding session.If the baby cannot nurse effectively, frequent drainage of milk from the breasts through hand expression and/or an electric double breast pump is recommended.The mothers use of medications and herbs should be evaluated, as some substance suppress lactation. The Academy of Breastfeeding Medicine protocol for low milk supply recommends that the mother be evaluated for medical causes of the problem, however health professionals and breastfeeding counsellors often do not do this.

Medications and herbs
After the above treatment methods have been attempted, many breastfeeding specialists and lactation consultants recommend medications or herbs that are believed to increase milk supply (galactagogues).  In 2010, a randomized, double-blinded, placebo-controlled study demonstrated that domperidone increased milk production in mothers of preterm infants. Another very small study of domperidone found that some women respond to it and others do not. As the effects of domperidone stop when use of the drug is stopped, it is sometimes used for months </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 Endometrial hyperplasia and can you explain it in depth? [/INST] Endometrial hyperplasia is a condition of excessive proliferation of the cells of the endometrium, or inner lining of the uterus.
Most cases of endometrial hyperplasia result from high levels of estrogens, combined with insufficient levels of the progesterone-like hormones which ordinarily counteract estrogens proliferative effects on this tissue. This may occur in a number of settings, including obesity, polycystic ovary syndrome, estrogen producing tumours (e.g. granulosa cell tumour) and certain formulations of estrogen replacement therapy.
Endometrial hyperplasia with atypia is a significant risk factor for the development or even co-existence of endometrial cancer, so careful monitoring and treatment of women with this disorder is essential.

Classification
Like other hyperplastic disorders, endometrial hyperplasia initially represents a physiological response of endometrial tissue to the growth-promoting actions of estrogen. However, the gland-forming cells of a hyperplastic endometrium may also undergo changes over time which predispose them to cancerous transformation </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 Vesicointestinal fistula 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 Healing and can you explain it in depth? [/INST] With physical trauma or disease suffered by an organism, healing involves the repairing of damaged tissue(s), organs and the biological system as a whole and resumption of (normal) functioning. Medicine includes the process by which the cells in the body regenerate and repair to reduce the size of a damaged or necrotic area and replace it with new living tissue. The replacement can happen in two ways: by regeneration in which the necrotic cells are replaced by new cells that form "like" tissue as was originally there; or by repair in which injured tissue is replaced with scar tissue. Most organs will heal using a mixture of both mechanisms.Within surgery, healing is more often referred to as recovery, and postoperative recovery has historically been viewed simply as restitution of function and readiness for discharge. More recently, it has been described as an energy‐requiring process to decrease physical symptoms, reach a level of emotional well‐being, regain functions, and re‐establish activitiesHealing is also referred to in the context of the grieving process.In psychiatry and psychology, healing is the process by which neuroses and psychoses are resolved to the degree that the client is able to lead a normal or fulfilling existence without being overwhelmed by psychopathological phenomena. This process may involve psychotherapy, pharmaceutical treatment or alternative approaches such as traditional spiritual healing.

Regeneration
In order for an injury to be healed by regeneration, the cell type that was destroyed must be able to replicate. Cells also need a collagen framework along which to grow. Alongside most cells there is either a basement membrane or a collagenous network made by fibroblasts that will guide the cells growth.  Since ischaemia and most toxins do not destroy collagen, it will continue to exist even when the cells around it are dead.

Example
Acute tubular necrosis (ATN) in the kidney is a case in which cells heal completely by regeneration. ATN occurs when the epithelial cells that line the kidney are destroyed by either a lack of oxygen (such as in hypovolemic shock, when blood supply to the kidneys is dramatically reduced), or by toxins (such as some antibiotics, heavy metals or carbon tetrachloride).Although many of these epithelial cells are dead, there is typically patchy necrosis, meaning that there are patches of epithelial cells still alive. In addition, the collagen framework of the tubules remains completely intact.The existing epithelial cells can replicate, and, using the basement membrane as a guide, eventually bring the kidney back to normal. After regeneration is complete, the damage is undetectable, even microscopically.Healing must happen by repair in the case of injury to cells that are unable to regenerate (e.g. neurons). Also, damage to the collagen network (e.g. by enzymes or physical destruction), or its total collapse (as can happen in an infarct) cause healing to take place by repair.

Genetics
Many genes play a role in healing. For instance, in wound healing, P21 has been found to allow mammals to heal spontaneously. It even allows some mammals (like mice) to heal wounds without scars. The LIN28 gene also plays a role in wound healing. It is dormant in most mammals. Also, the proteins MG53 and TGF beta 1 play important roles in wound healing.

Wound healing
In response to an incision or wound, a wound healing cascade is unleashed.  This cascade takes place in four phases: clot formation, inflammation, proliferation, and maturation.

Clotting phase
Healing of a wound begins with clot formation to stop bleeding and to reduce infection by bacteria, viruses and fungi. Clotting is followed by neutrophil invasion three to 24 hours after the wound has been incurred, with mitoses beginning in epithelial cells after 24 to 48 hours.

Inflammation phase
In the inflammatory phase, macrophages and other phagocytic cells kill bacteria, debride damaged tissue and release chemical factors such as growth hormones that encourage fibroblasts, epithelial cells and endothelial cells which make new capillaries to migrate to the area and divide.

Proliferative phase
In the proliferative phase, immature granulation tissue containing plump, active fibroblasts forms. Fibroblasts quickly produce abundant type III collagen, which fills the defect left by an open wound. Granulation tissue moves, as a wave, from the border of the injury towards the center.As granulation tissue matures, the fibroblasts produce less collagen and become more spindly in appearance. They begin to produce the much stronger type I collagen. Some of the fibroblasts mature into myofibroblasts which contain the same type of actin found in smooth muscle, which enables them to contract and reduce the size of the wound.

Maturation phase
During the maturation phase of wound healing, unnecessary vessels formed in granulation tissue are removed by apoptosis, and type III collagen is largely replaced by type I. Collagen which was originally disorganized is cross-linked and aligned along tension lines. This phase can last a year or longer. Ultimately a scar made of collagen, containing a small number of fibroblasts is left.

Tissue damaged by inflammation
After inflammation has damaged tissue (when combatting bacterial infection for example) and pro-inflammatory eicosanoids have completed their function, healing proceeds in 4 phases.

Recall phase
In the recall phase the adrenal glands increase production of cortisol which shuts down eicosanoid production and inflammation.

Resolution phase
In the Resolution phase, pathogens and damaged tissue are removed by macrophages (white blood cells). Red blood cells are also removed from the damaged tissue by macrophages. Failure to remove all of the damaged cells and pathogens may retrigger inflammation. The two subsets of macrophage M1 & M2 plays a crucial role in this phase, M1 macrophage being a pro inflammatory while as M2 is a regenerative and the plasticity between the two subsets determine the tissue inflammation or repair.

Regeneration phase
In the Regeneration phase, blood vessels are repaired and new cells form in the damaged site similar to the cells that were damaged and removed.  Some cells such as neurons and muscle cells (especially in the heart) are slow to recover.

Repair phase
In the Repair phase, new tissue is generated which requires a balance of anti-inflammatory and pro-inflammatory eicosanoids.  Anti-inflammatory eicosanoids include lipoxins, epi-lipoxins, and resolvins, which cause release of growth hormones.

See also
Scar free healing
Health

References
External links
How wounds heal and tumors form With this simple Flash demonstration, Harvard professor Donald Ingber explains how wounds heal, why scars form, and how tumors develop. Presented by Childrens Hospital Boston.
Wound Healing and Repair
Lorenz H.P. and Longaker M.T </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Carcinoid syndrome and can you explain it in depth? [/INST] Carcinoid syndrome is a paraneoplastic syndrome comprising the signs and symptoms that occur secondary to carcinoid tumors. The syndrome includes flushing and diarrhea, and less frequently, heart failure, vomiting and bronchoconstriction.  It is caused by endogenous secretion of mainly serotonin and kallikrein.

Signs and symptoms
The carcinoid syndrome occurs in approximately 5% of carcinoid tumors and becomes manifest when vasoactive substances from the tumors enter the systemic circulation escaping hepatic degradation. If the primary tumor is from the gastrointestinal tract (hence releasing serotonin into the hepatic portal circulation), carcinoid syndrome generally does not occur until the disease is so advanced that it overwhelms the livers ability to metabolize the released serotonin.
Flushing: The most important clinical finding is flushing of the skin, usually of the head and the upper part of thorax.
Diarrhea: It may be associated with abdominal cramping. This symptom is due to the action of serotonin, histamine, and gastrin
Abdominal pain: It is due to hepatomegaly, small bowel obstruction or lack of oxygen to small bowel.
Bronchoconstriction, which may be histamine or serotonin-induced, affects about 15% of those having carcinoid syndrome and often accompanies flushing, sneezing, and shortness of breath.
Carcinoid heart disease: About 19% to 60% of the those affected by carcinoid syndrome develop carcinoid heart disease. Serotonin induces fibrosis in valves of the right heart especially tricuspid valve.

Pathophysiology
Carcinoid tumors produce several vasoactive substances, most prominently serotonin. It is commonly thought that serotonin is the cause of the flushing, but this is only partially correct. The flushing also results from secretion of kallikrein, the enzyme that catalyzes the conversion of kininogen to lysyl-bradykinin. The latter is further converted to bradykinin, one of the most powerful vasodilators known.
Other components of the carcinoid syndrome are diarrhea (probably caused by the increased serotonin, which greatly increases peristalsis, leaving less time for fluid absorption), a pellagra-like syndrome (probably caused by diversion of large amounts of tryptophan from synthesis of the vitamin B3 niacin, which is needed for NAD production, to the synthesis of serotonin and other 5-hydroxyindoles), fibrotic lesions of the endocardium, particularly on the right side of the heart resulting in insufficiency of the tricuspid valve and, less frequently, the pulmonary valve and, uncommonly, bronchoconstriction.The pathogenesis of the cardiac lesions and the bronchoconstriction is unknown, but the former probably involves activation of serotonin 5-HT2B receptors by serotonin. When the primary tumor is in the gastrointestinal tract, as it is in the great majority of cases, the serotonin and kallikrein are inactivated in the liver; manifestations of carcinoid syndrome do not occur until there are metastases to the liver or when the cancer is accompanied by liver failure (cirrhosis). Carcinoid tumors arising in the bronchi may be associated with manifestations of carcinoid syndrome without liver metastases because their biologically active products reach the systemic circulation before passing through the liver and being metabolized.In most patients, there is an increased urinary excretion of 5-HIAA (5-hydroxyindoleacetic acid), a degradation product of serotonin.The biology of these tumors differs from many other tumor types. Ongoing research on the biology of these tumors may reveal new mechanisms for tumor development.

Diagnosis
With a certain degree of clinical suspicion, the most useful initial test is the 24-hour urine levels of 5-HIAA (5-hydroxyindoleacetic acid), the end product of serotonin metabolism. Patients with carcinoid syndrome usually excrete more than 25 mg of 5-HIAA per day.

Imaging
For localization of both primary lesions and metastasis, the initial imaging method is Octreoscan, where indium-111 labelled somatostatin analogues (octreotide) are used in scintigraphy for detecting tumors expressing somatostatin receptors. Median detection rates with octreoscan are about 89%, in contrast to other imaging techniques such as CT scan and MRI with detection rates of about 80%. Gallium-68 labelled somatostatin analogues such as 68Ga-DOTA-Octreotate (DOTATATE), performed on a PET/CT scanner is superior to conventional Octreoscan.
Usually, on a CT scan, a spider-like/crab-like change is visible in the mesentery due to the fibrosis from the release of serotonin. 18F-FDG PET/CT, which evaluate for increased metabolism of glucose, may also aid in localizing the carcinoid lesion or evaluating for metastases. Chromogranin A and platelets serotonin are increased.Transthoracic echocardiogram shows valve thickening and reduction in mobility of the valves. Cardiac MRI is useful in showing ventricular anatomy and function.

Localization of tumour
Tumour localization may be extremely difficult </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 Hepatopulmonary syndrome and can you explain it in depth? [/INST] In medicine, hepatopulmonary syndrome is a syndrome of shortness of breath and hypoxemia (low oxygen levels in the blood of the arteries) caused by vasodilation (broadening of the blood vessels) in the lungs of patients with liver disease. Dyspnea and hypoxemia are worse in the upright position (which is called platypnea and orthodeoxia, respectively).

Pathophysiology
The hepatopulmonary syndrome results from the formation of microscopic intrapulmonary arteriovenous dilatations in patients with both chronic and far less common, acute liver failure. The mechanism is unknown but is thought to be due to increased liver production or decreased liver clearance of vasodilators, possibly involving nitric oxide.The dilation of these blood vessels causes overperfusion relative to ventilation, leading to ventilation-perfusion mismatch and hypoxemia. There is an increased gradient between the partial pressure of oxygen in the alveoli of the lung and adjacent arteries (alveolar-arterial [A-a] gradient) while breathing room air. Patients with HPS have platypnea-orthodeoxia syndrome (POS); that is, because intrapulmonary vascular dilations (IPVDs) predominate in the bases of the lungs, standing worsens hypoxemia (orthodeoxia)/dyspnea (platypnea) and the supine position improves oxygenation as blood is redistributed from the bases to the apices. Additionally, late in cirrhosis, it is common to develop high output failure, which would lead to less time in capillaries per red blood cell, exacerbating the hypoxemia.

Diagnosis
The hepatopulmonary syndrome is suspected in any patient with known liver disease who reports dyspnea (particularly platypnea). Patients with clinically significant symptoms should undergo pulse oximetry. If the syndrome is advanced, arterial blood gasses should be measured on air. Hepatopulmonary syndrome (HPS) consists of the triad of liver dysfunction, otherwise unexplained hypoxemia, and intrapulmonary vascular dilation (IPVD).A useful diagnostic test is contrast echocardiography. Intravenous microbubbles (> 10 micrometers in diameter) from agitated normal saline that are normally obstructed by pulmonary capillaries (normally <8 to 15 micrometers) rapidly transit the lung and appear in the left atrium of the heart within 7 heart beats </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 Immune system and can you explain it in depth? [/INST] The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organisms own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.
Nearly all organisms have some kind of immune system. Bacteria have a rudimentary immune system in the form of enzymes that protect against virus infections. Other basic immune mechanisms evolved in ancient plants and animals and remain in their modern descendants. These mechanisms include phagocytosis, antimicrobial peptides called defensins, and the complement system. Jawed vertebrates, including humans, have even more sophisticated defense mechanisms, including the ability to adapt to recognize pathogens more efficiently. Adaptive (or acquired) immunity creates an immunological memory leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination.
Dysfunction of the immune system can cause autoimmune diseases, inflammatory diseases and cancer. Immunodeficiency occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. In humans, immunodeficiency can be the result of a genetic disease such as severe combined immunodeficiency, acquired conditions such as HIV/AIDS, or the use of immunosuppressive medication. Autoimmunity results from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Common autoimmune diseases include Hashimotos thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus erythematosus. Immunology covers the study of all aspects of the immune system.

Layered defense
The immune system protects its host from infection with layered defenses of increasing specificity. Physical barriers prevent pathogens such as bacteria and viruses from entering the organism. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all animals. If pathogens successfully evade the innate response, vertebrates possess a second layer of protection, the adaptive immune system, which is activated by the innate response. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered.
Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self molecules. In immunology, self molecules are components of an organisms body that can be distinguished from foreign substances by the immune system. Conversely, non-self molecules are those recognized as foreign molecules. One class of non-self molecules are called antigens (originally named for being antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune response.

Surface barriers
Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers. The waxy cuticle of most leaves, the exoskeleton of insects, the shells and membranes of externally deposited eggs, and skin are examples of mechanical barriers that are the first line of defense against infection. Organisms cannot be completely sealed from their environments, so systems act to protect body openings such as the lungs, intestines, and the genitourinary tract. In the lungs, coughing and sneezing mechanically eject pathogens and other irritants from the respiratory tract. The flushing action of tears and urine also mechanically expels pathogens, while mucus secreted by the respiratory and gastrointestinal tract serves to trap and entangle microorganisms.Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial peptides such as the β-defensins. Enzymes such as lysozyme and phospholipase A2 in saliva, tears, and breast milk are also antibacterials. Vaginal secretions serve as a chemical barrier following menarche, when they become slightly acidic, while semen contains defensins and zinc to kill pathogens. In the stomach, gastric acid serves as a chemical defense against ingested pathogens.Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers by competing with pathogenic bacteria for food and space and, in some cases, changing the conditions in their environment, such as pH or available iron. As a result, the probability that pathogens will reach sufficient numbers to cause illness is reduced.

Innate immune system
Microorganisms or toxins that successfully enter an organism encounter the cells and mechanisms of the innate immune system. The innate response is usually triggered when microbes are identified by pattern recognition receptors, which recognize components that are conserved among broad groups of microorganisms, or when damaged, injured or stressed cells send out alarm signals, many of which are recognized by the same receptors as those that recognize pathogens. Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way. This system does not confer long-lasting immunity against a pathogen. The innate immune system is the dominant system of host defense in most organisms, and the only one in plants.

Immune sensing
Cells in the innate immune system use pattern recognition receptors to recognize molecular structures that are produced by pathogens. They are proteins expressed, mainly, by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of hosts cells that are released during cell damage or cell death.Recognition of extracellular or endosomal PAMPs is mediated by transmembrane proteins known as toll-like receptors (TLRs). TLRs share a typical structural motif, the leucine rich repeats (LRR), which give them a curved shape. Toll-like receptors were first discovered in Drosophila and trigger the synthesis and secretion of cytokines and activation of other host defense programs that are necessary for both innate or adaptive immune responses. Ten toll-like receptors have been described in humans.Cells in the innate immune system have pattern recognition receptors, which detect infection or cell damage, inside. Three major classes of these "cytosolic" receptors are NOD–like receptors, RIG (retinoic acid-inducible gene)-like receptors, and cytosolic DNA sensors.

Innate immune cells
Some leukocytes (white blood cells) act like independent, single-celled organisms and are the second arm of the innate immune system. The innate leukocytes include the "professional" phagocytes (macrophages, neutrophils, and dendritic cells). These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms. The other cells involved in the innate response include innate lymphoid cells, mast cells, eosinophils, basophils, and natural killer cells.Phagocytosis is an important feature of cellular innate immunity performed by cells called phagocytes that engulf pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines. Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular vesicle called a phagosome, which subsequently fuses with another vesicle called a lysosome to form a phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that releases free radicals into the phagolysosome. Phagocytosis evolved as a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism. Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals.Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens. Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, representing 50% to 60% of total circulating leukocytes. During the acute phase of inflammation, neutrophils migrate toward the site of inflammation in a process called chemotaxis, and are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells that reside within tissues and produce an array of chemicals including enzymes, complement proteins, and cytokines, while they can also act as scavengers that rid the body of worn-out cells and other debris, and as antigen-presenting cells (APC) that activate the adaptive immune system.Dendritic cells are phagocytes in tissues that are in contact with the external environment; therefore, they are located mainly in the skin, nose, lungs, stomach, and intestines. They are named for their resemblance to neuronal dendrites, as both have many spine-like projections. Dendritic cells serve as a link between the bodily tissues and the innate and adaptive immune systems, as they present antigens to T cells, one of the key cell types of the adaptive immune system.Granulocytes are leukocytes that have granules in their cytoplasm. In this category are neutrophils, mast cells, basophils, and eosinophils. Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory response. They are most often associated with allergy and anaphylaxis. Basophils and eosinophils are related to neutrophils. They secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such as asthma.Innate lymphoid cells (ILCs) are a group of innate immune cells that are derived from common lymphoid progenitor and belong to the lymphoid lineage. These cells are defined by absence of antigen specific B or T cell receptor (TCR) because of the lack of recombination activating gene. ILCs do not express myeloid or dendritic cell markers.Natural killer cells (NK) are lymphocytes and a component of the innate immune system which does not directly attack invading microbes. Rather, NK cells destroy compromised host cells, such as tumor cells or virus-infected cells, recognizing such cells by a condition known as "missing self." This term describes cells with low levels of a cell-surface marker called MHC I (major histocompatibility complex)—a situation that can arise in viral infections of host cells. Normal body cells are not recognized and attacked by NK cells because they express intact self MHC antigens. Those MHC antigens are recognized by killer cell immunoglobulin receptors which essentially put the brakes on NK cells.

Inflammation
Inflammation is one of the first responses of the immune system to infection. The symptoms of inflammation are redness, swelling, heat, and pain, which are caused by increased blood flow into tissue. Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes). Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as shutting down protein synthesis in the host cell. Growth factors and cytotoxic factors may also be released. These cytokines and other chemicals recruit immune cells to the site of infection and promote healing of any damaged tissue following the removal of pathogens. The pattern-recognition receptors called inflammasomes are multiprotein complexes (consisting of an NLR, the adaptor protein ASC, and the effector molecule pro-caspase-1) that form in response to cytosolic PAMPs and DAMPs, whose function is to generate active forms of the inflammatory cytokines IL-1β and IL-18.

Humoral defenses
The complement system is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20 different proteins and is named for its ability to "complement" the killing of pathogens by antibodies. Complement is the major humoral component of the innate immune response. Many species have complement systems, including non-mammals like plants, fish, and some invertebrates. In humans, this response is activated by complement binding to antibodies that have attached to these microbes or the binding of complement proteins to carbohydrates on the surfaces of microbes. This recognition signal triggers a rapid killing response. The speed of the response is a result of signal amplification that occurs after sequential proteolytic activation of complement molecules, which are also proteases. After complement proteins initially bind to the microbe, they activate their protease activity, which in turn activates other complement proteases, and so on. This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback. The cascade results in the production of peptides that attract immune cells, increase vascular permeability, and opsonize (coat) the surface of a pathogen, marking it for destruction. This deposition of complement can also kill cells directly by disrupting their plasma membrane.

Adaptive immune system
The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as immunological memory, where each pathogen is "remembered" by a signature antigen. The adaptive immune response is antigen-specific and requires the recognition of specific "non-self" antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by "memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it.

Recognition of antigen
The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response. Killer T cells only recognize antigens coupled to Class I MHC molecules, while helper T cells and regulatory T cells only recognize antigens coupled to Class II MHC molecules. These two mechanisms of antigen presentation reflect the different roles of the two types of T cell. A third, minor subtype are the γδ T cells that recognize intact antigens that are not bound to MHC receptors. The double-positive T cells are exposed to a wide variety of self-antigens in the thymus, in which iodine is necessary for its thymus development and activity. In contrast, the B cell antigen-specific receptor is an antibody molecule on the B cell surface and recognizes native (unprocessed) antigen without any need for antigen processing. Such antigens may be large molecules found on the surfaces of pathogens, but can also be small haptens (such as penicillin) attached to carrier molecule. Each lineage of B cell expresses a different antibody, so the complete set of B cell antigen receptors represent all the antibodies that the body can manufacture. When B or T cells encounter their related antigens they multiply and many "clones" of the cells are produced that target the same antigen. This is called clonal selection.

Antigen presentation to T lymphocytes
Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a "non-self" target, such as a pathogen, only after antigens (small fragments of the pathogen) have been processed and presented in combination with a "self" receptor called a major histocompatibility complex (MHC) molecule.

Cell mediated immunity
There are two major subtypes of T cells: the killer T cell and the helper T cell. In addition there are regulatory T cells which have a role in modulating immune response.

Killer T cells
Killer T cells are a sub-group of T cells that kill cells that are infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional. As with B cells, each type of T cell recognizes a different antigen. Killer T cells are activated when their T-cell receptor binds to this specific antigen in a complex with the MHC Class I receptor of another cell. Recognition of this MHC:antigen complex is aided by a co-receptor on the T cell, called CD8. The T cell then travels throughout the body in search of cells where the MHC I receptors bear this antigen. When an activated T cell contacts such cells, it releases cytotoxins, such as perforin, which form pores in the target cells plasma membrane, allowing ions, water and toxins to enter. The entry of another toxin called granulysin (a protease) induces the target cell to undergo apoptosis. T cell killing of host cells is particularly important in preventing the replication of viruses. T cell activation is tightly controlled and generally requires a very strong MHC/antigen activation signal, or additional activation signals provided by "helper" T cells (see below).

Helper T cells
Helper T cells regulate both the innate and adaptive immune responses and help determine which immune responses the body makes to a particular pathogen. These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. They instead control the immune response by directing other cells to perform these tasks.Helper T cells express T cell receptors that recognize antigen bound to Class II MHC molecules. The MHC:antigen complex is also recognized by the helper cells CD4 co-receptor, which recruits molecules inside the T cell (such as Lck) that are responsible for the T cells activation. Helper T cells have a weaker association with the MHC:antigen complex than observed for killer T cells, meaning many receptors (around 200–300) on the helper T cell must be bound by an MHC:antigen to activate the helper cell, while killer T cells can be activated by engagement of a single MHC:antigen molecule. Helper T cell activation also requires longer duration of engagement with an antigen-presenting cell. The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types. Cytokine signals produced by helper T cells enhance the microbicidal function of macrophages and the activity of killer T cells. In addition, helper T cell activation causes an upregulation of molecules expressed on the T cells surface, such as CD40 ligand (also called CD154), which provide extra stimulatory signals typically required to activate antibody-producing B cells.

Gamma delta T cells
Gamma delta T cells (γδ T cells) possess an alternative T-cell receptor (TCR) as opposed to CD4+ and CD8+ (αβ) T cells and share the characteristics of helper T cells, cytotoxic T cells and NK cells. The conditions that produce responses from γδ T cells are not fully understood. Like other unconventional T cell subsets bearing invariant TCRs, such as CD1d-restricted natural killer T cells, γδ T cells straddle the border between innate and adaptive immunity. On one hand, γδ T cells are a component of adaptive immunity as they rearrange TCR genes to produce receptor diversity and can also develop a memory phenotype. On the other hand, the various subsets are also part of the innate immune system, as restricted TCR or NK receptors may be used as pattern recognition receptors. For example, large numbers of human Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted Vδ1+ T cells in epithelia respond to stressed epithelial cells.

Humoral immune response
A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen. This antigen/antibody complex is taken up by the B cell and processed by proteolysis into peptides. The B cell then displays these antigenic peptides on its surface MHC class II molecules. This combination of MHC and antigen attracts a matching helper T cell, which releases lymphokines and activates the B cell. As the activated B cell then begins to divide, its offspring (plasma cells) secrete millions of copies of the antibody that recognizes this antigen. These antibodies circulate in blood plasma and lymph, bind to pathogens expressing the antigen and mark them for destruction by complement activation or for uptake and destruction by phagocytes. Antibodies can also neutralize challenges directly, by binding to bacterial toxins or by interfering with the receptors that viruses and bacteria use to infect cells.Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection. Several layers of passive protection are provided by the mother. During pregnancy, a particular type of antibody, called IgG, is transported from mother to baby directly through the placenta, so human babies have high levels of antibodies even at birth, with the same range of antigen specificities as their mother. Breast milk or colostrum also contains antibodies that are transferred to the gut of the infant and protect against bacterial infections until the newborn can synthesize its own antibodies. This is passive immunity because the fetus does not actually make any memory cells or antibodies—it only borrows them. This passive immunity is usually short-term, lasting from a few days up to several months. In medicine, protective passive immunity can also be transferred artificially from one individual to another.

Immunological memory
When B cells and T cells are activated and begin to replicate, some of their offspring become long-lived memory cells. Throughout the lifetime of an animal, these memory cells remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again. This is "adaptive" because it occurs during the lifetime of an individual as an adaptation to infection with that pathogen and prepares the immune system for future challenges. Immunological memory can be in the form of either passive short-term memory or active long-term memory.

Physiological regulation
The immune system is involved in many aspects of physiological regulation in the body. The immune system interacts intimately with other systems, such as the endocrine and the nervous systems. The immune system also plays a crucial role in embryogenesis (development of the embryo), as well as in tissue repair and regeneration.

Hormones
Hormones can act as immunomodulators, altering the sensitivity of the immune system. For example, female sex hormones are known immunostimulators of both adaptive and innate immune responses. Some autoimmune diseases such as lupus erythematosus strike women preferentially, and their onset often coincides with puberty. By contrast, male sex hormones such as testosterone seem to be immunosuppressive. Other hormones appear to regulate the immune system as well, most notably prolactin, growth hormone and vitamin D.

Vitamin D
Although cellular studies indicate that vitamin D has receptors and probable functions in the immune system, there is no clinical evidence to prove that vitamin D deficiency increases the risk for immune diseases or vitamin D supplementation lowers immune disease risk. A 2011 United States Institute of Medicine report stated that "outcomes related to ... immune functioning and autoimmune disorders, and infections ... could not be linked reliably with calcium or vitamin D intake and were often conflicting.": 5

Sleep and rest
The immune system is affected by sleep and rest, and sleep deprivation is detrimental to immune function. Complex feedback loops involving cytokines, such as interleukin-1 and tumor necrosis factor-α produced in response to infection, appear to also play a role in the regulation of non-rapid eye movement (REM) sleep. Thus the immune response to infection may result in changes to the sleep cycle, including an increase in slow-wave sleep relative to REM sleep.In people with sleep deprivation, active immunizations may have a diminished effect and may result in lower antibody production, and a lower immune response, than would be noted in a well-rested individual. Additionally, proteins such as NFIL3, which have been shown to be closely intertwined with both T-cell differentiation and circadian rhythms, can be affected through the disturbance of natural light and dark cycles through instances of sleep deprivation. These disruptions can lead to an increase in chronic conditions such as heart disease, chronic pain, and asthma.In addition to the negative consequences of sleep deprivation, sleep and the intertwined circadian system have been shown to have strong regulatory effects on immunological functions affecting both innate and adaptive immunity. First, during the early slow-wave-sleep stage, a sudden drop in blood levels of cortisol, epinephrine, and norepinephrine causes increased blood levels of the hormones leptin, pituitary growth hormone, and prolactin. These signals induce a pro-inflammatory state through the production of the pro-inflammatory cytokines interleukin-1, interleukin-12, TNF-alpha and IFN-gamma. These cytokines then stimulate immune functions such as immune cell activation, proliferation, and differentiation. During this time of a slowly evolving adaptive immune response, there is a peak in undifferentiated or less differentiated cells, like naïve and central memory T cells. In addition to these effects, the milieu of hormones produced at this time (leptin, pituitary growth hormone, and prolactin) supports the interactions between APCs and T-cells, a shift of the Th1/Th2 cytokine balance towards one that supports Th1, an increase in overall Th cell proliferation, and naïve T cell migration to lymph nodes. This is also thought to support the formation of long-lasting immune memory through the initiation of Th1 immune responses.During wake periods, differentiated effector cells, such as cytotoxic natural killer cells and cytotoxic T lymphocytes, peak to elicit an effective response against any intruding pathogens. Anti-inflammatory molecules, such as cortisol and catecholamines, also peak during awake active times. Inflammation would cause serious cognitive and physical impairments if it were to occur during wake times, and inflammation may occur during sleep times due to the presence of melatonin. Inflammation causes a great deal of oxidative stress and the presence of melatonin during sleep times could actively counteract free radical production during this time.

Physical exercise
Physical exercise has a positive effect on the immune system and depending on the frequency and intensity, the pathogenic effects of diseases caused by bacteria and viruses are moderated. Immediately after intense exercise there is a transient immunodepression, where the number of circulating lymphocytes decreases and antibody production declines. This may give rise to a window of opportunity for infection and reactivation of latent virus infections, but the evidence is inconclusive.

Changes at the cellular level
During exercise there is an increase in circulating white blood cells of all types. This is caused by the frictional force of blood flowing on the endothelial cell surface and catecholamines affecting β-adrenergic receptors (βARs). The number of neutrophils in the blood increases and remains raised for up to  six hours and immature forms are present. Although the increase in neutrophils ("neutrophilia") is similar to that seen during bacterial infections, after exercise the cell population returns to normal by around 24 hours.The number of circulating lymphocytes (mainly natural  killer cells) decreases during intense exercise but returns to normal after 4 to 6 hours. Although up to 2% of the cells die most migrate from the blood to the tissues, mainly the intestines and lungs, where pathogens are most likely to be encountered.Some monocytes leave the blood circulation and migrate to the muscles where they differentiate and become macrophages. These cells differentiate into two types: proliferative macrophages, which are responsible for increasing the number of stem cells  and restorative macrophages, which are involved their maturing to muscle cells.

Repair and regeneration
The immune system, particularly the innate component, plays a decisive role in tissue repair after an insult. Key actors include macrophages and neutrophils, but other cellular actors, including γδ T cells, innate lymphoid cells (ILCs), and regulatory T cells (Tregs), are also important. The plasticity of immune cells and the balance between pro-inflammatory and anti-inflammatory signals are crucial aspects of efficient tissue repair. Immune components and pathways are involved in regeneration as well, for example in amphibians such as in axolotl limb regeneration. According to one hypothesis, organisms that can regenerate (e.g., axolotls) could be less immunocompetent than organisms that cannot regenerate.

Disorders of human immunity
Failures of host defense occur and fall into three broad categories: immunodeficiencies, autoimmunity, and hypersensitivities.

Immunodeficiencies
Immunodeficiencies occur when one or more of the components of the immune system are inactive. The ability of the immune system to respond to pathogens is diminished in both the young and the elderly, with immune responses beginning to decline at around 50 years of age due to immunosenescence. In developed countries, obesity, alcoholism, and drug use are common causes of poor immune function, while malnutrition is the most common cause of immunodeficiency in developing countries. Diets lacking sufficient protein are associated with impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody concentrations, and cytokine production. Additionally, the loss of the thymus at an early age through genetic mutation or surgical removal results in severe immunodeficiency and a high susceptibility to infection. Immunodeficiencies can also be inherited or acquired. Severe combined immunodeficiency is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations. Chronic granulomatous disease, where phagocytes have a reduced ability to destroy pathogens, is an example of an inherited, or congenital, immunodeficiency. AIDS and some types of cancer cause acquired immunodeficiency.

Autoimmunity
Overactive immune responses form the other end of immune dysfunction, particularly the autoimmune disorders. Here, the immune system fails to properly distinguish between self and non-self, and attacks part of the body. Under normal circumstances, many T cells and antibodies react with "self" peptides. One of the functions of specialized cells (located in the thymus and bone marrow) is to present young lymphocytes with self antigens produced throughout the body and to eliminate those cells that recognize self-antigens, preventing autoimmunity. Common autoimmune diseases include Hashimotos thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus erythematosus.

Hypersensitivity
Hypersensitivity is an immune response that damages the bodys own tissues. It is divided into four classes (Type I – IV) based on the mechanisms involved and the time course of the hypersensitive reaction. Type I hypersensitivity is an immediate or anaphylactic reaction, often associated with allergy. Symptoms can range from mild discomfort to death. Type I hypersensitivity is mediated by IgE, which triggers degranulation of mast cells and basophils when cross-linked by antigen.
Type II hypersensitivity occurs when antibodies bind to antigens on the individuals own cells, marking them for destruction. This is also called antibody-dependent (or cytotoxic) hypersensitivity, and is mediated by IgG and IgM antibodies. Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM antibodies) deposited in various tissues trigger Type III hypersensitivity reactions. Type IV hypersensitivity (also known as cell-mediated or delayed type hypersensitivity) usually takes between two and three days to develop. Type IV reactions are involved in many autoimmune and infectious diseases, but may also involve contact dermatitis. These reactions are mediated by T cells, monocytes, and macrophages.

Idiopathic inflammation
Inflammation is one of the first responses of the immune system to infection, but it can appear without known cause.
Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes). Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as shutting down protein synthesis in the host cell. Growth factors and cytotoxic factors may also be released. These cytokines and other chemicals recruit immune cells to the site of infection and promote healing of any damaged tissue following the removal of pathogens.

Manipulation in medicine
The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy, and transplant rejection, and to stimulate protective responses against pathogens that largely elude the immune system (see immunization) or cancer.

Immunosuppression
Immunosuppressive drugs are used to control autoimmune disorders or inflammation when excessive tissue damage occurs, and to prevent rejection after an organ transplant.Anti-inflammatory drugs are often used to control the effects of inflammation. Glucocorticoids are the most powerful of these drugs and can have many undesirable side effects, such as central obesity, hyperglycemia, and osteoporosis. Their use is tightly controlled. Lower doses of anti-inflammatory drugs are often used in conjunction with cytotoxic or immunosuppressive drugs such as methotrexate or azathioprine.
Cytotoxic drugs inhibit the immune response by killing dividing cells such as activated T cells. This killing is indiscriminate and other constantly dividing cells and their organs are affected, which causes toxic side effects. Immunosuppressive drugs such as cyclosporin prevent T cells from responding to signals correctly by inhibiting signal transduction pathways.

Immunostimulation
Claims made by marketers of various products and alternative health providers, such as chiropractors, homeopaths, and acupuncturists to be able to stimulate or "boost" the immune system generally lack meaningful explanation and evidence of effectiveness.

Vaccination
Long-term active memory is acquired following infection by activation of B and T cells. Active immunity can also be generated artificially, through vaccination. The principle behind vaccination (also called immunization) is to introduce an antigen from a pathogen to stimulate the immune system and develop specific immunity against that particular pathogen without causing disease associated with that organism. This deliberate induction of an immune response is successful because it exploits the natural specificity of the immune system, as well as its inducibility. With infectious disease remaining one of the leading causes of death in the human population, vaccination represents the most effective manipulation of the immune system mankind has developed.Many vaccines are based on acellular components of micro-organisms, including harmless toxin components. Since many antigens derived from acellular vaccines do not strongly induce the adaptive response, most bacterial vaccines are provided with additional adjuvants that activate the antigen-presenting cells of the innate immune system and maximize immunogenicity.

Tumor immunology
Another important role of the immune system is to identify and eliminate tumors. This is called immune surveillance. The transformed cells of tumors express antigens that are not found on normal cells. To the immune system, these antigens appear foreign, and their presence causes immune cells to attack the transformed tumor cells. The antigens expressed by tumors have several sources; some are derived from oncogenic viruses like human papillomavirus, which causes cancer of the cervix, vulva, vagina, penis, anus, mouth, and throat, while others are the organisms own proteins that occur at low levels in normal cells but reach high levels in tumor cells. One example is an enzyme called tyrosinase that, when expressed at high levels, transforms certain skin cells (for example, melanocytes) into tumors called melanomas. A third possible source of tumor antigens are proteins normally important for regulating cell growth and survival, that commonly mutate into cancer inducing molecules called oncogenes.

The main response of the immune system to tumors is to destroy the abnormal cells using killer T cells, sometimes with the assistance of helper T cells. Tumor antigens are presented on MHC class I molecules in a similar way to viral antigens. This allows killer T cells to recognize the tumor cell as abnormal. NK cells also kill tumorous cells in a similar way, especially if the tumor cells have fewer MHC class I molecules on their surface than normal; this is a common phenomenon with tumors. Sometimes antibodies are generated against tumor cells allowing for their destruction by the complement system.Some tumors evade the immune system and go on to become cancers. Tumor cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells. Some tumor cells also release products that inhibit the immune response; for example by secreting the cytokine TGF-β, which suppresses the activity of macrophages and lymphocytes. In addition, immunological tolerance may develop against tumor antigens, so the immune system no longer attacks the tumor cells.Paradoxically, macrophages can promote tumor growth when tumor cells send out cytokines that attract macrophages, which then generate cytokines and growth factors such as tumor-necrosis factor alpha that nurture tumor development or promote stem-cell-like plasticity. In addition, a combination of hypoxia in the tumor and a cytokine produced by macrophages induces tumor cells to decrease production of a protein that blocks metastasis and thereby assists spread of cancer cells. Anti-tumor M1 macrophages are recruited in early phases to tumor development but are progressively differentiated to M2 with pro-tumor effect, an immunosuppressor switch. The hypoxia reduces the cytokine production for the anti-tumor response and progressively macrophages acquire pro-tumor M2 functions driven by the tumor microenvironment, including IL-4 and IL-10. Cancer immunotherapy covers the medical ways to stimulate the immune system to attack cancer tumors.

Predicting immunogenicity
Some drugs can cause a neutralizing immune response, meaning that the immune system produces neutralizing antibodies that counteract the action of the drugs, particularly if the drugs are administered repeatedly, or in larger doses. This limits the effectiveness of drugs based on larger peptides and proteins (which are typically larger than 6000 Da). In some cases, the drug itself is not immunogenic, but may be co-administered with an immunogenic compound, as is sometimes the case for Taxol. Computational methods have been developed to predict the immunogenicity of peptides and proteins, which are particularly useful in designing therapeutic antibodies, assessing likely virulence of mutations in viral coat particles, and validation of proposed peptide-based drug treatments. Early techniques relied mainly on the observation that hydrophilic amino acids are overrepresented in epitope regions than hydrophobic amino acids; however, more recent developments rely on machine learning techniques using databases of existing known epitopes, usually on well-studied virus proteins, as a training set. A publicly accessible database has been established for the cataloguing of epitopes from pathogens known to be recognizable by B cells. The emerging field of bioinformatics-based studies of immunogenicity is referred to as immunoinformatics. Immunoproteomics is the study of large sets of proteins (proteomics) involved in the immune response.

Evolution and other mechanisms
Evolution of the immune system
It is likely that a multicomponent, adaptive immune system arose with the first vertebrates, as invertebrates do not generate lymphocytes or an antibody-based humoral response. Many species, however, use mechanisms that appear to be precursors of these aspects of vertebrate immunity. Immune systems appear even in the structurally simplest forms of life, with bacteria using a unique defense mechanism, called the restriction modification system to protect themselves from viral pathogens, called bacteriophages. Prokaryotes (bacteria and archea) also possess acquired immunity, through a system that uses CRISPR sequences to retain fragments of the genomes of phage that they have come into contact with in the past, which allows them to block virus replication through a form of RNA interference. Prokaryotes also possess other defense mechanisms. Offensive elements of the immune systems are also present in unicellular eukaryotes, but studies of their roles in defense are few.Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with pathogens. Antimicrobial peptides called defensins are an evolutionarily conserved component of the innate immune response found in all animals and plants, and represent the main form of invertebrate systemic immunity. The complement system and phagocytic cells are also used by most forms of invertebrate life. Ribonucleases and the RNA interference pathway are conserved across all eukaryotes, and are thought to play a role in the immune response to viruses.Unlike animals, plants lack phagocytic cells, but many plant immune responses involve systemic chemical signals that are sent through a plant. Individual plant cells respond to molecules associated with pathogens known as pathogen-associated molecular patterns or PAMPs. When a part of a plant becomes infected, the plant produces a localized hypersensitive response, whereby cells at the site of infection undergo rapid apoptosis to prevent the spread of the disease to other parts of the plant. Systemic acquired resistance is a type of defensive response used by plants that renders the entire plant resistant to a particular infectious agent. RNA silencing mechanisms are particularly important in this systemic response as they can block virus replication.

Alternative adaptive immune system
Evolution of the adaptive immune system occurred in an ancestor of the jawed vertebrates. Many of the classical molecules of the adaptive immune system (for example, immunoglobulins and T-cell receptors) exist only in jawed vertebrates. A distinct lymphocyte-derived molecule has been discovered in primitive jawless vertebrates, such as the lamprey and hagfish. These animals possess a large array of molecules called Variable lymphocyte receptors (VLRs) that, like the antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of genes. These molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with the same degree of specificity.

Manipulation by pathogens
The success of any pathogen depends on its ability to elude host immune responses. Therefore, pathogens evolved several methods that allow them to successfully infect a host, while evading detection or destruction by the immune system. Bacteria often overcome physical barriers by secreting enzymes that digest the barrier, for example, by using a type II secretion system. Alternatively, using a type III secretion system, they may insert a hollow tube into the host cell, providing a direct route for proteins to move from the pathogen to the host. These proteins are often used to shut down host defenses.An evasion strategy used by several pathogens to avoid the innate immune system is to hide within the cells of their host (also called intracellular pathogenesis). Here, a pathogen spends most of its life-cycle inside host cells, where it is shielded from direct contact with immune cells, antibodies and complement. Some examples of intracellular pathogens include viruses, the food poisoning bacterium Salmonella and the eukaryotic parasites that cause malaria (Plasmodium spp.) and leishmaniasis (Leishmania spp.). Other bacteria, such as Mycobacterium tuberculosis, live inside a protective capsule that prevents lysis by complement. Many pathogens secrete compounds that diminish or misdirect the hosts immune response. Some bacteria form biofilms to protect themselves from the cells and proteins of the immune system. Such biofilms are present in many successful infections, such as the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis. Other bacteria generate surface proteins that bind to antibodies, rendering them ineffective; examples include Streptococcus (protein G), Staphylococcus aureus (protein A), and Peptostreptococcus magnus (protein L).The mechanisms used to evade the adaptive immune system are more complicated. The simplest approach is to rapidly change non-essential epitopes (amino acids and/or sugars) on the surface of the pathogen, while keeping essential epitopes concealed. This is called antigenic variation. An example is HIV, which mutates rapidly, so the proteins on its viral envelope that are essential for entry into its host target cell are constantly changing. These frequent changes in antigens may explain the failures of vaccines directed at this virus. The parasite Trypanosoma brucei uses a similar strategy, constantly switching one type of surface protein for another, allowing it to stay one step ahead of the antibody response. Masking antigens with host molecules is another common strategy for avoiding detection by the immune system. In HIV, the envelope that covers the virion is formed from the outermost membrane of the host cell; such "self-cloaked" viruses make it difficult for the immune system to identify them as "non-self" structures.

History of immunology
Immunology is a science that examines the structure and function of the immune system. It originates from medicine and early studies on the causes of immunity to disease. The earliest known reference to immunity was during the plague of Athens in 430 BC. Thucydides noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time. In the 18th century, Pierre-Louis Moreau de Maupertuis experimented with scorpion venom and observed that certain dogs and mice were immune to this venom. In the 10th century, Persian physician al-Razi (also known as Rhazes) wrote the first recorded theory of acquired immunity, noting that a smallpox bout protected its survivors from future infections. Although he explained the immunity in terms of "excess moisture" being expelled from the blood—therefore preventing a second occurrence of the disease—this theory explained many observations about smallpox known during this time.These and other observations of acquired immunity were later exploited by Louis Pasteur in his development of vaccination and his proposed germ theory of disease. Pasteurs theory was in direct opposition to contemporary theories of disease, such as the miasma theory. It was not until Robert Kochs 1891 proofs, for which he was awarded a Nobel Prize in 1905, that microorganisms were confirmed as the cause of infectious disease. Viruses were confirmed as human pathogens in 1901, with the discovery of the yellow fever virus by Walter Reed.Immunology made a great advance towards the end of the 19th century, through rapid developments in the study of humoral immunity and cellular immunity. Particularly important was the work of Paul Ehrlich, who proposed the side-chain theory to explain the specificity of the antigen-antibody reaction; his contributions to the understanding of humoral immunity were recognized by the award of a joint Nobel Prize in 1908, along with the founder of cellular immunology, Elie Metchnikoff. In 1974, Niels Kaj Jerne developed the immune network theory; he shared a Nobel Prize in 1984 with Georges J </s>


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