<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 Cowpox and can you explain it in depth? [/INST] Cowpox is an infectious disease caused by the cowpox virus (CPXV). It presents with large blisters in the skin, a fever and swollen glands, historically typically following contact with an infected cow, though in the last several decades more often (though overall rarely) from infected cats. The hands and face are most frequently affected and the spots are generally very painful.The virus, part of the genus Orthopoxvirus, is closely related to the vaccinia virus. The virus is zoonotic, meaning that it is transferable between species, such as from cat to human. The transferral of the disease was first observed in dairymaids who touched the udders of infected cows and consequently developed the signature pustules on their hands. Cowpox is more commonly found in animals other than bovines, such as rodents. Cowpox is similar to, but much milder than, the highly contagious and often deadly smallpox disease. Its close resemblance to the mild form of smallpox and the observation that dairy farmers were immune to smallpox inspired the modern smallpox vaccine, created and administered by English physician Edward Jenner.The first description of cowpox was given by Jenner in 1798. "Vaccination" is derived from the Latin adjective vaccinus, meaning "of or from the cow".  Once vaccinated, a patient develops antibodies that make them immune to cowpox, but they also develop immunity to the smallpox virus, or Variola virus. The cowpox vaccinations and later incarnations proved so successful that in 1980, the World Health Organization announced that smallpox was the first disease to be eradicated by vaccination efforts worldwide. Other orthopox viruses remain prevalent in certain communities and continue to infect humans, such as the cowpox virus in Europe, vaccinia in Brazil, and monkeypox virus in Central and West Africa.

Medical use
Naturally occurring cases of cowpox were not common, but it was discovered that the vaccine could be "carried" in humans and reproduced and disseminated human-to-human. Jenners original vaccination used lymph from the cowpox pustule on a milkmaid, and subsequent "arm-to-arm" vaccinations applied the same principle. As this transfer of human fluids came with its own set of complications, a safer manner of producing the vaccine was first introduced in Italy. The new method used cows to manufacture the vaccine using a process called "retrovaccination", in which a heifer was inoculated with humanized cowpox virus, and it was passed from calf to calf to produce massive quantities efficiently and safely. This then led to the next incarnation, "true animal vaccine", which used the same process but began with naturally-occurring cowpox virus, and not the humanized form.This method of production proved to be lucrative and was taken advantage of by many entrepreneurs needing only calves and seed lymph from an infected cow to manufacture crude versions of the vaccine. W. F. Elgin of the National Vaccine Establishment presented his slightly refined technique to the Conference of State and Provincial Boards of Health of North America. A tuberculosis-free calf, stomach shaved, would be bound to an operating table, where incisions would be made on its lower body. Glycerinated lymph from a previously inoculated calf was spread along the cuts. After a few days, the cuts would have scabbed or crusted over. The crust was softened with sterilized water and mixed with glycerin, which disinfected it, then stored hermetically sealed in capillary tubes for later use.At some point, the virus in use was no longer cowpox, but vaccinia. Scientists have not determined exactly when the change or mutation occurred, but the effects of vaccinia and cowpox virus as vaccine are nearly the same.The virus is found in Europe, and mainly in the UK. Human cases today are very rare and most often contracted from domestic cats. The virus is not commonly found in cattle; the reservoir hosts for the virus are woodland rodents, particularly voles. From these rodents, domestic cats contract and transmit the virus to humans.
Symptoms in cats include lesions on the face, neck, forelimbs, and paws, and less commonly upper respiratory tract infections.  Symptoms of infection with cowpox virus in humans are localized, pustular lesions generally found on the hands and limited to the site of introduction.  The incubation period is 9 to 10 days. The virus is prevalent in late summer and autumn.

Origin
Discovery
In the years from 1770 to 1790, at least six people who had contact with a cow had independently tested the possibility of using the cowpox vaccine as an immunization for smallpox in humans. Among them were the English farmer Benjamin Jesty, in Dorset in 1774 and the German teacher Peter Plett in 1791. Jesty inoculated his wife and two young sons with cowpox, in a successful effort to immunize them to smallpox, an epidemic of which had arisen in their town. His patients who had contracted and recovered from the similar but milder cowpox (mainly milkmaids), seemed to be immune not only to further cases of cowpox, but also to smallpox. By scratching the fluid from cowpox lesions into the skin of healthy individuals, he was able to immunize those people against smallpox.Reportedly, farmers and people working regularly with cattle and horses were often spared during smallpox outbreaks. Investigations by the British Army in 1790 showed that horse-mounted troops were less infected by smallpox than infantry, due to probable exposure to the similar horsepox virus (Variola equina). By the early 19th century, more than 100,000 people in Great Britain had been vaccinated. The arm-to-arm method of transfer of the cowpox vaccine was also used to distribute Jenners vaccine throughout the Spanish Empire. Spanish king  Charles IVs daughter had been stricken with smallpox in 1798, and after she recovered, he arranged for the rest of his family to be vaccinated.In 1803, the king, convinced of the benefits of the vaccine, ordered his personal physician Francis Xavier de Balmis, to deliver it to the Spanish dominions in North and South America. To maintain the vaccine in an available state during the voyage, the physician recruited 22 young boys who had never had cowpox or smallpox before, aged three to nine years, from the orphanages of Spain. During the trip across the Atlantic, de Balmis vaccinated the orphans in a living chain. Two children were vaccinated immediately before departure, and when cowpox pustules had appeared on their arms, material from these lesions was used to vaccinate two more children.In 1796, English medical practitioner Edward Jenner tested the theory that cowpox could protect someone from being infected by smallpox. There had long been speculation regarding the origins of Jenners variolae vaccinae, until DNA sequencing data showed close similarities between horsepox and cowpox viruses. Jenner noted that farriers sometimes milked cows and that material from the equine disease could produce a vesicular disease in cows from which variolae vaccinae was derived.  Contemporary accounts provide support for Jenners speculation that the vaccine probably originated as an equine disease called "grease".
Although cowpox originates on the udder of cows, Jenner took his sample from a milkmaid, Sarah Nelmes.Jenner extracted the pus of one of the lesions formed by cowpox on Nelmes to James Phipps, an eight-year-old boy who had never had smallpox. He eventually developed a scab and fever that was manageable. Approximately six weeks later, Jenner then introduced an active sample of the smallpox virus into Phipps to test the theory. After being observed for an extended amount of time, it was recorded that Phipps did not receive a reaction from it. Although Jenner was not the first person to conceive the notion of cowpox protecting against the smallpox virus, his experiment proved the theory. It was later discovered that the cowpox vaccination only worked temporarily against the invasion of smallpox and the procedure would need to be repeated several times through ones lifetime to remain smallpox free.In later years, Jenner popularized the experiment, calling it a vaccination from the Latin for cow, vacca. The amount of vaccinations among people of that era increased drastically. It was widely considered to be a relatively safer procedure compared to the mainstream inoculation. Although Jenner was propelled into the spotlight from the vaccination popularity, he mainly focused on science behind why the cowpox allowed persons to not be infected by smallpox. The honour of the discovery of the vaccination is often attributed to Benjamin Jesty, but he was no scientist and did not repeat or publish his findings. He is considered to be the first to use cowpox as a vaccination, though the term vaccination was not invented yet.
During the midst of the smallpox outbreak, Jesty transferred pieces of cow udder which he knew had been infected with cowpox into the skin of his family members in the hopes of protecting them. Jesty did not publicize his findings, and Jenner, who performed his first inoculation 22 years later and publicized his findings, assumed credit. It is said that Jenner made this discovery by himself, possibly without knowing previous accounts 20 years earlier. Although Jesty may have been the first to discover it, Jenner made vaccination widely accessible and has therefore been credited for its invention.

Life Cycle
The genome for the CPXV is over 220kbp. This makes it the largest genome in the Orthopoxviral species. It can be divided into three different regions. There are two end regions called R1 and R2 and a main central region that is roughly half of the size of the genome. There are also inverted terminal repeats that are located at the terminal sites of the genome and measure around 10kbp. These inverted terminal repeats can then be divided into two more distinct regions. The first section is around 7.5kbp long and includes a coding region. The other section includes a terminal region that can be repeated up to as many times as thirty and is composed of 50 nucleotides. The CPXV genome encodes only 30-40% of products of which are involved in the pathogenesis of the virus. The CPXV genome has the most complete set of genes out of all of the orthopoxviruses. This unique feature of CPXV makes it ideal to be able to mutate into different strains of the virus. It is a double stranded DNA virus. The virus does have an envelope that surrounds the virion. The cowpoxs genome allows the virus to encode its own transcription machinery along with its own DNA replication machinery. The replication then takes place in the cytoplasm after the virus is in the cell and the virion is uncoated. The virion is then assembled and released from the host cell.The genome is arranged so that both of the ends contain the genes responsible for evading the defenses from the immune system of the host which is only activated in the extracellular portion. These receptors are able to be stopped by cytokine and chemokine secretion by blocking the cytokine and chemokine found extracellularly. This is the process responsible for attachment and entry of the virion into the host cell. Because of the large size of the genome, it makes the virus more likely and capable to fight back against the immunes system defenses. Out of all of the poxviruses, CPXV has the most cytokine responses that fight back against the immune system. It encodes cytokine receptors such as TNF, CrmB, CrmC, CrmD, and CrmE proteins. Another set of receptors that CPXV have are lymphotoxins such as IL-1ß, IFN-y, IFN 1, β-chemokines, and IL-18. However, not all of the receptors of CPXV are still not known. CPXV also encodes four tumor necrosis factors (TNF) and lymphotoxin which are the biggest group of homologous receptors for the virus. These receptors play a crucial role that are involved with the immune system. CPXV has two different types of inclusion bodies. All of the poxviruses have basophilic inclusions also called B-type inclusion bodies. The B-type inclusion bodies contain the factory where the virus produces necessary elements for the replication and maturation of the virion. CPXV has another inclusion body that is unique to only some chordopoxviruses called acidophilic inclusion bodies also called A-type inclusion bodies (ATIs). The ATIs are encoded by the cpxv158 gene and is then made the protein ATIP which is a late protein. However, the importance of these ATIs in the life cycle are still not well known or understood and research is still being done to better understand them. It is known that replication can still continue without the cpxv158 gene, and that the replication cycle shows no difference between a fully encoded virion versus the virion that had deleted cwpx158 gene. However, with studies done on mice, the lesions that were caused by the CPXV-BR△ati were able to heal faster due to less tissue that was lost than the CPXV-BR lesions that took longer to heal and lost more tissue. This suggests that this gene helps supports the idea that ATIs are partly involved in how the host responds to the virus infection.Another way that the virus is able to control and infect the host is by regulating cellular signaling pathways. During the infection, CPXV is known to use MEK/ERK/1/2/Egr-1, JNK1/2, and PI3K/Akt pathways. Some of these pathways are not unique only to CPXV, but how they function in response to the host is unique to this virus.One notable protein in the CPXV is the p28 protein. It is made up of 242 amino acids and contains two domains, and N terminal KilA-N and a C-terminal RING domain. One of those domains, the N-terminal KilA-N domain, allows for DNA to bind to it. The KilA-N domain facilitates this p28 protein that is translated early in the replication cycle in the cytoplasm and is then located in the cytoplasm for the rest of the life cycle of the virus. There is current research still being done to determine if the p28 protein could be a requital for an essential macrophage factor that is needed for the DNA replication.

Opposition
The majority of the population at the time accepted the up-and-coming vaccination. However, there was still opposition from individuals who were reluctant to change from the inoculations. In addition, there became a growing concern from parties who were worried about the unknown repercussions of infecting a human with an animal disease. One way individuals expressed their discontent was to draw comics that sometimes depicted small cows growing from the sites of vaccination. Others publicly advocated for the continuance of the inoculations; however, this was not because of their discontent for the vaccinations. Some of their reluctance had to do with an apprehensiveness for change. They had become so familiar with the process, outcome, positives, and negatives of inoculations that they did not want to be surprised by the outcome or effects of the vaccinations. Jenner soon eased their minds after extensive trials. However, others advocated against vaccinations for different reason. Because of the high price of inoculation, Jenner experienced very few common folk who were not willing to accept the vaccination. Due to this, Jenner found many subjects for his tests. He was able to publish his results in a pamphlet in 1798: An Inquiry into the Causes and Effects of Variolae Vaccinae, a Disease, Discovered in some of the Western Counties of England particularly Gloucestershire, and known by the Name of Cow Pox.

Historical use
After inoculation, vaccination using the cowpox virus became the primary defense against smallpox. After infection by the cowpox virus, the body (usually) gains the ability to recognize the similar smallpox virus from its antigens and is able to fight the smallpox disease much more efficiently.The cowpox virus contains 186 thousand base pairs of DNA, which contains the information for about 187 genes. This makes cowpox one of the most complicated viruses known. Some 100 of these genes give instructions for key parts of the human immune system, giving a clue as to why the closely related smallpox is so lethal. The vaccinia virus now used for smallpox vaccination is sufficiently different from the cowpox virus found in the wild as to be considered a separate virus.

British Parliament
While the vaccinations popularity increased exponentially, so did its monetary value. This was realized by the British Parliament, which compensated Jenner 10,000 pounds for the vaccination. In addition, they later compensated Jenner an additional 20,000 pounds. In the coming years, Jenner continued advocacy for his vaccination over the still popular inoculation. Eventually, in 1840, the inoculation became banned in England and was replaced with the cowpox vaccination as the main medical solution to combat smallpox. The cowpox vaccination saved the British Army thousands of soldiers, by making them immune to the effects of smallpox in upcoming wars. The cowpox also saved the United Kingdom thousands of pounds.

Kinepox
Kinepox is an alternative term for the smallpox vaccine used in early 19th-century America. Popularized by Jenner in the late 1790s, kinepox was a far safer method for inoculating people against smallpox than the previous method, variolation, which had a 3% fatality rate.In a famous letter to Meriwether Lewis in 1803, Thomas Jefferson instructed the Lewis and Clark Expedition to "carry with you some matter of the kine-pox; inform those of them with whom you may be, of its efficacy as a preservative from the smallpox; & encourage them in the use of it..." Jefferson had developed an interest in protecting American Indians from smallpox, having been aware of epidemics along the Missouri River during the previous century. A year before his special instructions to Lewis, Jefferson had persuaded a visiting delegation of North American Indian chieftains to be vaccinated with kinepox during the winter of 1801–1802. Unfortunately, Lewis never got the opportunity to use kinepox during the pairs expedition, as it had become inadvertently inactive—a common occurrence in a time before vaccines were stabilized with preservatives such as glycerol or kept at refrigeration temperatures.

Prevention
Today, the virus is found in Europe, mainly in the UK. Human cases are very rare (though in 2010 a laboratory worker contracted cowpox) and most often contracted from domestic cats. Human infections usually remain localized and self-limiting, but can become fatal in immunosuppressed patients </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 Gestation and can you explain it in depth? [/INST] Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during pregnancy can have one or more gestations at the same time, for example in a multiple birth.The time interval of a gestation is called the gestation period. In obstetrics, gestational age refers to the time since the onset of the last menses, which on average is fertilization age plus two weeks.

Mammals
In mammals, pregnancy begins when a zygote (fertilized ovum) implants in the females uterus and ends once the fetus leaves the uterus during labor or an abortion (whether induced or spontaneous).

Humans
In humans, pregnancy can be defined clinically or biochemically. Clinically, pregnancy starts from the mothers last missed period. Biochemically, pregnancy starts when a womans human chorionic gonadotropin (hCG) levels rise above 25 mIU/mL.Human pregnancy can be divided into three trimesters, each approximately three months long: the first, second, and third trimester. The first trimester is from the last menstrual period through the 13th week, the second trimester is 14th–28/29th week, and the third trimester is 29/30th–42nd week. Birth normally occurs at a gestational age of about 40 weeks, though it is common for births to occur from 37 to 42 weeks. Labor occurring prior to 37 weeks gestation is considered preterm labor and can result from multiple factors, including previous preterm deliveries.Prenatal care is important for the maintenance of a healthy pregnancy and surveillance of related complications. In high-income countries, prenatal care typically involves monthly visits during the first two trimesters, with an increasing number of visits closer to delivery. At these visits, healthcare providers will evaluate a variety of parental and fetal metrics, including fetal growth and heart rate, birth defects, maternal blood pressure, among others.After birth, health care providers will measure the babys weight, vital signs, reflexes, head circumference, muscle tone, and posture to help determine the gestational age.Various factors can influence the duration of gestation, including diseases in pregnancy and adequate prenatal care. The rates of morbidity and pre-existing diseases that predispose mothers to life-threatening, pregnancy-related complications in the United States are increasing. The brunt of this burden is experienced by non-Hispanic Black women. Inaccessibility of prenatal care may partially explain this ongoing disparity. Other factors that affect prenatal care utilization include socioeconomic status, insurance status, childcare, social support, housing, and immigration status.

Non-mammals
In viviparous animals, the embryo develops inside the body of the mother, as opposed to outside in an egg (oviparity). The mother then gives live birth. The less developed form of viviparity is called ovoviviparity, in which the mother carries embryos inside eggs. Most vipers exhibit ovoviviparity. The more developed form of viviparity is called placental viviparity; mammals are the best example, but it has also evolved independently in other animals, such as in scorpions, some sharks, and in velvet worms </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 Azoospermia and can you explain it in depth? [/INST] Azoospermia is the medical condition of a man whose semen contains no sperm. It is associated with male infertility, but many forms are amenable to medical treatment. In humans, azoospermia affects about 1% of the male population and may be seen in up to 20% of male infertility situations in Canada.In a non-pathological context, azoospermia is also the intended result of a successful vasectomy.

Classification
Azoospermia can be classified into three major types as listed. Many conditions listed may also cause various degrees of oligospermia rather than azoospermia. Pretesticular and testicular azoospermia are known as non-obstructive azoospermia, whereas post-testicular azoospermia is considered obstructive.

Pretesticular
Pretesticular azoospermia is characterized by inadequate stimulation of otherwise normal testicles and genital tract. Typically, follicle-stimulating hormone (FSH) levels are low (hypogonadotropic) commensurate with inadequate stimulation of the testes to produce sperm. Examples include hypopituitarism (for various causes), hyperprolactinemia, and exogenous FSH suppression by testosterone. Chemotherapy may suppress spermatogenesis. Pretesticular azoospermia is seen in about 2% of azoospermia. Pretesticular azoospermia is a kind of non-obstructive azoospermia.

Testicular
Testicular azoospermia means the testes are abnormal, atrophic, or absent, and sperm production severely disturbed to absent. FSH levels tend to be elevated (hypergonadotropic) as the feedback loop is interrupted (lack of feedback inhibition on FSH). The condition is seen in 49–93% of men with azoospermia. Testicular failure includes absence of failure production and low production and maturation arrest during the process of spermatogenesis.
Causes for testicular failure include congenital issues such as in certain genetic conditions (e.g. Klinefelter syndrome), some cases of cryptorchidism or Sertoli cell-only syndrome as well as acquired conditions by infection (orchitis), surgery (trauma, cancer), radiation, or other causes. Mast cells releasing inflammatory mediators appear to directly suppress sperm motility in a potentially reversible manner, and may be a common pathophysiological mechanism for many causes leading to inflammation. Testicular azoospermia is a kind of non-obstructive azoospermia.
Generally, men with unexplained hypergonadotropic azoospermia need to undergo a chromosomal evaluation.

Post-testicular
In post-testicular azoospermia, sperm are produced but not ejaculated, a condition that affects 7–51% of azoospermic men. The main cause is a physical obstruction (obstructive azoospermia) of the post-testicular genital tracts. The most common reason is a vasectomy done to induce contraceptive sterility. Other obstructions can be congenital (for example, agenesis of the vas deferens as seen in certain cases of cystic fibrosis) or acquired, such as ejaculatory duct obstruction for instance by infection.
Ejaculatory disorders include retrograde ejaculation and anejaculation; in these conditions sperm are produced but not expelled.

Unknown
Idiopathic azoospermia is where there is no known cause of the condition. It may be a result of multiple risk factors, such as age and weight. For example, a review in 2013 came to the result that oligospermia and azoospermia are significantly associated with being overweight (odds ratio 1.1), obese (odds ratio 1.3) and morbidly obese (odds ratio 2.0), but the cause of this is unknown. The review found no significant relation between oligospermia and being underweight.

Genetics
Genetic factors can cause  pretesticular, testicular, and post-testicular azoospermia  (or oligospermia)  and include the following situations: The frequency of chromosomal abnormalities is inversely proportional to the semen count, thus males with azoospermia are at risk to have a 10–15% (other sources citing 15–20% incidence) abnormalities on karyotyping versus about <1 % in the fertile male population.Pretesticular azoospermia may be caused by congential hypopituitarism, Kallmann syndrome, Prader-Willi syndrome and other genetic conditions that lead to GnRH or gonadotropin deficiency.
Testicular azoospermia is seen in Klinefelter syndrome (XXY) and the XX male syndrome.  In addition, 13% of men with azoospermia have a defective spermatogenesis that is linked to defects of the Y chromosome. Such defects tend to be de novo micro-deletions and affect usually the long arm of the chromosome. A section of the long arm of the Y chromosome has been termed Azoospermia Factor (AZF) at Yq11 and subdivided into AZFa, AZFb,  AZFc and possibly more subsections. Defects in this area can lead to oligospermia or azoospermia, however, a tight genotype-phenotype correlation has not been achieved.
Spermatogenesis is defective with gene defects for the androgen receptor.Post-testicular azoospermia can be seen with certain point mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene commonly associated with congenital vas deferens abnormalities.Genetic counselling is indicated for men with genetic causes of azoospermia. In terms of reproduction, it needs to be considered if the genetic defect could be transmitted to the offspring.

BRD7
BRD7, a transcription regulatory protein, is normally highly expressed in the testis.  Absent or reduced expression of BRD7 protein was observed in the testes of azoospermia patients exhibiting spermatogenesis arrest.  Homozygous knockout mice [BRD7(-/-)] are infertile and have higher levels of apoptosis and DNA damage in their germline cells.

Gene polymorphisms
The human breast cancer susceptibility gene 2 (BRCA2) is employed in DNA repair.  A common single nucleotide polymorphism in BRCA2 is associated with idiopathic male infertility with azoospermia.Four genes involved in DNA double-strand break repair and chromosome synapsis (TEX11, TEX15, MLH1 and MLH3) have key roles in genomic integrity, meiotic recombination and gametogenesis. Polymorphisms in these genes were tested for associations with male infertility.  Single nucleotide polymorphisms in two of these genes (TEX11 and MLH3) were found to be associated with male infertility involving azoospermy or oligospermia.

Diagnosis
Azoospermia is usually detected in the course of an infertility investigation. It is established on the basis of two semen analysis evaluations done at separate occasions (when the seminal specimen after centrifugation shows no sperm under the microscope) and requires a further work-up.The investigation includes a history, a physical examination including a thorough evaluation of the scrotum and testes, laboratory tests, and possibly imaging. History includes the general health, sexual health, past fertility, libido, and sexual activity. Past exposure to a number of agents needs to be queried including medical agents like hormone/steroid therapy, antibiotics, 5-ASA inhibitors (sulfasalazine), alpha-blockers, 5 alpha-reductase inhibitors, chemotherapeutic agents, pesticides, recreational drugs (marijuana, excessive alcohol), and heat exposure of the testes. A history of surgical procedures of the genital system needs to be elicited. The family history needs to be assessed to look for genetic abnormalities.Congenital absence of the vas deferens may be detectable on physical examination and can be confirmed by a transrectal ultrasound (TRUS). If confirmed, genetic testing for cystic fibrosis is in order. Transrectal ultrasound can also assess azoospermia caused by obstruction, or anomalies related to obstruction of the ejaculatory duct, such as abnormalities within the duct itself, a median cyst of the prostate (indicating a need for cyst aspiration), or an impairment of the seminal vesicles to become enlarged or emptied.
Retrograde ejaculation is diagnosed by examining a post-ejaculatory urine for presence of sperm after making it alkaline and centrifuging it.Low levels of LH and FSH with low or normal testosterone levels are indicative of pretesticular problems, while high levels of gonadotropins indicate testicular problems.  However, often this distinction is not clear and the differentiation between obstructive versus non-obstructive azoospermia may require a testicular biopsy. On the other hand, "In azoospermic men with a normal ejaculate volume, FSH serum level greater than two times the upper limit of the normal range is reliably diagnostic of dysfunctional spermatogenesis and, when found, a diagnostic testicular biopsy is usually unnecessary, although no consensus exists in this matter." Extremely high levels of FSH (>45 ID/mL) have been correlated with successful microdissection testicular sperm extraction.Serum inhibin-B weakly indicates presence of sperm cells in the testes, raising chances for successfully achieving pregnancy through testicular sperm extraction (TESE), although the association is not very substantial, having a sensitivity of 0.65 (95% confidence interval [CI]: 0.56–0.74) and a specificity of 0.83 (CI: 0.64–0.93) for prediction the presence of sperm in the testes in non-obstructive azoospermia.Seminal plasma proteins TEX101 and ECM1 were recently proposed for the differential diagnosis of azoospermia forms and subtypes, and for prediction of TESE outcome. Mount Sinai Hospital, Canada started clinical trial to test this hypothesis in 2016.Primary hypopituitarism may be linked to a genetic cause </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 Sex therapy and can you explain it in depth? [/INST] Sex therapy is a strategy for the improvement of sexual function and treatment of sexual dysfunction. This includes sexual dysfunctions such as premature ejaculation or delayed ejaculation, erectile dysfunction, lack of sexual interest or arousal, and painful sex (vaginismus and dyspareunia), as well as dealing with problems imposed by atypical sexual interests (paraphilias), gender dysphoria and being transgender, highly overactive libido or hypersexuality, a lack of sexual confidence, recovering from sexual abuse such as rape or sexual assault, and sexual issues related to aging, illness, or disability.

Practice
Modern sex therapy often integrates psychotherapeutic techniques and medical ones, such as Viagra (sildenafil) and Cialis (tadalafil) to increase erectile response and Paxil (paroxetine) to treat premature ejaculation.  Sex therapists assist those experiencing problems in overcoming them, in doing so possibly regaining an active sex life.  The transformative approach to sex therapy aims to understand the psychological, biological, pharmacological, relational, and contextual aspects of sexual problems.Sex therapy requires rigorous evaluation that includes a medical and psychological examination. The reason is that sexual dysfunction may have a somatic base or a psychogenic basis. A clear example is erectile dysfunction (sometimes still called "impotence"), whose causes may include circulatory problems and performance anxiety. Sex therapy is frequently short term, with duration depending on the causes for therapy.Sex therapy can be provided by licensed psychologists or physicians, who have undergone training and become certified. These trainings and certifications usually begin with a masters degree, and internship, and a license. This can take up to 2 years, and longer if a doctorates degree is desired.
Sex therapy is distinct from sex surrogates.  Whereas sex therapists discuss and instruct clients in sex-based exercises to be performed at home between sessions, sexual surrogates participate in the exercises with their clients as part of helping them to practice and develop improved skills.  Therapists and surrogates sometimes collaborate on cases.  Certified sex therapists do not have sexual contact with their clients.

Symptoms
Sex therapy sessions are focused on the individuals symptoms rather than on underlying psychodynamic conflicts. The sexual dysfunctions which may be addressed by sex therapy include non-consummation, premature ejaculation, erectile dysfunction, low libido, unwanted sexual fetishes, sexual addiction, painful sex, or a lack of sexual confidence, assisting people who are recovering from sexual assault, problems commonly caused by stress, tiredness, and other environmental and relationship factors. Sex therapy can either be on an individual basis or with the sex partner. Sex therapy can be conducted with any adult client, including older adults, any gender expression, and LGBTQ-identified people.A therapists misunderstanding of these conflicts can lead to resistance or serve as a barrier to improving sexual dysfunctions that are directly or indirectly related to sex. The interest in sex therapy among couples has increased along with the number of sexuality educators, counselors, and therapists. Today, sexual problems are no longer regarded as symptoms of hidden deviant, pathological, or psychological defects in maturity or development. Sex therapy has also influenced the emergence of sexual medicine and exploring integrative approaches to sex therapy, in addition to reducing or eliminating sexual problems and increasing sexual satisfaction for individuals of all stages of life. Health therapists, educators, and counselors are conducting research and administering surveys to fully understand normative sexual function – what most people do and experience as they grow older and live longer.

Aging and sexuality
Both physical and emotional transformation throughout various stages of life can affect the body and sexuality. The subsequent decline in hormone levels and changes in neurological and circulatory functioning may lead to sexual problems such as erectile dysfunction or vaginal pain. These physical changes often affect the intensity of youthful sex and may give way to more subdued responses during middle and later life. Issues with low libido and sexual dysfunction are usually considered to be a byproduct of old age. The emotional byproducts of maturity, however — increased confidence, better communication skills, and lessened inhibitions — can help create a richer, more nuanced, and ultimately satisfying sexual experience. During AARPs last surveys in 1999, 2004, and 2009 statistics show well-being among older adults has increased; however, overall sexual satisfaction has decreased. Nevertheless, older adults believed that an active sexual life offers great pleasure and contributes materially to overall emotional and physical health.

Older adults
Over the years, little attention has been paid to older adults and sexuality. As the population of older adults and life expectancy continue to grow, there is information about sex therapy but it is often not easily accepted. Cultural and sexual roles are always changing throughout the life-course. As people age, they are often viewed as asexual or as incapable of possessing sexual desires. The presence of sexual dysfunction during old age can be impacted by health problems. There are many endocrine, vascular and neurological disorders that may interfere in sexual function, along with some medications and surgeries. Older men experience changes that occur in sexual physiology and affect both erectile function and ejaculation. While older women experience physiological effects of aging after menopause, resulting in the decreased production of estrogen. This leads to increased vaginal dryness, general atrophy of vaginal tissue, and genital changes (reduced size of clitoral, vulvar, and labial tissue). Cognitive changes and decline is another factor that influences sexual activity. Dementia, Alzheimers and mental health disorders may have an effect on sexual behavior, producing disinhibition or relationship difficulties with subsequent effects on couples sexual relationships.Sex therapy with older adults looks at factors which influence sexuality in older adults, including sexual desire, sexual activity, the value of sexuality, and health. It can include sensate focus, communication, and fantasy exercises as well as psychodynamic therapy.Sex therapy for older adults is similar to sex therapy with other populations. It includes the use of water-based personal lubricants (for decreased vaginal lubrication), hormone therapy, and medications. Sex therapists working with older adults should know about sexuality and aging. They should also be aware of how stereotypes affect their clients. This is especially true for LGBT-identified clients.Older adults may also need more education about their sexuality and sexual functioning. Curriculum for this includes communication, masturbation, body image, and spirituality. It also teaches about talking to a doctor about sexual activity. It is optimal that sex education for older adults includes information about sexually transmitted infections (STDs/STIs), such as HIV/AIDS.

History
Sex therapy has existed in different cultures throughout time, including ancient India, China, Greece, and Rome. It has taken the form of manuals, spells, anaphrodisiacs or aphrodisiacs, and tantric yoga, among others. Much of sex therapy and sexual dysfunction in Western cultures was limited to scientific discussion, especially throughout the 19th century and into the early 20th century.Sexologists such as Henry Havelock Ellis and Alfred Kinsey began conducting research in the area of human sexuality during the first half of the 20th century </s>


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<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 Paravaccinia virus and can you explain it in depth? [/INST] Pseudocowpox is a disease caused by the Paravaccinia virus or Pseudocowpox virus, a virus of the family Poxviridae and the genus Parapoxvirus.: 393  Humans can contract the virus from contact with livestock infected with Bovine papular stomatitis and the disease is common among ranchers, milkers, and veterinarians. Infection in humans will present with fever, fatigue, and lesion on the skin.

Signs and symptoms
Paravaccinia virus presents itself with blisters, nodules, or lesions about 4 mm in diameter, typically in the area that has made contact with livestock that is infected with bovine papular stomatitis. Lesions may begin forming as late as three weeks after contact has been made with an infected animal. In rare cases, lesions may be seen systemic. General signs of infection are also common, such as fever and fatigue.
Infected livestock may present with blisters or lesions on their udders or snout. Often, however, infected livestock show little to no symptoms.

Mechanism
Paravaccinia is a member of the Parapoxvirus family. It has a cylindrical body about 140 X 310 nm in size, with convex ends covered in a criss-cross pattern of rope like structures. The virus is resistant to cold, dehydration, and temperatures up to 56 °C. Upon injecting a cell with its genome, the virus begins transcription in the cytoplasm using viral RNA polymerase. As the virus progresses through the cell, the host begins to replicate the viral genome between 140 minutes and 48 hours.

Diagnosis
Diagnosis of paravaccinia virus will often come from Polymerase chain reaction screening ordered by their physician. However, due to how common paravaccinia virus is in rural areas, individuals typically do not seek professional help in diagnosis. Instead individuals may refer to people with local knowledge of the cattle in their area such as ranchers, or veterinarians who have some familiarity with the infections in the region.It may appear similar to cowpox and orf.

Cause and prevention
Paravaccinia virus originates from livestock infected with bovine papular stomatitis. When a human makes physical contact with the livestocks muzzle, udders, or an infected area, the area of contact will become infected. Livestock may not show symptoms of bovine papular stomatitis and still be infected and contagious. Paravaccinia can enter the body though all pathways including: skin contact by mechanical means, through the respiratory tract, or orally. Oral or respiratory contraction may be more likely to cause systemic symptoms such as lesions across the whole bodyA person who has not previously been infected with paravaccinia virus should avoid contact with infected livestock to prevent contraction of disease. There is no commercially available vaccination for cattle or humans against paravaccinia. However, following infection, immunization has been noted in humans, making re-infection difficult. Unlike other pox viruses, there is no record of contracting paravaccinia virus from another human. Further, cattle only show a short immunization after initial infection, providing opportunity to continue to infect more livestock and new human hosts.

Treatment and prognosis
Lesions of paravaccinia virus will clear up with little to no scarring after 4 to 8 weeks </s>


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<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 Non-Hodgkin lymphoma and can you explain it in depth? [/INST] Non-Hodgkin lymphoma (NHL), also known as non-Hodgkins lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredness. Other symptoms may include bone pain, chest pain, or itchiness. Some forms are slow-growing while others are fast-growing.Lymphomas are types of cancer that develop from lymphocytes, a type of white blood cell. Risk factors include poor immune function, autoimmune diseases, Helicobacter pylori infection, hepatitis C, obesity, and Epstein–Barr virus infection. The World Health Organization  classifies lymphomas into five major groups, including one for Hodgkin lymphoma. Within the four groups for NHL are over 60 specific types of lymphoma. Diagnosis is by examination of a bone marrow or lymph node biopsy. Medical imaging is done to help with cancer staging.Treatment depends on whether the lymphoma is slow- or fast-growing and if it is in one area or many areas. Treatments may include chemotherapy, radiation, immunotherapy, targeted therapy, stem-cell transplantation, surgery, or watchful waiting. If the blood becomes overly thick due to high numbers of antibodies, plasmapheresis may be used. Radiation and some chemotherapy, however, increase the risk of other cancers, heart disease, or nerve problems over the subsequent decades.In 2015, about 4.3 million people had non-Hodgkin lymphoma, and 231,400 (5.4%) died. In the United States, 2.1% of people are affected at some point in their life. The most common age of diagnosis is between 65 and 75 years old. The five-year survival rate in the United States is 71%.

Signs and symptoms
The signs and symptoms of non-Hodgkin lymphoma vary depending upon its location within the body. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredness. Other symptoms may include bone pain, chest pain, or itchiness. Some forms are slow growing, while others are fast growing. Enlarged lymph nodes may cause lumps to be felt under the skin when they are close to the surface of the body. Lymphomas in the skin may also result in lumps, which are commonly itchy, red, or purple. Lymphomas in the brain can cause weakness, seizures, problems with thinking, and personality changes.While an association between non-Hodgkin lymphoma and endometriosis has been described, these associations are tentative.

Causes
The many different forms of lymphoma probably have different causes. These possible causes and associations with at least some forms of NHL include:

Infectious agents:
Epstein–Barr virus: associated with Burkitts lymphoma, follicular dendritic cell sarcoma, extranodal NK-T-cell lymphoma and diffuse large B-cell lymphoma.
Human T-cell leukemia virus: associated with adult T-cell lymphoma.
Helicobacter pylori: associated with gastric lymphoma.
HHV-8: associated with primary effusion lymphoma, multicentric Castleman disease.
Hepatitis C virus: associated with splenic marginal zone lymphoma, lymphoplasmacytic lymphoma and diffuse large B-cell lymphoma.
HIV infection.
Some chemicals, like polychlorinated biphenyls (PCBs), diphenylhydantoin, dioxin, and phenoxy herbicides.
Medical treatments, like radiation therapy and chemotherapy.
Genetic diseases, like Klinefelter syndrome, Chédiak–Higashi syndrome, ataxia–telangiectasia syndrome.
Autoimmune diseases, like Sjögren syndrome, celiac disease, rheumatoid arthritis, and systemic lupus erythematosus.
Bone trauma and microfractures associated with diffuse large B-cell lymphoma originating in bone marrow.
Implants, made from hard metals or silicone, associated with anaplastic large cell lymphoma.

Familial component
Familial lymphoid cancer is rare. The familial risk of lymphoma is elevated for multiple lymphoma subtypes, suggesting a shared genetic cause. However, a family history of a specific subtype is most strongly associated with risk for that subtype, indicating that these genetic factors are subtype-specific. Genome-wide association studies  have successfully identified 67 single-nucleotide polymorphisms  from 41 loci, most of which are subtype specific.

HIV/AIDS
The Centers for Disease Control and Prevention (CDC) included certain types of non-Hodgkin lymphoma as AIDS-defining cancers in 1987. Immune suppression rather than HIV itself is implicated in the pathogenesis of this malignancy, with a clear correlation between the degree of immune suppression and the risk of developing NHL. Additionally, other retroviruses, such as HTLV, may be spread by the same mechanisms that spread HIV, leading to an increased rate of co-infection. The natural history of HIV infection has greatly changed over time. As a consequence, rates of non-Hodgkin lymphoma (NHL) in people infected with HIV has significantly declined in recent years.

Treatment
The traditional treatment of NHL includes chemotherapy, radiotherapy, and stem-cell transplants. There have also been developments in immunotherapy used in the treatment of NHL.

Chemotherapy
The most common chemotherapy used for B-cell non-Hodgkin lymphoma is R-CHOP, which is a regimen of four drugs (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus rituximab.

Treatment complications
If participants receive stem-cell transplants, they can develop a graft-versus-host disease. When compared with placebo for treating immune mediated inflammation post transplantation and in autoimmunity, mesenchymal stromal cells (MSCs) may reduce the all-cause mortality if they are used for a therapeutic reason. Moreover, the therapeutic use of MSCs may increase the complete response of acute and chronic GvHD, but the evidence is very uncertain. The evidence suggests that MSCs for prophylactic reason result in little to no difference in the all-cause mortality, in the relapse of malignant diseases, and in the incidence of acute GvHD. The evidence suggests that MSCs for prophylactic reason reduce the incidence of chronic GvHD.Platelet transfusions may be necessary for those who receive chemotherapy or undergo a stem cell transplantation due to the higher risk for bleeding. When comparing therapeutic/non-prophylactic platelet transfusions to prophylactic platelet transfusions there is little to no difference in the mortality secondary to bleeding and they may result in a slight reduction in the number of days on which a significant bleeding event occurred. The evidence suggests that therapeutic platelet transfusions result in a large increase in the number of people with at least one significant bleeding event and they likely result in a large reduction in the number of platelet transfusions.

Other
It is unclear if including aerobic physical exercise, in addition to the standard treatment for adult patients with haematological malignancies, is effective at reducing anxiety and serious adverse effects. Aerobic physical exercises may result in little to no difference in the mortality, in the quality of life and in the physical functioning. These exercises may result in a slight reduction in depression and most likely reduce fatigue.

Prognosis
Prognosis depends on the subtype, the staging, a persons age, and other factors. Across all subtypes, 5-year survival for NHL is 71%, ranging from 81% for Stage 1 disease to 61% for Stage 4 disease.

Epidemiology
Globally, as of 2010, there were 210,000 deaths, up from 143,000 in 1990.Rates of non-Hodgkin lymphoma increase steadily with age. Up to 45 years NHL is more common among males than females.

Australia
With over 6,000 people being diagnosed yearly, NHL is the fifth most common cancer in Australia.

Canada
In Canada NHL is the fifth most common cancer in males and sixth most common cancer in females. The lifetime probability of developing a lymphoid cancer is 1 in 44 for males, and 1 in 51 for females.

United Kingdom
On average, according to data for the 2014–2016 period, around 13,900 people are diagnosed with NHL yearly </s>


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<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 Humerus and can you explain it in depth? [/INST] The humerus (; pl. humeri) is a long bone in the arm that runs from the shoulder to the elbow. It connects the scapula and the two bones of the lower arm, the radius and ulna, and consists of three sections. The humeral upper extremity consists of a rounded head, a narrow neck, and two short processes (tubercles, sometimes called tuberosities). The body is cylindrical in its upper portion, and more prismatic below. The lower extremity consists of 2 epicondyles, 2 processes (trochlea & capitulum), and 3 fossae (radial fossa, coronoid fossa, and olecranon fossa). As well as its true anatomical neck, the constriction below the greater and lesser tubercles of the humerus is referred to as its surgical neck due to its tendency to fracture, thus often becoming the focus of surgeons.

Etymology
The word "humerus" is derived from Latin: humerus, umerus meaning upper arm, shoulder, and is linguistically related to Gothic ams shoulder and Greek ōmos.

Structure
Upper extremity
The upper or proximal extremity of the humerus consists of the bones large rounded head joined to the body by a constricted portion called the neck, and two eminences, the greater and lesser tubercles.

Head
The head (caput humeri), is nearly hemispherical in form. It is directed upward, medialward, and a little backward, and articulates with the glenoid cavity of the scapula to form the glenohumeral joint (shoulder joint). The circumference of its articular surface is slightly constricted and is termed the anatomical neck, in contradistinction to a constriction below the tubercles called the surgical neck which is frequently the seat of fracture. Fracture of the anatomical neck rarely occurs.
The diameter of the humeral head is generally larger in men than in women.

Anatomical neck
The anatomical neck (collum anatomicum) is obliquely directed, forming an obtuse angle with the body. It is best marked in the lower half of its circumference; in the upper half it is represented by a narrow groove separating the head from the tubercles. The line separating the head from the rest of the upper end is called the anatomical neck. It affords attachment to the articular capsule of the shoulder-joint, and is perforated by numerous vascular foramina. Fracture of the anatomical neck rarely occurs.The anatomical neck of the humerus is an indentation distal to the head of the humerus on which the articular capsule attaches.

Surgical neck
The surgical neck is a narrow area distal to the tubercles that is a common site of fracture.  It makes contact with the axillary nerve and the posterior humeral circumflex artery.

Greater tubercle
The greater tubercle (tuberculum majus; greater tuberosity) is a large, posteriorly placed projection that is placed laterally. The greater tubercle is where supraspinatus, infraspinatus and teres minor muscles are attached. The crest of the greater tubercle forms the lateral lip of the bicipital groove and is the site for insertion of pectoralis major.
The greater tubercle is just lateral to the anatomical neck. Its upper surface is rounded and marked by three flat impressions: the highest of these gives insertion to the supraspinatus muscle; the middle to the infraspinatus muscle; the lowest one, and the body of the bone for about 2.5 cm. below it, to the teres minor muscle. The lateral surface of the greater tubercle is convex, rough, and continuous with the lateral surface of the body.

Lesser tubercle
The lesser tubercle (tuberculum minus; lesser tuberosity) is smaller, anterolaterally placed to the head of the humerus. The lesser tubercle provides insertion to subscapularis muscle. Both these tubercles are found in the proximal part of the shaft. The crest of the lesser tubercle forms the medial lip of the bicipital groove and is the site for insertion of teres major and latissimus dorsi muscles.
The lesser tuberosity, is more prominent than the greater: it is situated in front, and is directed medialward and forward. Above and in front it presents an impression for the insertion of the tendon of the subscapularis muscle.

Bicipital groove
The tubercles are separated from each other by a deep groove, the bicipital groove (intertubercular groove; bicipital sulcus), which lodges the long tendon of the biceps brachii muscle and transmits a branch of the anterior humeral circumflex artery to the shoulder-joint. It runs obliquely downward, and ends near the junction of the upper with the middle third of the bone. In the fresh state its upper part is covered with a thin layer of cartilage, lined by a prolongation of the synovial membrane of the shoulder-joint; its lower portion gives insertion to the tendon of the latissimus dorsi muscle. It is deep and narrow above, and becomes shallow and a little broader as it descends. Its lips are called, respectively, the crests of the greater and lesser tubercles (bicipital ridges), and form the upper parts of the anterior and medial borders of the body of the bone.

Shaft
The body or shaft of the humerus is triangular to cylindrical in cut section and is compressed anteroposteriorly. It has 3 surfaces, namely:

Anterolateral surface: the area between the lateral border of the humerus to the line drawn as a continuation of the crest of the greater tubercle. The antero-lateral surface is directed lateralward above, where it is smooth, rounded, and covered by the deltoid muscle; forward and lateralward below, where it is slightly concave from above downward, and gives origin to part of the Brachialis. About the middle of this surface is a rough, rectangular elevation, the deltoid tuberosity for the insertion of the deltoid muscle; below this is the radial sulcus, directed obliquely from behind, forward, and downward, and transmitting the radial nerve and profunda artery.
Anteromedial surface: the area between the medial border of the humerus to the line drawn as a continuation of the crest of the greater tubercle. The antero-medial surface, less extensive than the antero-lateral, is directed medialward above, forward and medialward below; its upper part is narrow, and forms the floor of the intertubercular groove which gives insertion to the tendon of the latissimus dorsi muscle; its middle part is slightly rough for the attachment of some of the fibers of the tendon of insertion of the coracobrachialis muscle; its lower part is smooth, concave from above downward, and gives origin to the brachialis muscle.
Posterior surface: the area between the medial and lateral borders. The posterior surface appears somewhat twisted, so that its upper part is directed a little medialward, its lower part backward and a little lateralward. Nearly the whole of this surface is covered by the lateral and medial heads of the Triceps brachii, the former arising above, the latter below the radial sulcus.Its three borders are:

Anterior: the anterior border runs from the front of the greater tubercle above to the coronoid fossa below, separating the antero-medial from the antero-lateral surface. Its upper part is a prominent ridge, the crest of the greater tubercle; it serves for the insertion of the tendon of the pectoralis major muscle. About its center it forms the anterior boundary of the deltoid tuberosity, on which the deltoid muscle attaches; below, it is smooth and rounded, affording attachment to the brachialis muscle.
Lateral: the lateral border runs from the back part of the greater tubercle to the lateral epicondyle, and separates the anterolateral from the posterior surface. Its upper half is rounded and indistinctly marked, serving for the attachment of the lower part of the insertion of the teres minor muscle, and below this giving origin to the lateral head of the triceps brachii muscle; its center is traversed by a broad but shallow oblique depression, the spiral groove (musculospiral groove). The radial nerve runs in the spiral groove.  Its lower part forms a prominent, rough margin, a little curved from backward, forward the lateral supracondylar ridge, which presents an anterior lip for the origin of the brachioradialis muscle above, and extensor carpi radialis longus muscle above, a posterior lip for the triceps brachii muscle, and an intermediate ridge for the attachment of the lateral intermuscular septum.
Medial: the medial border extends from the lesser tubercle to the medial epicondyle. Its upper third consists of a prominent ridge, the crest of the lesser tubercle, which gives insertion to the tendon of the teres major muscle. About its center is a slight impression for the insertion of the coracobrachialis muscle, and just below this is the entrance of the nutrient canal, directed downward; sometimes there is a second nutrient canal at the commencement of the radial sulcus. The inferior third of this border is raised into a slight ridge, the medial supracondylar ridge, which became very prominent below; it presents an anterior lip for the origins of the brachialis muscle and the pronator teres muscle, a posterior lip for the medial head of the triceps brachii muscle, and an intermediate ridge for the attachment of the medial intermuscular septum.

The Deltoid tuberosity is a roughened surface on the lateral surface of the shaft of the Humerus and acts as the site of insertion of deltoideus muscle. The posterorsuperior part of the shaft has a crest, beginning just below the surgical neck of the humerus and extends till the superior tip of the deltoid tuberosity. This is where the lateral head of triceps brachii  is attached.

The radial sulcus, also known as the spiral groove is found on the posterior surface of the shaft and is a shallow oblique groove through which the radial nerve passes along with deep vessels. This is located posteroinferior to the deltoid tuberosity. The inferior boundary of the spiral groove is continuous distally with the lateral border of the shaft.

The nutrient foramen of the humerus is located in the anteromedial surface of the humerus. The nutrient arteries enter the humerus through this foramen.

Distal humerus
The distal or lower extremity of the humerus is flattened from before backward, and curved slightly forward; it ends below in a broad, articular surface, which is divided into two parts by a slight ridge. Projecting on either side are the lateral and medial epicondyles.

Articular surface
The articular surface extends a little lower than the epicondyles, and is curved slightly forward; its medial extremity occupies a lower level than the lateral. The lateral portion of this surface consists of a smooth, rounded eminence, named the capitulum of the humerus; it articulates with the cup-shaped depression on the head of the radius, and is limited to the front and lower part of the bone.

Fossae
Above the front part of the trochlea is a small depression, the coronoid fossa, which receives the coronoid process of the ulna during flexion of the forearm.
Above the back part of the trochlea is a deep triangular depression, the olecranon fossa, in which the summit of the olecranon is received in extension of the forearm.

The coronoid fossa is the medial hollow part on the anterior surface of the distal humerus. The coronoid fossa is smaller than the olecranon fossa and receives the coronoid process of the ulna during maximum flexion of the elbow.

Above the front part of the capitulum is a slight depression, the radial fossa, which receives the anterior border of the head of the radius, when the forearm is flexed.

These fossæ are separated from one another by a thin, transparent lamina of bone, which is sometimes perforated by a supratrochlear foramen; they are lined in the fresh state by the synovial membrane of the elbow-joint, and their margins afford attachment to the anterior and posterior ligaments of this articulation.
The Capitulum is a rounded eminence forming the lateral part of the distal humerus. The head of the radius articulates with the capitulum.

The trochlea is spool-shaped medial portion of the distal humerus and articulates with the ulna.

Epicondyles
The epicondyles are continuous above with the supracondylar ridges.

The lateral epicondyle is a small, tuberculated eminence, curved a little forward, and giving attachment to the radial collateral ligament of the elbow-joint, and to a tendon common to the origin of the Supinator and some of the Extensor muscles.
The medial epicondyle, larger and more prominent than the lateral, is directed a little backward; it gives attachment to the ulnar collateral ligament of the elbow-joint, to the Pronator teres, and to a common tendon of origin of some of the Flexor muscles of the forearm; the ulnar nerve runs in a groove on the back of this epicondyle.

The Medial supracondylar crest forms the sharp medial border of the distal humerus continuing superiorly from the medial epicondyle. The Lateral Supracondylar crest forms the sharp lateral border of the distal humerus continuing superiorly from the lateral epicondyle.

Borders
The medial portion of the articular surface is named the trochlea, and presents a deep depression between two well-marked borders; it is convex from before backward, concave from side to side, and occupies the anterior, lower, and posterior parts of the extremity.

The lateral border separates it from the groove which articulates with the margin of the head of the radius.
The medial border is thicker, of greater length, and consequently more prominent, than the lateral.The grooved portion of the articular surface fits accurately within the semilunar notch of the ulna; it is broader and deeper on the posterior than on the anterior aspect of the bone, and is inclined obliquely downward and forward toward the medial side.

Articulations
At the shoulder, the head of the humerus articulates with the glenoid fossa of the scapula. More distally, at the elbow, the capitulum of the humerus articulates with the head of the radius, and the trochlea of the humerus articulates with the trochlear notch of the ulna.

Nerves
The axillary nerve is located at the proximal end, against the shoulder girdle. Dislocation of the humeruss glenohumeral joint has the potential to injure the axillary nerve or the axillary artery. Signs and symptoms of this dislocation include a loss of the normal shoulder contour and a palpable depression under the acromion.
The radial nerve follows the humerus closely. At the midshaft of the humerus, the radial nerve travels from the posterior to the anterior aspect of the bone in the spiral groove. A fracture of the humerus in this region can result in radial nerve injury.
The ulnar nerve lies at the distal end of the humerus near the elbow. When struck, it can cause a distinct tingling sensation, and sometimes a significant amount of pain. It is sometimes popularly referred to as the funny bone, possibly due to this sensation (a "funny" feeling), as well as the fact that the bones name is a homophone of humorous. It lies posterior to the medial epicondyle, and is easily damaged in elbow injuries.

Function
Muscular attachment
The deltoid originates on the lateral third of the clavicle, acromion and the crest of the spine of the scapula. It is inserted on the deltoid tuberosity of the humerus and has several actions including abduction, extension, and circumduction of the shoulder. The supraspinatus also originates on the spine of the scapula. It inserts on the greater tubercle of the humerus, and assists in abduction of the shoulder.
The pectoralis major, teres major, and latissimus dorsi insert at the intertubercular groove of the humerus. They work to adduct and medially, or internally, rotate the humerus.
The infraspinatus and teres minor insert on the greater tubercle, and work to laterally, or externally, rotate the humerus. In contrast, the subscapularis muscle inserts onto the lesser tubercle and works to medially, or internally, rotate the humerus.
The biceps brachii, brachialis, and brachioradialis (which attaches distally) act to flex the elbow. (The biceps do not attach to the humerus.) The triceps brachii and anconeus extend the elbow, and attach to the posterior side of the humerus.
The four muscles of supraspinatus, infraspinatus, teres minor and subscapularis form a musculo-ligamentous girdle called the rotator cuff. This cuff stabilizes the very mobile but inherently unstable glenohumeral joint. The other muscles are used as counterbalances for the actions of lifting/pulling and pressing/pushing.

Other animals
Primitive fossils of amphibians had little, if any, shaft connecting the upper and lower extremities, making their limbs very short </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 Acanthamoeba and can you explain it in depth? [/INST] Acanthamoeba is a genus of amoebae that are commonly recovered from soil, fresh water, and other habitats.
Acanthamoeba has two evolutive forms, the metabolically active trophozoite and a dormant, stress-resistant cyst. Trophozoites are small, usually 15 to 25 μm in length and amoeboid in shape. In nature, Acanthamoeba species are free-living bacterivores, but in certain situations, they can cause infections (acanthamebiasis) in humans and other animals.

Distribution
Acanthamoeba spp. are among the most prevalent protozoa found in the environment. They are distributed worldwide, and have been isolated from soil, air, sewage, seawater, chlorinated swimming pools, domestic tap water, bottled water, dental treatment units, hospitals, air-conditioning units, and contact lens cases. Additionally, they have been isolated from human skin, nasal cavities, throats, and intestines, as well as plants and other mammals.

Role in disease
Diseases caused by Acanthamoeba include keratitis and granulomatous amoebic encephalitis
(GAE). The latter is often but not always seen in immunosuppressed patients. GAE is caused by the amoebae entering the body through an open wound and then spreading to the brain. The combination of host immune responses and secreted amoebal proteases causes massive brain swelling resulting in death in about 95% of those infected.

Granulomatous amoebic encephalitis (GAE)
Granulomatous amoebic encephalitis (GAE) is caused by amoebic infection of the central nervous system (CNS). It is characterized by neurological symptoms including headache, seizures, and mental-status abnormalities. These worsen progressively over weeks to months, leading to death in most patients. Infection is generally associated with underlying conditions such as immunodeficiency, diabetes, malignancies, malnutrition, systemic lupus erythematosus, and alcoholism. The parasite enters the body through cuts in the skin or by being inhaled into the upper respiratory tract. The parasite then spreads through the blood into the CNS. Acanthamoeba crosses the blood–brain barrier by means that are not yet understood. Subsequent invasion of the connective tissue and induction of pro-inflammatory responses leads to neuronal damage that can be fatal within days. Pure granulomatous lesions are rare in patients with AIDS and other related immunodeficiency states, as the patients do not have adequate numbers of CD+ve T-cells to mount a granulomatous response to Acanthamoeba infection in CNS and other organs and tissues. A perivascular cuffing with amoebae in necrotic tissue is usual finding in the AIDS and related T-cell immunodeficiency conditions.
Brain biopsy normally reveals severe oedema and hemorrhagic necrosis. A patient who has contracted this illness usually displays subacute symptoms, including altered mental status, headaches, fever, neck stiffness, seizures, and focal neurological signs (such as cranial nerve palsies and coma), all leading to death within one week to several months. Due to the rarity of this parasite and a lack of knowledge, no good diagnoses or treatments for Acanthamoeba infection are now known. Acanthamoeba keratitis cases in the past have resolved from a therapy consisting of atropine and some other drugs with no antimicrobial effects. Recent publications show atropine to interfere with the protists CHRM1 receptor, causing cell death.Infection usually mimics that of bacterial leptomeningitis, tuberculous meningitis, or viral encephalitis. The misdiagnosis often leads to erroneous, ineffective treatment. In the case that the Acanthamoeba is diagnosed correctly, the current treatments, such as amphotericin B, rifampicin, trimethoprim-sulfamethoxazole, ketoconazole, fluconazole, sulfadiazine, or albendazole, are only tentatively successful. Correct and timely diagnosis, as well as improved treatment methods and an understanding of the parasite, are important factors in improving the outcome of infection by Acanthamoeba. A paper published in 2013 has shown substantial effects of some FDA-approved drugs with an in vitro kill rate above 90%. These results were in vitro effects, but as the drugs are already approved, human infections can be targeted after dose calculations in clinical trials done with these diverse groups of drugs.

Acanthamoebic keratitis
When present in the eye, Acanthamoeba strains can cause acanthamoebic keratitis, which may lead to corneal ulcers or even blindness. This condition occurs most often among contact lens wearers who do not properly disinfect their lenses, exacerbated by a failure to wash hands prior to handling the lenses.  Multipurpose contact lens solutions are largely ineffective against Acanthamoeba, whereas hydrogen peroxide-based solutions have good disinfection characteristics.The first cure of a corneal infection was achieved in 1985 at Moorfields Eye Hospital.In May 2007, Advanced Medical Optics, manufacturer of Complete Moisture Plus Contact Lens Solution products, issued a voluntary recall of their Complete Moisture Plus solutions.  The fear was that contact lens wearers who used their solution were at higher risk of acanthamoebic keratitis than contact lens wearers who used other solutions.  The manufacturer recalled the product after the Centers for Disease Control in the United States found that 21 people had possibly received an Acanthamoeba infection after using Complete Moisture Plus in the month prior to diagnosis.

As a bacterial reservoir
Several species of bacteria that can cause human disease are also able to infect and replicate within Acanthamoeba species. These include Legionella pneumophila, Pseudomonas aeruginosa, and some strains of Escherichia coli and Staphylococcus aureus. For some of these bacteria, replication inside Acanthamoeba has been associated with enhanced growth in macrophages, and increased resistance to some antibiotics. Furthermore, due to the high prevalence of Acanthamoeba in the environment, these amoebae have been proposed to serve as an environmental reservoir for some human pathogens.

Ecology
A. castellanii can be found at high densities in various soil ecosystems. It preys on bacteria, but also fungi and other protozoa.
This species is able to lyse bacteria and produce a wide range of enzymes, such as cellulases or chitinases, and probably contributes to the breakdown of organic matter in soil, contributing to the microbial loop.

Physiology
Role as a model organism
Because Acanthamoeba does not differ greatly at the ultrastructural level from a mammalian cell, it is an attractive model for cell-biology studies; it is important in cellular microbiology, environmental biology, physiology, cellular interactions, molecular biology, biochemistry, and evolutionary studies, due to the organisms versatile roles in the ecosystem and ability to capture prey by phagocytosis, act as vectors and reservoirs for microbial pathogens, and to produce serious human infections. In addition, Acanthamoeba has been used extensively to understand the molecular biology of cell motility and cancer cell dormancy by in-depth exploration of the process of encystation.The recently available Acanthamoeba genome sequence revealed several orthologs of genes employed in meiosis of sexual eukaryotes.  These genes included Spo11, Mre11, Rad50, Rad51, Rad52, Mnd1, Dmc1, Msh, and Mlh. This finding suggests that Acanthamoeba is capable of some form of meiosis and may be able to undergo sexual reproduction.  Furthermore, since Acanthamoeba diverged early from the eukaryotic family tree, these results suggest that meiosis was present early in eukaryotic evolution.
Owing to its ease and economy of cultivation, the Neff strain of A. castellanii, discovered in a pond in Golden Gate Park in the 1960s, has been effectively used as a classic model organism in the field of cell biology. From just 30 L of simple medium inoculated with A. castellanii, about 1 kg of cells can be obtained after several days of aerated culture at room temperature. Pioneered in the laboratory of Edward D. Korn at the National Institutes of Health (NIH), many important biological molecules have been discovered and their pathways elucidated using the Acanthamoeba model. Thomas Dean Pollard applied this model at the NIH, Harvard Medical School, Johns Hopkins University School of Medicine, and the Salk Institute for Biological Studies to discover and characterize many proteins that are essential for cell motility, not only in amoebae, but also in many other eukaryotic cells, especially those of the human nervous and immune systems, the developing embryo, and cancer cells. Acanthamoeba also has served as a model to study the evolution of certain G-proteins. This unicellular eukaryote expresses few GPCRs over its cell membrane that serve vital role for the microorganism, structural homology bioinformatics tools have been used to show the presence of a homolog of human M1-muscarinic receptor in A. castellanii. Blocking these muscarinic receptors in past studies has proven to be amoebicidal in Acanthamoeba spp. More recently, voltage-gated calcium channels in Acanthamoeba spp. (CavAc) have been reported to have similarities with human voltage-gated calcium channels such as TPC-1 and L-type calcium channels and respond to Ca-channel blockers such as loperamide. This model microbe has been studied to understand complex neurodegenerative states including Alzheimers disease. Scientists have isolated a neurotransmitter acetylcholine in Acanthamoeba and the enzymatic machinery needed for its synthesis.

Endosymbionts
Acanthamoeba spp. contain diverse bacterial endosymbionts that are similar to human pathogens, so they are considered to be potential emerging human pathogens. The exact nature of these symbionts and the benefit they represent for the amoebic host still have to be clarified. These include Legionella and Legionella-like pathogens.

Giant viruses
The giant viruses Mimivirus, Megavirus, and Pandoravirus infect Acanthamoeba.Members of the genus Acanthamoeba are unusual in serving as hosts for a variety of giant viruses (that have more than 1000 protein-coding genes; for instance, Pandoravirus, which has about 2500 protein-coding genes in its genome).

Diversity
Acanthamoeba can be distinguished from other genera of amoebae based on morphological characteristics. However, differentiating one species of Acanthamoeba from another by morphology has proven difficult. Based on 18S rDNA sequencing, known Acanthamoeba strains can be organized into 12 groups, denoted T1-T12. Most disease-causing isolates belong to type T4.Below is a list of described species of Acanthamoeba, with sequence types noted where known. Species that have been identified in diseased patients are marked with *.

A. astronyxis (Ray & Hayes 1954) Page 1967 * (T7)
A. byersi Qvarnstrom, Nerad & Visvesvara 2013 *
A. castellanii Volkonski 1931 * (T4) [A. terricola Pussard 1964]
A. comandoni Pussard 1964 (T9)
A. culbertsoni (Singh & Das 1970) Griffin 1972 * (T10)
A. divionensis Pussard & Pons 1977 (T4)
A. echinulata Pussard & Pons 1977
A. gigantea Schmöller 1964
A. glebae (Dobell 1914)
A. gleichenii Volkonsky 1931
A. griffini Sawyer 1971 (T3)
A. hatchetti Sawyer, Visvesvara & Harke 1977 * (T11)
A. healyi Moura, Wallace & Visvesvara 1992 (T12)
A. hyalina Dobel & Oconnor 1921
A. jacobsi Sawyer, Nerad & Visvesvara 1992
A. keratitis  *
A. lenticulata Molet & Ermolieff-braun 1976 (T3)
A. lugdunensis Pussard & Pons 1977 * (T4)
A. mauritaniensis Pussard & Pons 1977 (T4)
A. micheli Corsaro et al. 2015
A. palestinensis (Reich 1933) Page 1977 * (T1)
A. paradivionensis Pussard & Pons 1977 (T4)
A. pearcei Nerad et al. 1995
A. polyphaga (Puschkarew 1913) Volkonsky 1931 * (T4)
A. pustulosa Pussard & Pons 1977 (T2)
A. pyriformis (Olive & Stoianovitch 1969) Spiegel & Shadwick 2016
A. quina Pussard & Pons 1977 *
A. rhysodes (Singh 1952) Griffin 1972 * (T4)
A. royreba Willaert, Stevens & Tyndall 1978
A. sohi Kyung-il & Shin 2003
A. stevensoni Sawyer et al. 1993 (T11)
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