<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 Creutzfeldt–Jakob disease and can you explain it in depth? [/INST] Creutzfeldt–Jakob disease (CJD), also known as subacute spongiform encephalopathy or neurocognitive disorder due to prion disease, is an invariably fatal degenerative brain disorder. Early symptoms include memory problems, behavioral changes, poor coordination, and visual disturbances. Later symptoms include dementia, involuntary movements, blindness, weakness, and coma. About 70% of people die within a year of diagnosis. The name Creutzfeldt–Jakob disease was introduced by Walther Spielmeyer in 1922, after the German neurologists Hans Gerhard Creutzfeldt and Alfons Maria Jakob.CJD is caused by a type of abnormal protein known as a prion. Infectious prions are misfolded proteins that can cause normally folded proteins to also become misfolded. About 85% of cases of CJD occur for unknown reasons, while about 7.5% of cases are inherited in an autosomal dominant manner. Exposure to brain or spinal tissue from an infected person may also result in spread. There is no evidence that sporadic CJD can spread among people via normal contact or blood transfusions, although this is possible in variant Creutzfeldt–Jakob disease. Diagnosis involves ruling out other potential causes. An electroencephalogram, spinal tap, or magnetic resonance imaging may support the diagnosis.There is no specific treatment for CJD. Opioids may be used to help with pain, while clonazepam or sodium valproate may help with involuntary movements. CJD affects about one person per million people per year. Onset is typically around 60 years of age. The condition was first described in 1920. It is classified as a type of transmissible spongiform encephalopathy. Inherited CJD accounts for about 10% of prion disease cases. Sporadic CJD is different from bovine spongiform encephalopathy (mad cow disease) and variant Creutzfeldt–Jakob disease (vCJD).

Signs and symptoms
The first symptom of CJD is usually rapidly progressive dementia, leading to memory loss, personality changes, and hallucinations. Myoclonus (jerky movements) typically occurs in 90% of cases, but may be absent at initial onset. Other frequently occurring features include anxiety, depression, paranoia, obsessive-compulsive symptoms, and psychosis. This is accompanied by physical problems such as speech impairment, balance and coordination dysfunction (ataxia), changes in gait, and rigid posture. In most people with CJD, these symptoms are accompanied by involuntary movements. The duration of the disease varies greatly, but sporadic (non-inherited) CJD can be fatal within months or even weeks. Most affected people die six months after initial symptoms appear, often of pneumonia due to impaired coughing reflexes. About 15% of people with CJD survive for two or more years.The symptoms of CJD are caused by the progressive death of the brains nerve cells, which are associated with the build-up of abnormal prion proteins forming in the brain. When brain tissue from a person with CJD is examined under a microscope, many tiny holes can be seen where the nerve cells have died. Parts of the brain may resemble a sponge where the prions were infecting the areas of the brain.

Cause
CJD is a type of transmissible spongiform encephalopathy (TSE), which are caused by prions. Prions are misfolded proteins that occur in the neurons of the central nervous system (CNS). They are thought to affect signaling processes, damaging neurons and resulting in degeneration that causes the spongiform appearance in the affected brain.The CJD prion is dangerous because it promotes refolding of native prion protein into the diseased state. The number of misfolded protein molecules will increase exponentially and the process leads to a large quantity of insoluble protein in affected cells. This mass of misfolded proteins disrupts neuronal cell function and causes cell death. Mutations in the gene for the prion protein can cause a misfolding of the dominantly alpha helical regions into beta pleated sheets. This change in conformation disables the ability of the protein to undergo digestion. Once the prion is transmitted, the defective proteins invade the brain and induce other prion protein molecules to misfold in a self-sustaining feedback loop. These neurodegenerative diseases are commonly called prion diseases.People can also develop CJD because they carry a mutation of the gene that codes for the prion protein (PRNP). This occurs in only 5–10% of all CJD cases. In sporadic cases, the misfolding of the prion protein is a process that is hypothesized to occur as a result of the effects of aging on cellular machinery, explaining why the disease often appears later in life. An EU study determined that "87% of cases were sporadic, 8% genetic, 5% iatrogenic and less than 1% variant."

Transmission
The defective protein can be transmitted by contaminated harvested human brain products, corneal grafts, dural grafts, or electrode implants and human growth hormone.It can be familial (fCJD); or it may appear without clear risk factors (sporadic form: sCJD). In the familial form, a mutation has occurred in the gene for PrP, PRNP, in that family. All types of CJD are transmissible irrespective of how they occur in the person.It is thought that humans can contract the variant form of the disease by eating food from animals infected with bovine spongiform encephalopathy (BSE), the bovine form of TSE also known as mad cow disease. However, it can also cause sCJD in some cases.Cannibalism has also been implicated as a transmission mechanism for abnormal prions, causing the disease known as kuru, once found primarily among women and children of the Fore people in Papua New Guinea, who previously engaged in funerary cannibalism. While the men of the tribe ate the muscle tissue of the deceased, women and children consumed other parts, such as the brain, and were more likely than men to contract kuru from infected tissue.Prions, the infectious agent of CJD, may not be inactivated by means of routine surgical instrument sterilization procedures. The World Health Organization and the US Centers for Disease Control and Prevention recommend that instrumentation used in such cases be immediately destroyed after use; short of destruction, it is recommended that heat and chemical decontamination be used in combination to process instruments that come in contact with high-infectivity tissues.  Thermal depolymerization also destroys prions in infected organic and inorganic matter, since the process chemically attacks protein at the molecular level, although more effective and practical methods involve destruction by combinations of detergents and enzymes similar to biological washing powders.

Diagnosis
Testing for CJD has historically been problematic, due to nonspecific nature of early symptoms and difficulty in safely obtaining brain tissue for confirmation. The diagnosis may initially be suspected in a person with rapidly progressing dementia, particularly when they are also found with the characteristic medical signs and symptoms such as involuntary muscle jerking, difficulty with coordination/balance and walking, and visual disturbances. Further testing can support the diagnosis and may include:

Electroencephalography – may have characteristic generalized periodic sharp wave pattern. Periodic sharp wave complexes develop in half of the people with sporadic CJD, particularly in the later stages.
Cerebrospinal fluid (CSF) analysis for elevated levels of 14-3-3 protein could be supportive in the diagnosis of sCJD. However, a positive result should not be regarded as sufficient for the diagnosis. The Real-Time Quaking-Induced Conversion (RT-QuIC) assay has a diagnostic sensitivity of more than 80% and a specificity approaching 100%, tested in detecting PrPSc in CSF samples of people with CJD. It is therefore suggested as a high-value diagnostic method for the disease.
MRI of the brain – often shows high signal intensity in the caudate nucleus and putamen bilaterally on T2-weighted images.In recent years, studies have shown that the tumour marker neuron-specific enolase (NSE) is often elevated in CJD cases; however, its diagnostic utility is seen primarily when combined with a test for the 14-3-3 protein. As of 2010, screening tests to identify infected asymptomatic individuals, such as blood donors, are not yet available, though methods have been proposed and evaluated.

Imaging
Imaging of the brain may be performed during medical evaluation, both to rule out other causes and to obtain supportive evidence for diagnosis. Imaging findings are variable in their appearance, and also variable in sensitivity and specificity. While imaging plays a lesser role in diagnosis of CJD, characteristic findings on brain MRI in some cases may precede onset of clinical manifestations.Brain MRI is the most useful imaging modality for changes related to CJD. Of the MRI sequences, diffuse-weighted imaging sequences are most sensitive. Characteristic findings are as follows:

Focal or diffuse diffusion-restriction involving the cerebral cortex and/or basal ganglia. In about 24% of cases DWI shows only cortical hyperintensity; in 68%, cortical and subcortical abnormalities; and in 5%, only subcortical anomalies. The most iconic and striking cortical abnormality has been called "cortical ribboning" or "cortical ribbon sign" due to hyperintensities resembling ribbons appearing in the cortex on MRI. The involvement of the thalamus can be found in sCJD, is even stronger and constant in vCJD.
Varying degree of symmetric T2 hyperintense signal changes in the basal ganglia (i.e., caudate and putamen), and to a lesser extent globus pallidus and occipital cortex.
Cerebellar atrophyBrain FDG PET-CT tends to be markedly abnormal, and is increasingly used in the investigation of dementias.

Patients with CJD will normally have hypometabolism on FDG PET.

Histopathology
Testing of tissue remains the most definitive way of confirming the diagnosis of CJD, although it must be recognized that even biopsy is not always conclusive.In one-third of people with sporadic CJD, deposits of "prion protein (scrapie)", PrPSc, can be found in the skeletal muscle and/or the spleen. Diagnosis of vCJD can be supported by biopsy of the tonsils, which harbor significant amounts of PrPSc; however, biopsy of brain tissue is the definitive diagnostic test for all other forms of prion disease. Due to its invasiveness, biopsy will not be done if clinical suspicion is sufficiently high or low. A negative biopsy does not rule out CJD, since it may predominate in a specific part of the brain.The classic histologic appearance is spongiform change in the gray matter: the presence of many round vacuoles from one to 50 micrometers in the neuropil, in all six cortical layers in the cerebral cortex or with diffuse involvement of the cerebellar molecular layer. These vacuoles appear glassy or eosinophilic and may coalesce. Neuronal loss and gliosis are also seen. Plaques of amyloid-like material can be seen in the neocortex in some cases of CJD.However, extra-neuronal vacuolization can also be seen in other disease states. Diffuse cortical vacuolization occurs in Alzheimers disease, and superficial cortical vacuolization occurs in ischemia and frontotemporal dementia. These vacuoles appear clear and punched-out. Larger vacuoles encircling neurons, vessels, and glia are a possible processing artifact.

Classification
Types of CJD include:
Sporadic (sCJD), caused by the spontaneous misfolding of prion-protein in an individual. This accounts for 85% of cases of CJD.
Familial (fCJD), caused by an inherited mutation in the prion-protein gene. This accounts for the majority of the other 15% of cases of CJD.
Acquired CJD, caused by contamination with tissue from an infected person, usually as the result of a medical procedure (iatrogenic CJD). Medical procedures that are associated with the spread of this form of CJD include blood transfusion from the infected person, use of human-derived pituitary growth hormones, gonadotropin hormone therapy, and corneal and meningeal transplants. Variant Creutzfeldt–Jakob disease (vCJD) is a type of acquired CJD potentially acquired from bovine spongiform encephalopathy or caused by consuming food contaminated with prions.

Treatment
As of 2022, there is no cure or effective treatment for CJD. Some of the symptoms like twitching can be managed, but otherwise treatment is palliative care. Psychiatric symptoms like anxiety and depression can be treated with sedatives and antidepressants. Myoclonic jerks can be handled with clonazepam or sodium valproate. Opiates can help in pain. Seizures are very uncommon but can nevertheless be treated with antiepileptic drugs.

Prognosis
The condition is universally fatal. As of 1981, no one is known to have lived longer than 2.5 years after the onset of CJD symptoms. The longest recorded survivor of variant Creutzfeldt–Jakob disease (vCJD) was Jonathan Simms, a Northern Irish man who lived 10 years after his diagnosis.

Epidemiology
CDC monitors the occurrence of CJD in the United States through periodic reviews of national mortality data. According to the CDC:
CJD occurs worldwide at a rate of about 1 case per million population per year.
On the basis of mortality surveillance from 1979 to 1994, the annual incidence of CJD remained stable at approximately 1 case per million people in the United States.
In the United States, CJD deaths among people younger than 30 years of age are extremely rare (fewer than five deaths per billion per year).
The disease is found most frequently in people 55–65 years of age, but cases can occur in people older than 90 years and younger than 55 years of age.
In more than 85% of cases, the duration of CJD is less than one year (median: four months) after the onset of symptoms.Further information from the CDC:
Risk of developing CJD increases with age.
CJD incidence was 3.5 cases per million among those over 50 years of age between 1979 and 2017.
Approximately 85% of CJD cases are sporadic and 10-15% of CJD cases are due to inherited mutations of the prion protein gene.
CJD deaths and age-adjusted death rate in the United States indicate an increasing trend in the number of deaths between 1979 and 2017.Although not fully understood, additional information suggests that CJD rates in African American and nonwhite groups are lower than in whites. While the mean onset is approximately 67 years of age, cases of sCJD have been reported as young as 17 years and over 80 years of age. Mental capabilities rapidly deteriorate and the average amount of time from onset of symptoms to death is 7 to 9 months.According to a 2020 systematic review on the international epidemiology of CJD:
Surveillance studies from 2005 and later show the estimated global incidence is 1–2 cases per million population per year.
Sporadic CJD (sCJD) incidence increased from the years 1990–2018 in the UK.
Probable or definite sCJD deaths also increased from the years 1996–2018 in twelve additional countries.
CJD incidence is greatest in those over the age of 55 years old, with an average age of 67 years old.The intensity of CJD surveillance increases the number of reported cases, often in countries where CJD epidemics have occurred in the past and where surveillance resources are greatest. An increase in surveillance and reporting of CJD is most likely in response to BSE and vCJD. Possible factors contributing to an increase of CJD incidence are an aging population, population increase, clinician awareness, and more accurate diagnostic methods. Since CJD symptoms are similar to other neurological conditions, it is also possible that CJD is mistaken for stroke, acute nephropathy, general dementia, and hyperparathyroidism.

History
The disease was first described by German neurologists Hans Gerhard Creutzfeldt in 1920 and shortly afterward by Alfons Maria Jakob, giving it the name Creutzfeldt–Jakob. Some of the clinical findings described in their first papers do not match current criteria for Creutzfeldt–Jakob disease, and it has been speculated that at least two of the people in initial studies had a different ailment. An early description of familial CJD stems from the German psychiatrist and neurologist Friedrich Meggendorfer (1880–1953). A study published in 1997 counted more than 100 cases worldwide of transmissible CJD and new cases continued to appear at the time.The first report of suspected iatrogenic CJD was published in 1974. Animal experiments showed that corneas of infected animals could transmit CJD, and the causative agent spreads along visual pathways. A second case of CJD associated with a corneal transplant was reported without details. In 1977, CJD transmission caused by silver electrodes previously used in the brain of a person with CJD was first reported. Transmission occurred despite the decontamination of the electrodes with ethanol and formaldehyde. Retrospective studies identified four other cases likely of similar cause. The rate of transmission from a single contaminated instrument is unknown, although it is not 100%. In some cases, the exposure occurred weeks after the instruments were used on a person with CJD. In the 1980s it was discovered that Lyodura, a dura mater transplant product, was shown to transmit CJD from the donor to the recipient. This led to the product being banned in Canada but it was used in other countries such as Japan until 1993.A review article published in 1979 indicated that 25 dura mater cases had occurred by that date in Australia, Canada, Germany, Italy, Japan, New Zealand, Spain, the United Kingdom, and the United States.By 1985, a series of case reports in the United States showed that when injected, cadaver-extracted pituitary human growth hormone could transmit CJD to humans.In 1992, it was recognized that human gonadotropin administered by injection could also transmit CJD from person to person.Stanley B. Prusiner of the University of California, San Francisco (UCSF) was awarded the Nobel Prize in Physiology or Medicine in 1997 "for his discovery of Prions—a new biological principle of infection".Yale University neuropathologist Laura Manuelidis has challenged the prion protein (PrP) explanation for the disease. In January 2007, she and her colleagues reported that they had found a virus-like particle in naturally and experimentally infected animals. "The high infectivity of comparable, isolated virus-like particles that show no intrinsic PrP by antibody labeling, combined with their loss of infectivity when nucleic acid–protein complexes are disrupted, make it likely that these 25-nm particles are the causal TSE virions".

Australia
Australia has documented 10 cases of healthcare-acquired CJD (iatrogenic or ICJD). Five of the deaths resulted after the patients, who were in treatment either for infertility or short stature, were treated using contaminated pituitary extract hormone but no new cases have been noted since 1991. The other five deaths occurred due to dura grafting procedures that were performed during brain surgery, in which the covering of the brain is repaired. There have been no other ICJD deaths documented in Australia due to transmission during healthcare procedures.

New Zealand
A case was reported in 1989 in a 25-year-old man from New Zealand, who also received dura mater transplant. Five New Zealanders have been confirmed to have died of the sporadic form of Creutzfeldt–Jakob disease (CJD) in 2012.

United States
In 1988, there was a confirmed death from CJD of a person from Manchester, New Hampshire. Massachusetts General Hospital believed the person acquired the disease from a surgical instrument at a podiatrists office. In September 2013, another person in Manchester was posthumously determined to have died of the disease. The person had undergone brain surgery at Catholic Medical Center three months before his death, and a surgical probe used in the procedure was subsequently reused in other operations. Public health officials identified thirteen people at three hospitals who may have been exposed to the disease through the contaminated probe, but said the risk of anyones contracting CJD is "extremely low". In January 2015, former speaker of the Utah House of Representatives Rebecca D. Lockhart died of the disease within a few weeks of diagnosis. John Carroll, former editor of The Baltimore Sun and Los Angeles Times, died of CJD in Kentucky in June 2015, after having been diagnosed in January. American actress Barbara Tarbuck (General Hospital, American Horror Story) died of the disease on December 26, 2016. José Baselga, clinical oncologist having headed the AstraZeneca Oncology division, died in Cerdanya, March 21, 2021, from CJD.

Research
Diagnosis
In 2010, a team from New York described detection of PrPSc in sheeps blood, even when initially present at only one part in one hundred billion (10−11) in sheeps brain tissue. The method combines amplification with a novel technology called surround optical fiber immunoassay (SOFIA) and some specific antibodies against PrPSc </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 Carcinoma in situ and can you explain it in depth? [/INST] Carcinoma in situ (CIS) is a group of abnormal cells. While they are a form of neoplasm, there is disagreement over whether CIS should be classified as cancer. This controversy also depends on the exact CIS in question (i.e. cervical, skin, breast). Some authors do not classify them as cancer, however, recognizing that they can potentially become cancer. Others classify certain types as a non-invasive form of cancer. The term "pre-cancer" has also been used.
These abnormal cells grow in their normal place, thus "in situ" (from Latin for "in its place"). For example, carcinoma in situ of the skin, also called Bowens disease, is the accumulation of dysplastic epidermal cells within the epidermis only, that has failed to penetrate into the deeper dermis. For this reason, CIS will usually not form a tumor. Rather, the lesion is flat (in the skin, cervix, etc.) or follows the existing architecture of the organ (in the breast, lung, etc.) </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 Pannus and can you explain it in depth? [/INST] Pannus is an abnormal layer of fibrovascular tissue or granulation tissue. Common sites for pannus formation include over the cornea, over a joint surface (as seen in rheumatoid arthritis), or on a prosthetic heart valve. Pannus may grow in a tumor-like fashion, as in joints where it may erode articular cartilage and bone.
In common usage, the term pannus is often used to refer to a panniculus (a hanging flap of tissue).

Pannus in rheumatoid arthritis
The term "pannus" is derived from the Latin for "tablecloth". Inflammation and exuberant proliferation of the synovium leads to formation of pannus and destruction of cartilage, bone, tendons, ligaments, and blood vessels. Basically, the hypertrophied synovium is called pannus </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 Holoprosencephaly and can you explain it in depth? [/INST] Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed and the face begins to develop in the fifth and sixth weeks of human pregnancy. The condition also occurs in other species.
Holoprosencephaly is estimated to occur in approximately 1 in every 250 conceptions and most cases are not compatible with life and result in fetal death in utero due to deformities to the skull and brain. However, holoprosencephaly is still estimated to occur in approximately 1 in every 8,000 live births.When the embryos forebrain does not divide to form bilateral cerebral hemispheres (the left and right halves of the brain), it causes defects in the development of the face and in brain structure and function.
The severity of holoprosencephaly is highly variable. In less severe cases, babies are born with normal or near-normal brain development and facial deformities that may affect the eyes, nose, and upper lip.

Signs and symptoms
Symptoms of holoprosencephaly range from mild (no facial/organ defects, anosmia, or only a single central incisor) to moderate to severe (cyclopia). The symptoms are dependent upon the classification type.There are four classifications of holoprosencephaly as well as a mild "microform".

Alobar
Most severe form includes formation of synophthalmia (a single central eye), proboscis, and severe impairment.
Semilobar
Can present with severely decreased distance between eyes, a flat nasal bridge, eye defects, cleft lip and palate, and severe impairment.
Lobar
Can present with decreased distance between eyes, a flat nasal bridge, closely spaced nostrils, mental and locomotion delays may be present.
Syntelencephaly or middle interhemispheric variant of holoprosencephaly (MIHV)
Mild phenotypic presentation which can present with flat nasal bridge, metopic prominence, shallow philtrum, and possible mental and locomotion delays.
"Microform"
Mild phenotypic presentation with reduced distance between eyes, sharp nasal bridge, single maxillary central incisor.

Diagnosis
Holoprosencephaly is typically diagnosed during fetal development when there are abnormalities found on fetal brain imaging, however it can also be diagnosed after birth. The Protocol for diagnosis includes neuroimaging (Ultrasound or fetal MRI prior to birth or Ultrasound, MRI or CT post birth), syndrome evaluation, cytogenetics, molecular testing, and genetic counseling.There are four classifications of holoprosencephaly as well as a “microform". These classifications can be distinguished by their anatomical differences.
Alobar holoprosencephaly
Small single forebrain ventricle
No interhemispheric division
Absence of olfactory bulbs and tracts
Absence of corpus callosum
Non separation of deep gray nuclei
Semilobar holoprosencephaly
Rudimentary cerebral lobes
Incomplete interhemispheric division
Absence or hypoplasia of olfactory bulbs and tracts
Absence of corpus callosum
Varying non separation of deep gray nuclei
Lobar holoprosencephaly
Fully-developed cerebral lobes
Distinct interhemispheric division
Midline continuous frontal neocortex
Absent, hypoplasic or normal corpus callosum
Separation of deep gray nuclei
Syntelencephaly, or middle interhemispheric variant of holoprosencephaly (MIHV)
Failure of separation of the posterior frontal and parietal lobes
Callosal genu and splenium normally formed
Absence of corpus callosum
Hypothalamus and lentiform nuclei normally separated
Heterotopic gray matter
Microform
Subtle defects of corpus callosum
Subtle midline brain defects

Causes
In Holoprosencephaly, the neural tube fails to segment, resulting in incomplete separation of the prosencephalon at the fifth week of gestation.The exact cause(s) of HPE are yet to be determined. Mutations in the gene encoding the SHH protein, which is involved in the development of the central nervous system (CNS), can cause holoprosencephaly. In other cases, it often seems that there is no specific cause at all.

Genetics
Armand Marie Leroi describes the cause of cyclopia as a genetic malfunctioning during the process by which the embryonic brain is divided into two. Only later does the visual cortex take recognizable form, and at this point an individual with a single forebrain region will be likely to have a single, possibly rather large, eye (at such a time, individuals with separate cerebral hemispheres would form two eyes).
Increases in expression of such genes as Pax-2, as well as inhibition of Pax-6, from the notochord have been implicated in normal differentiation of cephalic midline structures. Inappropriate expression of any of these genes may result in mild to severe forms of holoprosencephaly. Other candidate genes have been located, including the SHH (holoprosencephaly type 3 a.k.a. HPE3), TGIF, ZIC2, SIX3 and BOC genes.Although many children with holoprosencephaly have normal chromosomes, specific chromosomal abnormalities have been identified in some patients (trisomy of chromosome 13, also known as Patau syndrome). There is evidence that in some families, HPE is inherited (autosomal dominant as well as autosomal or X-linked recessive inheritance). Features consistent with familial transmission of the disease (e.g., a single central maxillary incisor) should be carefully assessed in parents and family members.

Non-genetic factors
Numerous possible risk factors have been identified, including gestational diabetes, transplacental infections (the "TORCH complex"), first trimester bleeding, and a history of miscarriage. As well, the disorder is found twice as often in female babies </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 Cardiac allograft vasculopathy and can you explain it in depth? [/INST] Cardiac allograft vasculopathy (CAV) is a progressive type of coronary artery disease in people who have had a heart transplant. As the donor heart has lost its nerve supply there is typically no chest pain, and CAV is usually detected on routine testing. It may present with symptoms such as tiredness and breathlessness.It arises when the blood vessels supplying the transplanted heart change in structure. They gradually narrow and restrict its blood flow, subsequently leading to impairment of the heart muscle or sudden death. In addition to the same risk factors for coronary artery disease due to the build up of plaque, CAV is more likely to occur if the donor was older or died from explosive brain death, and if there is cytomegalovirus infection. Its mechanism involves immunological (innate and adaptive) and nonimmunological factors, with distinct features on histological samples of coronary arteries. Other major causes of death following heart transplantation include graft failure, organ rejection and infection.Diagnosis is by regular follow-up and monitoring of the transplanted heart for early signs of disease. Tests include coronary angiography, intravascular ultrasound, dobutamine stress echocardiography, positron emission tomography, computed tomographic angiography (CT angiography) and several biomarkers.Statins and aspirin are commenced early after transplantation and on detection of CAV. Medications including sirolimus and everolimus can slow disease progression. A repeat heart transplantation may be required.CAV affects around half of heart transplant recipients within 10 years. It contributes to the death of 11-13% one year from heart transplantation.

Definition
Cardiac allograft vasculopathy is an accelerated type of coronary artery disease in people who have had a heart transplantation.

Signs and symptoms
Unlike the chest tightness of angina in those who have not had a heart transplant, people with CAV typically do not experience chest pain because the donor heart has lost its nerve supply. A few regain nerves some years later and may develop unusual chest pain. People with CAV may present with a broad spectrum of symptoms including tiredness, nausea, or abdominal discomfort or may have no symptoms at all. Shortness of breath and arrythmias may also occur.

Risk factors
Similar to coronary artery disease in those who have not had a heart transplant, risk factors to CAV include high blood pressure, high cholesterol, and diabetes mellitus. Other risk factors exclusive to CAV include older donors, cytomegalovirus infection and circulating antibodies after heart transplantation. The mechanism of donor brain death, particularly explosive brain death in the donor has been shown to be a significant factor. It is probably the combination of injuries to the allograft that determine the risk of developing CAV.

Mechanism
Immunological (innate and adaptive) and nonimmunological factors contribute to the complex pathogenesis of CAV.In those nontransplanted people who develop coronary artery disease due to atherosclerosis, progression of disease is slow, histological changes are confined mainly to the main coronary arteries and arterial dilatation is observed as a form of compensatory remodelling. However, in CAV, histology specimens typically show concentric thickening of the intimal layer of the main coronary arteries on the surface of the heart and in intramyocardial arteries which can become obliterated within a few years. There is smooth muscle cell migration, foamy macrophages and lymphocytic infiltrates. This can be seen to affect the whole length of the coronary arteries and often the smaller arteries. Calcification does not always occur in CAV and if it does appear, it happens late.  The compensatory arterial dilation does not occur in CAV. Unlike in nontransplanted people with coronary artery disease due to atherosclerosis, in CAV occlusion with thrombus of the vessel lumen is rare.Inflammation and endothelial injury can be triggered by the donor arrest, organ procurement, and allograft ischaemia and reperfusion.

Diagnosis
As symptoms are so variable and often absent, diagnosis has been a challenge. Hence, regular follow-up and monitoring of the allograft for early signs of disease is advocated.

Coronary angiography
Surveillance is performed by regularly repeating coronary angiography in the cardiac catheterization laboratory, the diagnostic test of choice. This is typically performed annually for the first five years after transplantation. Angiography in CAV characteristically demonstrates diffuse stenoses in large coronary arteries and a reduced number of smaller coronary arteries, also known as "peripheral pruning". However, because CAV frequently affects the entire length of the coronary artery, CAV may not be apparent by angiography alone.

Intravascular ultrasound (IVUS)
Intravascular ultrasound (IVUS) is more sensitive at reliably detecting subtle changes in the thickness of the intimal layer of the artery walls and provide measurements of artery lumen. Following transplantation, serial measurements are compared to the baseline. A greater than 0.5 mm increase in intimal thickness one year after transplantation is predictive of CAV changes on angiography within five years. The paradoxical reduction in the number of blood vessels, can also be detected by intravascular ultrasound.IVUS, however, tends to be used for research due to its drawbacks of being invasive, requiring the use of contrast material and cost.

Dobutamine stress-echocardiography (DSE)
Alternatively, dobutamine stress echocardiography (DSE) is commonly performed and has an 85% sensitivity for the presence of CAV. A negative DSE correlates with a good prognosis.Other noninvasive diagnostics include positron emission tomography and computed tomographic angiography (CT angiography). In addition, ECGs may show atypical features of ischaemia.

Biomarkers
Biomarkers for increased risk of CAV include C-reactive protein, serum brain natriuretic peptide and troponin I have been suggested.

Classification
The degree of CAV after heart transplantation has been obtained from a variety of sources including The Cardiac Transplant Research Database, the ISHLT registry and The United Network for Organ Sharing registry.The International Society for Heart and Lung Transplantation (ISHLT) have formulated and standardized a terminology, based on diagnostic findings, to define the presence and severity of CAV, which in turn reflects prognosis. The severity of CAV is defined by the degree of narrowing of the coronary arteries and the presence of restrictive heart disease.

Treatment
Statins
Prevention of CAV progression is important as once developed, CAV existing treatments are often ineffective. Commencing the statins pravastatin and simvastatin early after transplantation reduces the incidence and severity of CAV.

Vitamins
When combined with immunosuppressants, the progression of CAV could possibly be slowed by vitamins C and E.

Aspirin
Since the role of aspirin is already established in coronary artery disease in those who have not had a heart transplant, it is usually given after heart transplantation too.

Antiproliferative agents
On detection of CAV, medications including mTOR inhibitors sirolimus and everolimus have been shown to slow disease progression.

Other treatment options
Clinically significant CAV may require percutaneous coronary interventions for focal disease, but the likelihood of restenosis is high. A repeat heart transplantation may be considered.

Outcome
Once there is reduced left ventricular ejection fraction and symptoms of heart failure, the outcome is typically poor. The risk of major adverse cardiovascular events is increased by 3.4 fold if CAV is present on angiography.

Epidemiology
The frequency of CAV after heart transplantation has been obtained from a variety of sources including The Cardiac Transplant Research Database, the ISHLT registry and The United Network for Organ Sharing registry. In comparison to between 1994 and 2001, there has been a decline in incidence of CAV between 2001 and 2007. ISHLT figures show an incidence of CAV of around 50% at 10 years after heart transplantation.CAV is a leading cause of late mortality following heart transplantation </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 Erectile dysfunction and can you explain it in depth? [/INST] Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men. Through its connection to self-image and to problems in sexual relationships, erectile dysfunction can cause psychological harm.
In about 80% of cases, physical causes can be identified. These include cardiovascular disease; diabetes mellitus; neurological problems, such as those following prostatectomy; hypogonadism; and drug side effects. About 10% of cases are psychological impotence, caused by thoughts or feelings; here, there is a strong response to placebo treatment.
The term erectile dysfunction is not used for other disorders of erection, such as priapism.
Treatment involves addressing the underlying causes, lifestyle modifications, and addressing psychosocial problems. In many cases, treatment is attempted by drugs, specifically PDE5 inhibitors (such as sildenafil), which dilate blood vessels, allowing more blood to flow through the spongy tissue of the penis (akin to opening a valve further in order to allow more water to enter a fire hose). Other treatments, less commonly used, include prostaglandin pellets, inserted in the urethra; smooth-muscle relaxants and vasodilators, injected into the penis; penile implants; penis pumps; and vascular reconstructive surgery.

Signs and symptoms
ED is characterized by the regular or repeated inability to achieve or maintain an erection of sufficient rigidity to accomplish sexual activity. It is defined as the "persistent or recurrent inability to achieve and maintain a penile erection of sufficient rigidity to permit satisfactory sexual activity for at least 3 months."

Psychological impact
ED often has an impact on the emotional well-being of both men and their partners. Many men do not seek treatment due to feelings of embarrassment. About 75% of diagnosed cases of ED go untreated.

Causes
Causes of or contributors to ED include the following:

Diets high in saturated fat are linked to heart diseases, and men with heart diseases are more likely to experience ED. By contrast, plant-based diets show a lower risk for ED.
Prescription drugs (e.g., SSRIs, beta blockers, antihistamines, alpha-2 adrenergic receptor agonists, thiazides, hormone modulators, and 5α-reductase inhibitors)
Neurogenic disorders (e.g., diabetic neuropathy, temporal lobe epilepsy, multiple sclerosis, Parkinsons disease, multiple system atrophy)
Cavernosal disorders (e.g., Peyronies disease)
Hyperprolactinemia (e.g., due to a prolactinoma)
Psychological causes: performance anxiety, stress, and mental disorders
Surgery (e.g., radical prostatectomy)
Ageing: after age 40 years, ageing itself is a risk factor for ED, although numerous other pathologies that may occur  with ageing, such as testosterone deficiency, cardiovascular diseases, or diabetes, among others, appear to have interacting effects
Kidney disease: ED and chronic kidney disease have pathological mechanisms in common, including vascular and hormonal dysfunction, and may share other comorbidities, such as hypertension and diabetes mellitus that can contribute to ED
Lifestyle habits, particularly smoking, which is a key risk factor for ED as it promotes arterial narrowing. Due to its propensity for causing detumescence and erectile dysfunction, some studies have described tobacco as an anaphrodisiacal substance.
COVID-19: preliminary research indicates that COVID-19 viral infection may affect sexual and reproductive healthSurgical intervention for a number of conditions may remove anatomical structures necessary to erection, damage nerves, or impair blood supply. ED is a common complication of treatments for prostate cancer, including prostatectomy and destruction of the prostate by external beam radiation, although the prostate gland itself is not necessary to achieve an erection. As far as inguinal hernia surgery is concerned, in most cases, and in the absence of postoperative complications, the operative repair can lead to a recovery of the sexual life of people with preoperative sexual dysfunction, while, in most cases, it does not affect people with a preoperative normal sexual life.ED can also be associated with bicycling due to both neurological and vascular problems due to compression. The increased risk appears to be about 1.7-fold.Concerns that use of pornography can cause ED have little support in epidemiological studies, according to a 2015 literature review. According to Gunter de Win, a Belgian professor and sex researcher, "Put simply, respondents who watch 60 minutes a week and think theyre addicted were more likely to report sexual dysfunction than those who watch a care-free 160 minutes weekly."

Pathophysiology
Penile erection is managed by two mechanisms: the reflex erection, which is achieved by directly touching the penile shaft, and the psychogenic erection, which is achieved by erotic or emotional stimuli. The former involves the peripheral nerves and the lower parts of the spinal cord, whereas the latter involves the limbic system of the brain. In both cases, an intact neural system is required for a successful and complete erection. Stimulation of the penile shaft by the nervous system leads to the secretion of nitric oxide (NO), which causes the relaxation of the smooth muscles of the corpora cavernosa (the main erectile tissue of the penis), and subsequently penile erection.  Additionally, adequate levels of testosterone (produced by the testes) and an intact pituitary gland are required for the development of a healthy erectile system. As can be understood from the mechanisms of a normal erection, impotence may develop due to hormonal deficiency, disorders of the neural system, lack of adequate penile blood supply or psychological problems. Spinal cord injury causes sexual dysfunction, including ED. Restriction of blood flow can arise from impaired endothelial function due to the usual causes associated with coronary artery disease, but can also be caused by prolonged exposure to bright light.

Diagnosis
In many cases, the diagnosis can be made based on the persons history of symptoms. In other cases, a physical examination and laboratory investigations are done to rule out more serious causes such as hypogonadism or prolactinoma.One of the first steps is to distinguish between physiological and psychological ED. Determining whether involuntary erections are present is important in eliminating the possibility of psychogenic causes for ED. Obtaining full erections occasionally, such as nocturnal penile tumescence when asleep (that is, when the mind and psychological issues, if any, are less present), tends to suggest that the physical structures are functionally working. Similarly, performance with manual stimulation, as well as any performance anxiety or acute situational ED, may indicate a psychogenic component to ED.Another factor leading to ED is diabetes mellitus, a well known cause of neuropathy). ED is also related to generally poor physical health, poor dietary habits, obesity, and most specifically cardiovascular disease, such as coronary artery disease and peripheral vascular disease.  Screening for cardiovascular risk factors, such as smoking, dyslipidemia,  hypertension, and alcoholism, is helpful.In some cases, the simple search for a previously undetected groin hernia can prove useful since it can affect sexual functions in men and is relatively easily curable.The current diagnostic and statistical manual of mental diseases (DSM-IV) lists ED.

Ultrasonography
Penile ultrasonography with doppler can be used to examine the erect penis. Most cases of ED of organic causes are related to changes in blood flow in the corpora cavernosa, represented by occlusive artery disease (in which less blood is allowed to enter the penis), most often of atherosclerotic origin, or due to failure of the veno-occlusive mechanism (in which too much blood circulates back out of the penis). Before the Doppler sonogram, the penis should be examined in B mode, in order to identify possible tumors, fibrotic plaques, calcifications, or hematomas, and to evaluate the appearance of the cavernous arteries, which can be tortuous or atheromatous.Erection can be induced by injecting 10–20 µg of prostaglandin E1, with evaluations of the arterial flow every five minutes for 25–30 min (see image). The use of prostaglandin E1 is contraindicated in patients with predisposition to priapism (e.g., those with sickle cell anemia), anatomical deformity of the penis, or penile implants. Phentolamine (2 mg) is often added. Visual and tactile stimulation produces better results. Some authors recommend the use of sildenafil by mouth to replace the injectable drugs in cases of contraindications, although the efficacy of such medication is controversial.Before the injection of the chosen drug, the flow pattern is monophasic, with low systolic velocities and an absence of diastolic flow. After injection, systolic and diastolic peak velocities should increase, decreasing progressively with vein occlusion and becoming negative when the penis becomes rigid (see image below). The reference values vary across studies, ranging from > 25 cm/s to > 35 cm/s. Values above 35 cm/s indicate the absence of arterial disease, values below 25 cm/s indicate arterial insufficiency, and values of 25–35 cm/s are indeterminate because they are less specific (see image below). The data obtained should be correlated with the degree of erection observed. If the peak systolic velocities are normal, the final diastolic velocities should be evaluated, those above 5 cm/s being associated with venogenic ED.

Other workup methods
Penile nerves function
Tests such as the bulbocavernosus reflex test are used to ascertain whether there is enough nerve sensation in the penis. The physician squeezes the glans (head) of the penis, which immediately causes the anus to contract if nerve function is normal. A physician measures the latency between squeeze and contraction by observing the anal sphincter or by feeling it with a gloved finger in the anus.Nocturnal penile tumescence (NPT)
It is normal for a man to have five to six erections during sleep, especially during rapid eye movement (REM). Their absence may indicate a problem with nerve function or blood supply in the penis. There are two methods for measuring changes in penile rigidity and circumference during nocturnal erection: snap gauge and strain gauge. A significant proportion [give us the percentage] of men who have no sexual dysfunction nonetheless do not have regular nocturnal erections.Penile biothesiometry
This test uses electromagnetic vibration to evaluate sensitivity and nerve function in the glans and shaft of the penis.Dynamic infusion cavernosometry (DICC)
Technique in which fluid is pumped into the penis at a known rate and pressure. It gives a measurement of the vascular pressure in the corpus cavernosum during an erection.Corpus cavernosometry
Cavernosography measurement of the vascular pressure in the corpus cavernosum.  Saline is infused under pressure into the corpus cavernosum with a butterfly needle, and the flow rate needed to maintain an erection indicates the degree of venous leakage. The leaking veins responsible may be visualized by infusing a mixture of saline and x-ray contrast medium and performing a cavernosogram. In Digital Subtraction Angiography (DSA), the images are acquired digitally.Magnetic resonance angiography (MRA)
This is similar to magnetic resonance imaging. Magnetic resonance angiography uses magnetic fields and radio waves to provide detailed images of the blood vessels. The doctor may inject into the patients bloodstream a contrast agent, which causes vascular tissues to stand out against other tissues, so that information about blood supply and vascular anomalies is easier to gather.

Treatment
Treatment depends on the underlying cause. In general, exercise, particularly of the aerobic type, is effective for preventing ED during midlife. Counseling can be used if the underlying cause is psychological, including how to lower stress or anxiety related to sex. Medications by mouth and vacuum erection devices are first-line treatments,: 20, 24  followed by injections of drugs into the penis, as well as penile implants.: 25–26  Vascular reconstructive surgeries are beneficial in certain groups. Treatments, other than surgery, do not fix the underlying physiological problem, but are used as needed before sex.

Medications
The PDE5 inhibitors sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis) are prescription drugs which are taken by mouth.: 20–21  As of 2018, sildenafil is available in the UK without a prescription.  Additionally, a cream combining alprostadil with the permeation enhancer DDAIP has been approved in Canada as a first line treatment for ED. Penile injections, on the other hand, can involve one of the following medications: papaverine, phentolamine, and prostaglandin E1, also known as alprostadil. In addition to injections, there is an alprostadil suppository that can be inserted into the urethra. Once inserted, an erection can begin within 10 minutes and last up to an hour. Medications to treat ED may cause a side effect called priapism.

Prevalence of medical diagnosis
In a study published in 2016, based on US health insurance claims data, out of 19,833,939 US males aged ≥18 years, only 1,108,842 (5.6%), were medically diagnosed with erectile dysfunction or on a PDE5I prescription (μ age 55.2 years, σ 11.2 years). Prevalence of diagnosis or prescription was the highest for age group 60–69 at 11.5%, lowest for age group 18–29 at 0.4%, and 2.1% for 30–39, 5.7% for 40–49, 10% for 50–59, 11% for 70–79, 4.6% for 80–89, 0.9% for ≥90, respectively.

Focused shockwave therapy
Focused shockwave therapy involves passing short, high frequency acoustic pulses through the skin and into the penis. These waves break down any plaques within the blood vessels, encourage the formation of new vessels, and stimulate repair and tissue regeneration.Focused shockwave therapy appears to work best for men with vasculogenic ED, which is a blood vessel disorder that affects blood flow to tissue in the penis. The treatment is painless and has no known side effects. Treatment with shockwave therapy can lead to a significant improvement of the IIEF (International Index of Erectile Function).

Testosterone
Men with low levels of testosterone can experience ED. Taking testosterone may help maintain an erection. Men with type 2 diabetes are twice as likely to have lower levels of testosterone, and are three times more likely to experience ED than non-diabetic men.

Pumps
A vacuum erection device helps draw blood into the penis by applying negative pressure. This type of device is sometimes referred to as penis pump and may be used just prior to sexual intercourse. Several types of FDA approved vacuum therapy devices are available under prescription.  When pharmacological methods fail, a purpose-designed external vacuum pump can be used to attain erection, with a separate compression ring fitted to the base of the penis to maintain it. These pumps should be distinguished from other penis pumps (supplied without compression rings) which, rather than being used for temporary treatment of impotence, are claimed to increase penis length if used frequently, or vibrate as an aid to masturbation. More drastically, inflatable or rigid penile implants may be fitted surgically.

Surgery
Often, as a last resort, if other treatments have failed, the most common procedure is prosthetic implants which involves the insertion of artificial rods into the penis.: 26  Some sources show that vascular reconstructive surgeries are viable options for some people.

Alternative medicine
The Food and Drug Administration (FDA) does not recommend alternative therapies to treat sexual dysfunction. Many products are advertised as "herbal viagra" or "natural" sexual enhancement products, but no clinical trials or scientific studies support the effectiveness of these products for the treatment of ED, and synthetic chemical compounds similar to sildenafil have been found as adulterants in many of these products. The FDA has warned consumers that any sexual enhancement product that claims to work as well as prescription products is likely to contain such a contaminant. A 2021 review indicated that ginseng had "only trivial effects on erectile function or satisfaction with intercourse compared to placebo".

History
Attempts to treat ED date back well over 1,000 years.  In the 8th century, men of Ancient Rome and Greece wore talismans of rooster and goat genitalia, believing these talismans would serve as an aphrodisiac and promote sexual function.  In the 13th century Albertus Magnus recommended ingesting roasted wolf penis as a remedy for impotence.During the late 16th and 17th centuries in France, male impotence was considered a crime, as well as legal grounds for a divorce. The practice, which involved inspection of the complainants by court experts, was declared obscene in 1677.The first successful vacuum erection device, or penis pump, was developed by Vincent Marie Mondat in the early 1800s.  A more advanced device, based on a bicycle pump, was developed by Geddings Osbon, a Pentecostal preacher, in the 1970s.  In 1982, he received FDA approval to market the product as the ErecAid®.John R. Brinkley initiated a boom in male impotence cures in the U.S. in the 1920s and 1930s. His radio programs recommended expensive goat gland implants and "mercurochrome" injections as the path to restored male virility, including operations by surgeon Serge Voronoff.
Modern drug therapy for ED made a significant advance in 1983, when British physiologist Giles Brindley dropped his trousers and demonstrated to a shocked Urodynamics Society audience his papaverine-induced erection. The drug Brindley injected into his penis was a non-specific vasodilator, an alpha-blocking agent, and the mechanism of action was clearly corporal smooth muscle relaxation. The effect that Brindley discovered established the fundamentals for the later development of specific, safe, and orally effective drug therapies.The current first-line treatment for ED, the oral PDE5 inhibitor, was introduced by Pfizer in 1999.

Anthropology
Anthropological research presents ED not as a disorder but, as a normal, and sometimes even welcome sign of healthy aging. Wentzells study of 250 Mexican men in their 50s and 60s found that “most simply did not see decreasing erectile function as a biological pathology”. The men interviewed described the decrease in erectile function “as an aid for aging in socially appropriate ways”. A common theme amongst the interviewees showed that respectable older men shifted their focus toward the domestic sphere into a “second stage of life”.  The Mexican men of this generation often pursued sex outside of marriage; decreasing erectile function acted as an aid to overcoming infidelity thus helping to attain the ideal “second stage” of life. A 56-year-old about to retire from the public health service said he would now "dedicate myself to my wife, the house, gardening, caring for the grandchildren—the Mexican classic". Wentzell found that treating ED as a pathology was antithetical to the social view these men held of themselves, and their purpose at this stage of their lives.
In the 20th and 21st centuries, anthropologists investigated how common treatments for ED are built upon assumptions of institutionalized social norms. In offering a range of clinical treatments to ‘correct’ a persons ability to produce an erection, biomedical institutions encourage the public to strive for prolonged sexual function. Anthropologists argue that a biomedical focus places emphasis on the biological processes of fixing the body thereby disregarding holistic ideals of health and aging. By relying on a wholly medical approach, Western biomedicine can become blindsided by bodily dysfunctions which can be understood as appropriate functions of age, and not as a medical problem. Anthropologists understand that a biosocial approach to ED considers a persons decision to undergo clinical treatment more likely a result of "society, political economy, history, and culture" than a matter of personal choice. In rejecting biomedical treatment for ED, men can challenge common forms of medicalized social control by deviating from what is considered the normal approach to dysfunction.

Lexicology
The Latin term impotentia coeundi describes simple inability to insert the penis into the vagina; it is now mostly replaced by more precise terms, such as erectile dysfunction (ED). The study of ED within medicine is covered by andrology, a sub-field within urology. Research indicates that ED is common, and it is suggested that approximately 40% of males experience symptoms compatible with ED, at least occasionally </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 Athelia (disease) 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 Quintuplets and can you explain it in depth? [/INST] Quintuplets is an American sitcom that aired 22 episodes on Fox from June 16, 2004 to January 12, 2005. The program starred Andy Richter and Rebecca Creskoff and shared some of their experiences parenting teenage quintuplets.

Synopsis
The series is set in Nutley, New Jersey, and looks like a typical family sitcom.  Much of the storyline focuses on the difficulty of supporting a large family of teens, both financially and emotionally, as they grapple with the reality that theyre no longer as cute as when they were babies.
The house is a typical three-bedroom family home.  The three male siblings share a room with bunk beds, the two females share another room.  The kitchen contains a double-wide beer cooler as a refrigerator, and the basement contains a walk-in freezer, both to store the large amounts of food such a large family requires.  The situation may be seen to parallel and parody the old sitcom The Brady Bunch, by highlighting the impracticality of the large family.
The theme song, "Suck or Shine," was performed by Chris and Tad.

Cast and characters
Bob Chase (Andy Richter) – The father sells office cubicles and barely makes enough money to support his large family. Most of his time is spent trying to save money, and he only occasionally provides parenting for his five teens, but hed prefer to get away whenever he has the chance. He also opines that he thinks half his children are freaks, blaming this and the fact that there were so many at once, on the fact that they were artificially inseminated.
Carol Chase (Rebecca Creskoff) – The mother maintains the large family and house in "typical sitcom homemaker" mode. In one episode she attempts to go back to work, but nobody wants her because shes been raising kids for 15 years. She goes back to being a homemaker and remains one for the rest of the show. She enforces the house rules.
Parker Chase (Jake McDorman) – The popular boy. Tallest of the children, good-looking, successful in academics and sports. He teases his brothers mercilessly, especially Pearce, but is also quick to defend them. The male quints share a deep bond, probably from sharing the womb </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 Actinomycetoma 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 Mucolipidosis type IV and can you explain it in depth? [/INST] Mucolipidosis type IV (ML IV, ganglioside sialidase deficiency, or ML4) is an autosomal recessive lysosomal storage disorder. Individuals with the disorder have many symptoms including delayed psychomotor development and various ocular aberrations. The disorder is caused by mutations in the MCOLN1 gene, which encodes a non-selective cation channel, mucolipin1. These mutations disrupt cellular functions and lead to a neurodevelopmental disorder through an unknown mechanism. Researchers dispute the physiological role of the protein product and which ion it transports.

Signs and symptoms
Most patients with ML IV show psychomotor retardation (i.e., delayed development of movement and coordination), corneal opacity, retinal degeneration and other ophthalmological abnormalities. Other symptoms include agenesis of the corpus callosum, iron deficiency resulting from an absence of acid secretion in the stomach, achlorhydria. Achlorhydria in these patients results in an increase in blood gastrin levels. These symptoms typically manifest early in life (within the first year). After disease onset there occurs a period of stability, typically lasting two to three decades during which very little disease progression occurs.

Pathophysiology
Mucolipin1 is thought to be localized in endosomes. An important property of mucolipin1 is that decreasing pH (acidification) results in deactivation of the protein, likely through an assembly defect. There are at least 29 known mutations in MCOLN1, located throughout the gene. Many of the known mutations result in no expression of mucolipin1. Milder mutations, such as ΔF408 and V446L, produce a dysfunctioning form of the cation channel. Mutations that alter only the C-terminal of the protein also result in a mild phenotype of the disorder, usually sparing the brain </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is California encephalitis orthobunyavirus and can you explain it in depth? [/INST] California encephalitis orthobunyavirus type strain California encephalitis virus was discovered in Kern County, California, and causes encephalitis in humans. Encephalitis is an acute inflammation of the brain that can cause minor symptoms, such as headaches, to more severe symptoms such as seizures.  Mosquitoes serve as its carrier and for this reason this virus is known as an arbovirus (arthropod-borne virus).
California encephalitis orthobunyavirus belongs to the Bunyavirales order of viruses. The La Crosse Virus from the same genus is also a common cause of encephalitis in the United States. Other viruses with similar disease symptoms but genetically unrelated include: Saint Louis encephalitis and West Nile virus.

Signs and symptoms
The incubation period of California encephalitis is usually 3–7 days.  An early symptoms phase of 1–4 days commonly precedes the onset of encephalitis, manifesting as fever, chills, nausea, vomiting, headache, lethargy and abdominal pain.The encephalitis is characterized by fever, drowsiness, and lack of mental alertness and orientation. Seizures occur in 50% of children. Focal neurologic findings, like focal motor abnormalities and paralysis, irregular and abnormal reflexes develop in 20% of children.  10% of patients develop coma.
The total duration of illness rarely exceeds 10–14 days. Recurrent unprovoked seizures occur even after the illness has passed develops in 20% of patients, especially those who had seizures during the acute illness.  In adults, infection is asymptomatic, which means that the patient is a carrier of the infection, but experiences no symptoms or only mild feverish illness.The mortality rate is less than 1% and most patients with encephalitis clinical symptoms recover completely. Up to 20% of patients develop behavioral problems or recurrent seizures.

Pathophysiology
Initial infection by the virus and primary spread of the virus causes the onset of non-specific symptoms such as headache and fever. Secondary spread and the multiplication of the virus in the CNS (central nervous system) causes symptoms such as stiff neck, lethargy and seizures.  It then can result in encephalitis, when inflammation of the brain, produced by infection by the virus, damages nerve cells, which affects signaling of the brain to the body.
After the virus enters the body via a mosquito bite, the virus undergoes local replication at the skin site where virus entered the body.  A primary spread of virus occurs, with seeding of the reticuloendothelial system, mainly in the liver, spleen, and lymph nodes.  With the ongoing replication of the virus a secondary spread occurs, with the seeding of the CNS.  Not all the cases reach this stage, depending on the efficiency of viral replication at the different stages and the degree of virus spread.  The California encephalitis virus invades the CNS through either the cerebral capillary endothelial cells or the choroid plexus.

Treatment
Treatments are given to manage the symptoms the patient is having.  In patients who are very sick, supportive treatment, such as mechanical ventilation, is equally important. Corticosteroids are used to reduce brain swelling and inflammation.  Sedatives may be needed for irritability or restlessness </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 Delayed ejaculation and can you explain it in depth? [/INST] Delayed ejaculation (DE) describes a mans inability or persistent difficulty in achieving orgasm, despite typical sexual desire and sexual stimulation. Generally, a man can reach orgasm within a few minutes of active thrusting during sexual intercourse, whereas a man with delayed ejaculation either does not have orgasms at all or cannot have an orgasm until after prolonged intercourse which might last for 30–45 minutes or more. Delayed ejaculation is closely related to anorgasmia.
In the Diagnostic and Statistical Manual of Mental Disorders (DSM), fifth edition, the definition of DE requires 1 of 2 symptoms: either a marked delay in or a marked infrequency or absence of ejaculation on 75% to 100% of occasions for at least 6 months of partnered sexual activity without the individual desiring delay, and causing significant distress to the individual. DE is meant to describe any and all of the ejaculatory disorders that result in a delay or absence of ejaculation. The Third International Consultation on Sexual Medicine defined DE as an IELT threshold beyond 20 to 25
minutes of sexual activity, as well as negative personal consequences such as bother or distress. Of note, most mens intravaginal ejaculation latency time range is approximately 4 to 10 minutes. While ejaculatory latency and control were significant criteria to differentiate men with DE from those without ejaculatory disorders, bother/distress did not emerge as a significant factor.Delayed ejaculation is the least common of the male sexual dysfunctions, and can result as a side effect of some medications. In one survey, 8% of men reported being unable to achieve orgasm over a two-month period or longer in the previous year. DEs are either primary and lifelong or acquired. Acquired DEs may be situational. While most men do experience occasional or short term delayed ejaculation issues, the prevalence of lifelong DE and acquired long term DE is estimated around 1% and 4%, respectively.

Signs and symptoms
Delayed ejaculation can be mild (men who still experience orgasm during intercourse, but only under certain conditions), moderate (cannot ejaculate during intercourse, but can during fellatio or manual stimulation), severe (can ejaculate only when alone), or most severe (cannot ejaculate at all). All forms may result in a sense of sexual frustration. In most cases, delayed ejaculation presents the condition in which the man can climax and ejaculate only during masturbation, but not during sexual intercourse.

Causes
The etiologies of delayed ejaculation can be age-related, organic, psychological, or pharmacological.Primary lifelong DEs are poorly understood and rarely explained by few congenital anatomic causes (viz., Müllerian duct cyst, Wolfian duct abnormalities, prune belly syndrome, imperforate anus, congenital ejaculatory duct obstruction, genetic abnormalities including cystic fibrosis, etc.)

Anatomic causes (acquired ejaculatory duct obstruction)
Infective/Inflammation (residual damage from acute infections, chronic infections, urethritis, prostatitis, orchitis, genitourinary tuberculosis, schistosomiasis, lichen sclerosis, etc.)
Neurogenic causes (diabetic autonomic neuropathy, spinal cord or nerve root injury from trauma or disc prolapse, multiple sclerosis, etc.). DE can be due to the injury to pelvic nerves responsible for orgasm from trauma as a result of pelvic surgery (viz., prostate surgery including  transurethral resection of prostate and bladder neck incision, proctocolectomy, bilateral sympathectomy, abdominal aortic aneurysmectomy, para-aortic lymphadenectomy etc.). Some men report a lack of sensation in the nerves of the glans penis, which may or may not be related to external factors, including a history of circumcision.
Endocrine (hypogonadism, pituitary disorders such as hyperprolactinaemia and Cushings disease, thyroid disorders, etc.). Although low testosterone level had been considered a risk factor in the past, more recent studies have not confirmed any association between ejaculation times and serum testosterone levels.
Delayed ejaculation is a possible side effect of alcohol  and certain medications, including antipsychotics, antidepressants including selective serotonin reuptake inhibitors (SSRIs), opiates such as morphine or oxycodone, many benzodiazepines such as Valium or Xanax, and certain antihypertensives including thiazide diuretics, alpha-adrenergic blockers and ganglion blockers. Although they may increase sexual desire, stimulants such as amphetamines and cocaine have an inhibitory effect on ejaculation, and can cause erectile dysfunction and reduced penile sensitivity via their vasoconstrictive effects.
Psychological (acute psychological distress, relationship distress, psychosexual skill deficit, disconnect between arousal and sexual situations, masturbation style and frequency, etc.)
Psychological and lifestyle factors have been discussed as potential contributors, including insufficient sleep, distraction due to worry, distraction from the environment, anxiety about pleasing their partner and anxiety about relationship problems.
Idiosyncratic masturbation and lack of desire for stimuli are also proposed risk factors for DE. The word Idiosyncratic means something that pertains to an individual. In this case, it means a person who has a way of masturbating that is unique (or out of the ordinary). Most men stroke their penis with their hand in a way that vaguely imitates the stimulation from intercourse. An idiosyncratic style is defined as a technique not easily duplicated by a partner utilizing their hand, mouth, anus, or vagina. In these patients delayed ejaculation is adaptation to a certain masturbatory technique. Lawrence Sank (1998) wrote about the "Traumatic masturbatory syndrome", when the sensations a man feels when masturbating may bear little resemblance to the sensations he experiences during intercourse. Factors such as pressure, angle and grip during masturbation can make for an experience so different from sex with a partner that the ability to ejaculate is reduced or eliminated. One in three men with DE report Idiosyncratic masturbation. Also, high-frequency masturbation is associated with prolonged DE in penetrative sex with the partner accounting for another one third of the cases. Fantasy/partner disparity – that is to say, variant sexual fantasy during masturbation that was not incorporated into sex with their partner – accounted for one in five DEs. According to DSM-5-TR, "Delayed ejaculation is associated with highly frequent masturbation, use of masturbation techniques not easily duplicated by a partner, and marked disparities between sexual fantasies during masturbation and the reality of sex with a partner."
Intravaginal ejaculation disorder is a peculiar Japanese case, but is very similar to "traumatic masturbatory syndrome," which is also mainly caused by intense masturbation.

Diagnosis
Diagnosis and management of DE warrant one of the most comprehensive medical evaluation in sexual health assessment that includes a full medical and sexual history performed along with a detailed physical examination. Understanding the quality of the sexual response cycle (desire, arousal, ejaculation, orgasm, and refractory period); details of the ejaculatory response, sensation, frequency, and sexual activity/techniques; cultural context and history of the disorder; partners assessment of the disorder and if the partner has any sexual dysfunction themselves; and the overall satisfaction of the sexual relationship are all important to garner during history-taking.Relatively normal latency to orgasm with self masturbation as compared to insertive or intravaginal ejaculation latency time reasonably rules out most of the organic causes of DEs.

Treatment
Primary, lifelong DEs are poorly understood and hence less well studied. Organic causes in the acquired DEs should be addresses promptly. Retraining masturbatory practices and re-calibrating the mismatch of sexual fantasies with arousal are essential when these are contributing to DE. Techniques geared towards reduction of anxiety are important skills that can help overcome performance anxiety, as this can often interrupt the natural erectile function through orgasmic progression.

Sex therapy
Therapy usually involves homework assignments and exercises intended to help a man get used to having orgasms through insertional intercourse, vaginal, anal, or oral, that is through the way to which he is not accustomed. Commonly, the couple is advised to go through three stages. At the first stage, a man masturbates in the presence of his partner </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 Kashin–Beck disease and can you explain it in depth? [/INST] Kashin–Beck disease (KBD) is a chronic, endemic type of osteochondropathy (disease of the bone) that is mainly distributed from northeastern to southwestern China, including 15 provinces. As of 2011, Tibet has the highest incidence rate of KBD in China. Southeast Siberia and North Korea are other affected areas. KBD usually involves children ages 5–15. To date, more than a million individuals have had KBD. The symptoms of KBD include joint pain, morning stiffness in the joints, disturbances of flexion and extension in the elbows, enlarged inter-phalangeal joints, and limited motion in many joints of the body. Death of cartilage cells in the growth plate and articular surface is the basic pathologic feature; this can result in growth retardation and secondary osteoarthrosis. Histological diagnosis of KBD is particularly difficult; clinical and radiological examinations have proved to be the best means for identifying KBD. Little is known about the early stages of KBD before the visible appearance of the disease becomes evident in the destruction of the joints.This disease has been recognized for over 150 years but its cause has not yet been completely defined. Currently, the accepted potential causes of KBD include mycotoxins present in grain, trace mineral deficiency in nutrition, and high levels of fulvic acid in drinking water. Selenium and iodine have been considered the major deficiencies associated with KBD. Mycotoxins produced by fungi can contaminate grain, which may cause KBD because mycotoxins cause the production of free radicals. T-2 is the mycotoxin implicated with KBD, produced by members of several fungal genera. T-2 toxin can cause lesions in hematopoietic, lymphoid, gastrointestinal, and cartilage tissues, especially in physeal cartilage. Fulvic acid present in drinking water damages cartilage cells. Selenium supplementation in selenium deficient areas has been shown to prevent this disease. However, selenium supplementation in some areas showed no significant effect, meaning that deficiency of selenium may not be the dominant cause in KBD. Recently a significant association between SNP rs6910140 of COL9A1 and Kashin–Beck disease was discovered genetically, suggesting a role of COL9A1 in the development of Kashin–Beck disease.

Cause
The cause of KBD remains controversial. Studies of the pathogenesis and risk factors of KBD have proposed selenium deficiency, inorganic (e.g. manganese, phosphate) and organic matter (humic and fulvic acids) in drinking water, and fungi on self-produced storage grain (Alternaria sp., Fusarium sp.) producing trichotecene (T2) mycotoxins.
Most authors accept that the cause of KBD is multifactorial, selenium deficiency being the underlying factor that predisposes the target cells (chondrocytes) to oxidative stress from free-radical carriers, such as mycotoxins in storage grain and fulvic acid in drinking water.
In Tibet, epidemiological studies carried out in 1995–1996 by MSF and coll. showed that KBD was associated with iodine deficiency and with fungal contamination of barley grains by Alternaria sp., Trichotecium sp., Cladosporium sp. and Drechslera sp. Indications existed as well with respect to the role of organic matters in drinking water.
A severe selenium deficiency was documented as well, but selenium statuswas not associated with the disease, suggesting that selenium deficiency alone could not explain the occurrence of KBD in the villages under study.An association with the gene Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 Beta (PPARGC1B) has been reported. This gene is a transcription factor and mutations in this gene would be expected to affect several other genes.

Prevention
Prevention of Kashin–Beck disease has a long history. Intervention strategies were mostly based on one of the three major theories of its cause.
Selenium supplementation, with or without additional antioxidant therapy (vitamin E and vitamin C) has been reported to be successful, but in other studies no significant decrease could be shown compared to a control group. Major drawbacks of selenium supplementation are logistic difficulties (including daily or weekly intake and drug supply), potential toxicity (in case of less well-controlled supplementation strategies), associated iodine deficiency (that should be corrected before selenium supplementation to prevent further deterioration of thyroid status) and low compliance. The latter was certainly the case in Tibet, where selenium supplementation has been implemented from 1987 to 1994 in areas of high endemicity.
With the mycotoxin theory in mind, backing of grains before storage was proposed in Guangxi province, but results are not reported in international literature. Changing from grain source has been reported to be effective in Heilongjiang Province and North Korea.
With respect to the role of drinking water, changing of water sources to deep well water has been reported to decrease the X-ray metaphyseal detection rate in different settings.
In general, the effect of preventive measures however remains controversial, due to methodological problems (no randomised controlled trials), lack of documentation, or, as discussed above, inconsistency of results.

Treatment
Treatment of KBD is palliative. Surgical corrections have been made with success by Chinese and Russian orthopedists. By the end of 1992, Médecins Sans Frontières—Belgium started a physical therapy programme aiming at alleviating the symptoms of KBD patients with advanced joint impairment and pain (mainly adults), in Nyemo county, Lhasa prefecture </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 Galactorrhea and can you explain it in depth? [/INST] Galactorrhea (also spelled galactorrhoea) (galacto- + -rrhea) or lactorrhea (lacto- + -rrhea) is the spontaneous flow of milk from the breast, unassociated with childbirth or nursing.
Galactorrhea is reported to occur in 5–32% of women. Much of the difference in reported incidence can be attributed to different definitions of galactorrhea. Although frequently benign, it may be caused by serious underlying conditions and should be properly investigated. Galactorrhea also occurs in males, newborn infants and adolescents of both sexes.

Causes
Galactorrhea can take place as a result of dysregulation of certain hormones </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 Stepsibling and can you explain it in depth? [/INST] Step-siblings are children born of two different families who have been joined by marriage, A male step-sibling is a stepbrother and a female is a stepsister. The step-siblings relationship is connected through law and is not a blood relation.
Step-siblings are sometimes abbreviated informally as stepsibs.

Culture
In many fairy tales, the central character has a stepmother and the step-siblings serve as an extension of their mother </s>