<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Ductal carcinoma in situ and explain in detail? [/INST] Ductal carcinoma in situ (DCIS), also known as intraductal carcinoma, is a pre-cancerous or non-invasive cancerous lesion of the breast. DCIS is classified as Stage 0. It rarely produces symptoms or a breast lump one can feel, typically being detected through screening mammography. It has been diagnosed in a significant percentage of men (see male breast cancer).In DCIS, abnormal cells are found in the lining of one or more milk ducts in the breast. In situ means "in place" and refers to the fact that the abnormal cells have not moved out of the mammary duct and into any of the surrounding tissues in the breast ("pre-cancerous" refers to the fact that it has not yet become an invasive cancer). In some cases, DCIS may become invasive and spread to other tissues, but there is no way of determining which lesions will remain stable without treatment, and which will go on to become invasive. DCIS encompasses a wide spectrum of diseases ranging from low-grade lesions that are not life-threatening to high-grade (i.e. potentially highly aggressive) lesions.
DCIS has been classified according to the architectural pattern of the cells (solid, cribriform, papillary, and micropapillary), tumor grade (high, intermediate, and low grade), the presence or absence of comedo histology, or the cell type forming the lesion in the case of the apocrine cell-based in situ carcinoma, apocrine ductal carcinoma in situ. DCIS can be detected on mammograms by examining tiny specks of calcium known as microcalcifications. Since suspicious groups of microcalcifications can appear even in the absence of DCIS, a biopsy may be necessary for diagnosis.
About 20–30% of those who do not receive treatment develop breast cancer. It is the most common type of pre-cancer in women. There is some disagreement on its status as a cancer; some bodies include DCIS when calculating breast cancer statistics, while others do not.

Terminology
Ductal carcinoma in situ (DCIS) literally means groups of "cancerous" epithelial cells which remained in their normal location (in situ) within the ducts and lobules of the mammary gland. Clinically, it is considered a premalignant (i.e. potentially malignant) condition, because the biologically abnormal cells have not yet crossed the basement membrane to invade the surrounding tissue. When multiple lesions (known as "foci" of DCIS) are present in different quadrants of the breast, this is referred to as "multicentric" disease.For statistical purposes, some count DCIS as a "cancer", whereas others do not. When classified as a cancer, it is referred to as a non-invasive or pre-invasive form. The National Cancer Institute describes it as a "noninvasive condition".

Signs and symptoms
Most of the women who develop DCIS do not experience any symptoms. The majority of cases (80-85%) are detected through screening mammography. The first signs and symptoms may appear if the cancer advances. Because of the lack of early symptoms, DCIS is most often detected at screening mammography.
In a few cases, DCIS may cause:

A lump or thickening in or near the breast or under the arm
A change in the size or shape of the breast
Nipple discharge or nipple tenderness; the nipple may also be inverted, or pulled back into the breast
Ridges or pitting of the breast; the skin may look like the skin of an orange
A change in the way the skin of the breast, areola, or nipple looks or feels such as warmth, swelling, redness or scaliness.

Causes
The specific causes of DCIS are still unknown. The risk factors for developing this condition are similar to those for invasive breast cancer.Some women are however more prone than others to developing DCIS. Women considered at higher risks are those who have a family history of breast cancer, those who have had their periods at an early age or who have had a late menopause. Also, women who have never had children or had them late in life are also more likely to get this condition.
Long-term use of estrogen-progestin hormone replacement therapy (HRT) for more than five years after menopause, genetic mutations (BRCA1 or BRCA2 genes), atypical hyperplasia, as well as radiation exposure or exposure to certain chemicals may also contribute in the development of the condition. Nonetheless, the risk of developing noninvasive cancer increases with age and it is higher in women older than 45 years.

Diagnosis
80% of cases in the United States are detected by mammography screening. More definitive diagnosis is made by breast biopsy for histopathology.

Treatment
There are different opinions on the best treatment of DCIS. Surgical removal, with or without additional radiation therapy or tamoxifen, is the recommended treatment for DCIS by the National Cancer Institute. Surgery may be either a breast-conserving lumpectomy or a mastectomy (complete or partial removal of the affected breast). If a lumpectomy is used it is often combined with radiation therapy. Tamoxifen may be used as hormonal therapy if the cells show estrogen receptor positivity. Research shows that survival is the same with lumpectomy as it is with mastectomy, whether or not a woman has radiation after lumpectomy. Chemotherapy is not needed for DCIS since the disease is noninvasive.While surgery reduces the risk of subsequent cancer, many people never develop cancer even without treatment and the associated side effects. There is no evidence comparing surgery with watchful waiting and some feel watchful waiting may be a reasonable option in certain cases.

Radiation therapy
Use of radiation therapy after lumpectomy provides equivalent survival rates to mastectomy, although there is a slightly higher risk of recurrent disease in the same breast in the form of further DCIS or invasive breast cancer. Systematic reviews (including a Cochrane review) indicate that the addition of radiation therapy to lumpectomy reduces recurrence of DCIS or later onset of invasive breast cancer in comparison with breast-conserving surgery alone, without affecting mortality. The Cochrane review did not find any evidence that the radiation therapy had any long-term toxic effects. While the authors caution that longer follow-up will be required before a definitive conclusion can be reached regarding long-term toxicity, they point out that ongoing technical improvements should further restrict radiation exposure in healthy tissues </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Vestibular schwannoma and explain in detail? [/INST] A vestibular schwannoma (VS), also called acoustic neuroma, is a benign tumor that develops on the vestibulocochlear nerve that passes from the inner ear to the brain. The tumor originates when Schwann cells that form the insulating myelin sheath on the nerve malfunction. Normally, Schwann cells function beneficially to protect the nerves which transmit balance and sound information to the brain. However, sometimes a mutation in the tumor suppressor gene, NF2, located on chromosome 22, results in abnormal production of the cell protein named Merlin, and Schwann cells multiply to form a tumor. The tumor originates mostly on the vestibular division of the nerve rather than the cochlear division, but hearing as well as balance will be affected  as the tumor enlarges.
The great majority of these VSs (95%) are unilateral, in one ear only. They are called "sporadic" (i.e., by-chance, non-hereditary). Although non-cancerous, they can do harm or even become life-threatening if they grow to press on other cranial nerves and vital structures such as the brainstem. Variations in the mutation determine the nature of the tumors development. The only environmental exposure that has been definitely associated with the growth of a VS is therapeutic radiation exposure to the head.

Symptoms of Sporadic VS
Sporadic VSs originate within the confining bony walls of the small (ca. 2 cm long) internal auditory canal. The most common early symptoms of these intracanalicular (IAC) VSs are gradual hearing loss and a feeling of fullness in the affected ear, some imbalance or dizziness, and tinnitus (ringing or other noise in the ear). Gradual single-sided hearing loss in the high frequencies is the first most obvious symptom for the great majority of patients. Headache as a presenting symptom of VS specifically is rare; facial symptoms (facial numbness, weakness) usually occur only as the tumor grows out of the canal and/or after therapeutic treatment. Delayed diagnosis and misdiagnosis are not unusual. Initial hearing loss is usually subtle and may be attributed mistakenly to aging, earwax buildup, or perhaps exposure to some loud environmental noise. A sudden hearing loss, which is uncommon, might be misdiagnosed as Ménières disease, an abnormality of the inner ear that also has tinnitus as a symptom. The brains vestibular system usually compensates for early balance problems.
There have been cases of tumors that were actually asymptomatic until very large and at a critical stage. Tumor growth rates are highly variable: some small VSs (perhaps 50%) do not grow at all; some few grow for a time and then shrink; some appear dormant but suddenly grow rapidly. In general, although studies differ, VSs that grow are slow-growing at an average rate of 1.2 to 1.9 mm per year. IAC tumors that grow beyond 1.5 cm in diameter expand into the relatively empty space of the cerebellopontine angle, taking on the characteristic ice-cream-cone appearance seen on MRIs. As space-occupying-lesions, the tumors can reach 3 to 4 cm or more in size and infringe on the facial nerve (facial expression) and trigeminal nerve (facial sensation). Advanced hearing loss and spells of true vertigo may occur. Very large tumors are life-threatening when they press on the cerebellum or cause brainstem compression. Late symptoms of very large VS include headache, nausea, vomiting, sleepiness, mental confusion and eventually coma.

Neurofibromatosis Type 2 (NF2)
For the most part, unilateral sporadic vestibular schwannomas are readily treated successfully by modern medical techniques. Having bilateral VSs is a more troublesome condition. Bilateralism is considered to be the hallmark and main diagnostic criterion of Neurofibromatosis Type II (NF2), a genetic disorder that is heritable, progressive, difficult to manage, and has a 1 in 2 chance of being passed on to each offspring. NF2 patients tend to have a more severe mutation, although there are mild mosaic cases in which only some cells carry the mutation. Genetic testing confirming mutation of the NF2 gene is recommended. About 50% of people with NF2 have a de novo mutation, and about 50% of these new mutations will be mild mosaic cases which are less likely to be passed on. NF2 patients may develop other cranial and spine tumors. NF2 develops during the teens or early adulthood, whereas sporadic VSs are diagnosed mostly in patients between the ages of 40–60 years. Both varieties of VS (sporadic and NF2) are very rare, accounting for only about 8% of all primary brain tumors. The incidence of NF2 is approximately 1 per 60,000 people.

Tumor sizes
Patient surveys in the U.S. by the national Acoustic Neuroma Association (1998, 2007–08, 2012, 2014) showed that the percentage of diagnosed tumors 1.5 cm or less increased significantly from 23% to 47%. Researchers in Denmark reported (2004): "The size of diagnosed tumors has decreased from a median of 35 mm in 1979 to 10 mm in 2001." In general, tumor size (diameter) is described as small (less than 1.5 cm), medium (1.5 to 2.5 cm), large (2.5 to 4.0 cm) and giant (more than 4.0 cm). (Note: 1 inch = 2.54 cm) Radiologists reporting on MRI scans use the Koos Grading Scale which relates tumor size to its proximity to the brainstem and nearby cranial nerves. Thus Koos grade 1 is a purely intrameatal (IAC) tumor, 1–10 mm in size; Koos grade 2, 10–20 mm, has extended into the cerebellopontine angle (CPA), but with no brainstem contact; Koos grade 3, 20–30 mm, fills the CPA space and touches on the brainstem, but without compression; and Koos grade 4, more than 30 mm in size, compresses the brainstem and nearby nerves, and displaces critical arteries.

Diagnosis
Preliminary diagnostic procedures include ear examination, hearing and vestibular testing. The auditory brainstem response test (ABR) is a cost-effective test to see if a VS has perhaps compromised the cochlear nerve.Computed tomography (CT scan) of the head will detect moderate to large sized VS but can miss small sized VS. VS appears as isodense to surrounding brain parenchyma on CT. VS does not have calcifications in it. Large VS will expand the size of internal acoustic meatus (IAC), thus associated with poor hearing function because the nerves within the IAC are compressed, particularly the cochlear nerve. However, facial nerve is less commonly affected. The main advantage of CT scan is to assess the extent of bony involvement by VS. VS enhances when iodinated contrast is given. Contrasted CT scan of temporal bone can done if the subject is unsuitable to undergo MRI scan.MRI scan is the imaging of choice because it can more accurately differentiate the mass from other tumours such as meningioma, facial nerve schwannoma, epidermoid cyst, arachnoid cyst, aneurysm, and brain metastasis. MRI scan also helps in surgical planning and follow-up of the tumour after surgery. VC is usually isointense on T1 weighted images, hyperintense on T2 weighted images, and enhances after given gadolinium contrast.

Management
Microsurgery for Sporadic VS
The Guidelines on the Treatment of Adults with Vestibular Schwannoma issued in 2018 by the Congress of Neurological Surgeons in the U.S. looked at the long-term evolution of treatments for VS. The Introduction to the Guidelines stated: "The evolution in treatment over the last century has ultimately led to an environment where functional outcome has taken precedence over disease eradication. With multiple noninvasive management options available, the tolerance of cranial neuropathy in patients with small and medium-sized tumors is low. Today, hearing preservation, facial nerve function, and tumor control remain the primary benchmarks used to evaluate treatment effectiveness and compare outcomes." In other words, tumor management was able to give greater attention to preserving quality of life.
The three main surgical approaches to the tumor were the translabyrinthine (incision behind the ear to reach the bony labyrinth), the retrosigmoid (incision behind the ear to reach cerebellopontine angle) and the middle cranial fossa (incision in front of the ear to access the IAC from above). Tumor size was a major factor in determining approach selection. Adjunctive use of the endoscope for enhanced visualization during surgery for IAC tumors gained attention as an emerging technique with advancing technology. For large tumors, a facial nerve sparing surgery evolved offering partial removals, to be followed (as needed) by stereotactic radiosurgery or radiotherapy for residuals. The rate of tumor control appeared to be similar to that for gross total removal surgeries. For small to medium size tumors, the appropriateness of so-called hearing preservation surgery via either the Middle Fossa or Retrosigmoid approach remained controversial. Data from Denmark indicated that primary observation offered the best chance to preserve good hearing the longest. But preserving good hearing in the affected ear remained an elusive goal. Even during observation, although tumors showed no significant growth, hearing deterioration occurred. Stangerup et al. reported (2010) that most patients with 100% speech discrimination at diagnosis had the best chance of maintaining good hearing after ten years of observation.
Structured surgical training of neurosurgeons and official accreditation replaced the ages-old informal apprenticeship model. Advances in microsurgical instrumentation, the refinement of operative techniques including the introduction of intraoperative facial and cochlear nerve monitoring, and the development of multidisciplinary team-based patient care reduced the incidence of complications related to treatment. There was a trend toward the emergence of high-patient-volume centers for VS surgery where good outcomes and routine patient discharges could become commonplace. The mortality rate for VS surgery fell to less than 1%. In 1991 the NIH Consensus Statement for Acoustic Neuroma observed: "The best published surgical outcomes in the treatment of vestibular schwannoma are from medical centers that have highly organized and dedicated teams with a specific interest in these tumors and sufficient continuing experience to develop, refine and maintain proficiency."ref>Sweeney A, Breen JT, Vrabec JT (2019). "Chapter 29: Training in Vestibular Schwannoma Surgery".  In Carlson ML, Link MJ, Driscoll CL,  et al. (eds.). Comprehensive Management of Vestibular Schwannoma. New York. ISBN 978-1-62623-332-4.</ref>

Radiosurgery and radiotherapy
The 1991 NIH Consensus Statement recognized radiation therapy as "a treatment option limited in current practice primarily to patients unable or unwilling to undergo otherwise indicated surgery." The beneficiaries of radiation therapy soon greatly exceeded this limited clientele. The Patient Survey in the U.S. in 2014 by the national Acoustic Neuroma Association showed that 29% of VS patients reported radiosurgery (17%) or radiotherapy (12%) as their treatment of choice. Radiosurgery is the delivery to the VS of a concentrated high radiation dose in a one-day session, whereas radiotherapy involves multiple treatment sessions where the total radiation dose is spread out in fractions over a few days or 3–4 weeks. The main objective in either case is tumor control by damaging tumor cell DNA and stopping blood vessel proliferation (angiogenesis) needed for tumor growth.
Tumors may swell following radiation, but this increase in size is transient and does not signal a failed procedure. A failed radiosurgery is uncommon. Radiation doses are calculated in terms of Gray/Gy—the measure of energy deposited by ionizing radiation per kilogram of matter -- "named after the British physicist Louis Harold Gray (1905–1965), a pioneer in the measurement of X-ray and radium radiation and their effects on living tissue."  Since VSs are noninvasive and well-demarcated from surrounding tissues, as is apparent on MRI scans, radiosurgeons are able to target the tumor volume closely and minimize normal tissue damage. Multisession radiotherapy recommends the advantage of giving time between sessions for biological repair of any damage to normal tissues that may occur, and allows for radiation of the tumor at different times in the cell growth cycle.
The CyberKnife radiation system introduced in 1994 recommends a protocol of three sessions known as hypofractionation. Radiation dosages overall were reduced over the years as experience showed that excellent tumor control rates could be maintained even as dosages were lowered to benefit hearing preservation and facial nerve function. Generally, single-session Gamma Knife radiosurgery is limited in use to VSs less than 3 cm in diameter to avoid possible complications with facial nerves, brainstem and the cochlea apparatus. The risk of radiation-induced secondary tumors is very small, in the range of 0.01-0.02%. The risk for NF2 patients appears to be slightly higher.

Medical and gene therapies
The 1991 NIH Consensus Statement recommended attention to "the development of pharmaceutical and other alternative medical treatments, such as tumor suppressing agents." Ideally, a drug could be found to permanently shrink or eradicate VSs, with minimal side effects. A key step forward in 1993 was the identification of the NF2 gene and its protein product Merlin, which modulates the complex molecular signaling pathways that control cell proliferation. These pathways that drive VS formation (tumorigenesis) and growth are currently under investigation.
A second important field of study in molecular biology investigates ways to stop the formation (angiogenesis) of the new blood vessels that are needed to support tumor growth by supplying nutrients and oxygen. In 1998, the glycoprotein named VEGF (vascular endothelial growth factor) that initiates proliferation was discovered. An anti-VEGF drug named bevacizumab (Avastin) was developed and showed promise in stopping this vascular proliferation. Unfortunately, when tested for NF2 tumors, the therapy required prolonged treatment resulting in hypertension and impaired wound healing. Clinical trials are in progress for other drugs such as everolimus, lapatinib and mifepristone. Common aspirin has been studied as a low-risk therapeutic option.
To date, there is no fully efficacious medical therapy for VS. The complexity of the molecular biology research involved is truly challenging. The development of a new generation of drugs may become a secondary therapy in view of advances in genome editing during the 1990s that led to the invention of CRISPR in 2009. CRISPR has become the preferred genome editing tool whereby diseases may be treated by correcting causative mutations directly in a patients genome.

Observation of Small VS
The 1991 NIH Consensus Statement observed: "There is evidence that some patients with unilateral vestibular schwannoma and a subgroup of patients with NF2 may have tumors that fail to progress rapidly, resulting in stable neurologic function for a long time. The use of MRI with contrast enhancement has resulted in the identification of patients with very small, relatively asymptomatic vestibular schwannomas for whom the natural history is unknown. Conservative management may be appropriate for these patients." At the time, conservative management (i.e., observation, wait-and-watch/wait-and-scan) was reserved mainly for elderly or infirm patients.
Data on tumor sizes at diagnosis and tumor growth behavior was sparse or contradictory and mainly short-term. The Central Brain Tumor Registry of the U.S., established in 1992, only began to keep records for benign tumors like VS in 2004. In 2006, a landmark study from Denmark, entitled "The Natural History of Vestibular Schwannoma," initiated a significant trend toward observation for managing small VS. Researchers in Copenhagen had the advantage that data for all Danish patients diagnosed with VS since 1976 was entered into a national database. The 2006 study by Stangerup et al. looked at the data for 1,818 patients (1976–2004) comparing intrameatal VS (in the auditory canal) and extrameatal VS (into the cerebellopontine angle). Remarkably, for the 729 patients having observation management via interval MRI scans, tumor growth was observed in only 17% of intrameatal tumors and 29% of extrameatal tumors. The mean observation time was 3.6 years (range 1–15 years). The researchers concluded: "VS growth occurs within the first 5 years after diagnosis in a limited number of tumors, primarily in tumors with an extrameatal extension. These findings justify primary observation of small tumors." The medical community and VS patients responded positively to these findings.
Patient Surveys in the U.S. by the national Acoustic Neuroma Association showed an increase in "Wait-and-Watch" from 4% of respondents in 1998 to 20% in 2012. An important study in 2015 entitled "The Changing Landscape of Vestibular Schwannoma Management in the United States – A Shift Toward Conservatism," predicted that half of all cases of VS would be managed initially with observation by 2026. Stangerup et al. have urged caution (2019): "Most studies show that if tumor growth occurs, it is usually detected within the first few years of diagnosis. However, long-term observational studies are desperately needed to guide the development of evidence-based surveillance algorithms designed to detect late tumor progression." Also (see Medical and Gene Therapies, above): "Basic science and identification of genes, molecular pathways, and networks related to tumor growth are likely to change our approach to treatment including conservative management."

Incidence of Sporadic VS
The U.S. National Institutes of Health (NIH) consensus statement for Acoustic Neuroma in 1991 estimated that 2–3,000 cases of VS were diagnosed in the U.S. annually—an incidence rate of about 10 per million of population per year. In 2015, researchers at the Cleveland Clinic in Ohio used population-based data of the Central Brain Tumor Registry of the U.S. to calculate an incidence of 10.9 per million of population, or about 3,300 cases of VS per year. A higher incidence up to 29.3 per million of population was found for the 65-74 year-old age group. There was no significant difference in incidence by gender. Incidence was higher in Asian Pacific Islanders, and lower in African Americans and Hispanics. The annual number of diagnosed VS increased significantly worldwide by the early 1990s with the introduction of magnetic resonance imaging (MRI). Notably, epidemiologists in Denmark (population of 5.7 million in 2015) reported 193 cases of VS for 2015—an incidence of 34 per million of population per year. The first MRI scanner in Denmark was functional in 1989, and by 2015 the number increased to approximately 100.

History
Early descriptions
In 1777, Eduard Sandifort of Leiden, the Netherlands, wrote a postmortem first description of a vestibular schwannoma. He observed "a certain hard body adherent to the auditory nerve," and concluded this cause of deafness was beyond the reach of medication or surgery and was therefore incurable. The Schwann cells that multiply to form a VS on the vestibulocochlear nerve were identified 60 years later in 1838 by the German physiologist Theodor Schwann, the co-founder with the botanist Matthias Schleiden of the critically important cell theory that all living things are composed of cells. In 1895, Thomas Annandale, a general surgeon at the Royal Infirmary in Edinburgh, Scotland, was the first to successfully localize and surgically remove a VS. His achievement was exceptional. Finger dissection of VS to shell out the tumor was typical. The main goal when dealing with large tumors was preservation of life.

Early surgeries
In the early 1900s the mortality rate for VS surgery was in the range of 75 to 85%. Surgeons typically delayed invasive intervention as long as possible as a last resort. Harvey Cushing (1869–1939) is known as the father of neurosurgery for VS. His basic study published in 1917 was entitled Tumors of the Nervus Acusticus and the Syndrome of the Cerebellopontine Angle. Cushing perfected the retrosigmoid surgical approach, and by doing suboccipital craniotomy and subtotal removals he was able to reduce mortality to 4% by 1931. Cushing worked at Brigham Hospital in Boston. An equally famous specialist for VS at Johns Hopkins in Baltimore was Walter E. Dandy (1886–1946), a former pupil of Cushing who advocated total tumor removals. In 1931, he reported a complete removal with preservation of the facial nerve.

Imaging
A major problem for the pioneers in VS neurosurgery was the lack of adequate imaging for spotting small tumors. Treating tumors that grew overly large in the cerebellopontine angle resulted in poor outcomes for the goals of facial nerve and hearing preservation. For imaging, conventional X-rays began to be used in the 1920s and CT scanners were introduced in the 1960s, but all were superseded by gold standard MRIs in the 1980s. Facial nerve monitoring was added in 1979. William F. House (1923–2012) pioneered the use of the operating microscope, and (with William Hitselberger) popularized the translabyrinthine and middle fossa surgery approaches for VS. The operating microscope would be used in virtually all operations by 1998. Houses son, John W. House, proposed (1983) and, with Derald E. Brackmann, developed the House-Brackmann grading system for reporting facial nerve outcomes following VS surgery.

Treatment
Surgical treatment
In 1986, at a meeting for neurosurgeons in San Francisco, the House group endorsed a guideline for the surgical treatment of VS: "The best opportunity for successful removal of an acoustic neuroma is when it is small: when first diagnosed."  At the time of the NIH Consensus Development Conference for Acoustic Neuroma in 1991, microsurgery was definitely the predominant management strategy for VS. The consensus conferences panel of experts reported: "Currently, the ideal treatment for symptomatic patients with vestibular schwannoma is the total excision of the tumor in a single stage with minimal morbidity and mortality and with preservation of neurological function." Total surgical removal was not, however, the only treatment indicated at the time. Partial removals were in use to debulk very large VSs threatening to compress vital structures. And long-term observation management was deemed appropriate as MRI scans began to reveal more and more small tumors with stable neurological symptoms.

Radiosurgery
By the 1980s, radiation therapy was also becoming an attractive option for VS patients. At the Karolinska Institute in Stockholm, Sweden, Lars Leksell (1907–1986) pioneered Gamma Knife radiosurgery </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Charcot–Marie–Tooth disease and explain in detail? [/INST] Charcot–Marie–Tooth disease (CMT) is a hereditary motor and sensory neuropathy of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. This disease is the most commonly inherited neurological disorder, affecting about one in 2,500 people. It is named after those who classically described it: the Frenchman Jean-Martin Charcot (1825–1893), his pupil Pierre Marie (1853–1940), and the Briton Howard Henry Tooth (1856–1925).There is no known cure. Care focuses on maintaining function. CMT was previously classified as a subtype of muscular dystrophy.

Signs and symptoms
Symptoms of CMT usually begin in early childhood or early adulthood but can begin later. Some people do not experience symptoms until their early 30s or 40s. Usually, the initial symptom is foot drop early in the course of the disease. This can also cause hammertoe, where the toes are always curled. Wasting of muscle tissue of the lower parts of the legs may give rise to a "stork leg" or "inverted champagne bottle" appearance. Weakness in the hands and forearms occurs in many people as the disease progresses.Loss of touch sensation in the feet, ankles, and legs as well as in the hands, wrists, and arms occurs with various types of the disease. Early- and late-onset forms occur with on and off painful spasmodic muscular contractions that can be disabling when the disease activates.  High-arched feet (pes cavus) or flat-arched feet (pes planus) are classically associated with the disorder. Sensory and proprioceptive nerves in the hands and feet are often damaged, while unmyelinated pain nerves are left intact. Overuse of an affected hand or limb can activate symptoms including numbness, spasm, and painful cramping.Symptoms and progression of the disease can vary. Involuntary grinding of teeth and squinting are prevalent and often go unnoticed by the person affected. Breathing can be affected in some, as can hearing, vision, and neck and shoulder muscles. Scoliosis is common, causing hunching and loss of height. Hip sockets can be malformed. Gastrointestinal problems can be part of CMT, as can difficulty chewing, swallowing, and speaking (due to atrophy of vocal cords). A tremor can develop as muscles waste. Pregnancy has been known to exacerbate CMT, as well as severe emotional stress. Patients with CMT must avoid periods of prolonged immobility such as when recovering from a secondary injury, as prolonged periods of limited mobility can drastically accelerate symptoms of CMT.Pain due to postural changes, skeletal deformations, muscle fatigue, and cramping is fairly common in people with CMT. It can be mitigated or treated by physical therapies, surgeries, and corrective or assistive devices. Analgesic medications may also be needed if other therapies do not provide relief from pain. Neuropathic pain is often a symptom of CMT, though, like other symptoms of CMT, its presence and severity vary from case to case. For some people, pain can be significant to severe and interfere with daily life activities. However, pain is not experienced by all people with CMT. When neuropathic pain is present as a symptom of CMT, it is comparable to that seen in other peripheral neuropathies, as well as postherpetic neuralgia and complex regional pain syndrome, among other diseases.

Causes
Charcot–Marie–Tooth disease is caused by genetic mutations that cause defects in neuronal proteins. Nerve signals are conducted by an axon with a myelin sheath wrapped around it. Most mutations in CMT affect the myelin sheath, but some affect the axon.

Classification
CMT is a heterogeneous disease and the mutations linked to it may occur in a number of different genes. Based on the affected gene, CMT is categorized into several types and subtypes.

Chromosome 17
The most common cause of CMT (70–80% of the cases) is the duplication of a large region on the short arm of chromosome 17 that includes the gene PMP22.Some mutations affect the gene MFN2, on chromosome 1, which codes for a mitochondrial protein. Mutated MFN2 causes the mitochondria to form large clusters, or clots, which are unable to travel down the axon towards the synapses. This prevents the synapses from functioning.

X-linked CMT and Schwann cells
CMT can also be produced by X-linked mutations and is named X-linked CMT (CMTX). In CMTX, mutated connexons create nonfunctional gap junctions that interrupt molecular exchange and signal transport.The mutation can appear in GJB1 coding for connexin 32, a gap junction protein expressed in Schwann cells. Because this protein is also present in oligodendrocytes, demyelination can appear in the CNS.Schwann cells create the myelin sheath, by wrapping its plasma membrane around the axon.Neurons, Schwann cells, and fibroblasts work together to create a functional nerve. Schwann cells and neurons exchange molecular signals by gap junctions that regulate survival and differentiation.Demyelinating Schwann cells causes abnormal axon structure and function. They may cause axon degeneration, or they may simply cause axons to malfunction.The myelin sheath allows nerve cells to conduct signals faster. When the myelin sheath is damaged, nerve signals are slower, and this can be measured by a common neurological test, electromyography. When the axon is damaged, though, this results in a reduced compound muscle action potential.GARS1-Related Axonal Neuropathy
CMT2 types are typically referred to as axonal neuropathies due to the axonal degeneration observed. CMT2 types are a result of damage to the nerve axons rather than damage to the myelin sheath (as is the case with CMT1). Damaged axons cause slowed transmission of signals to the muscles and brain, causing symptoms including muscle atrophy, weakness, decreased sensitivity, and foot deformity. Symptoms of CMT2 types typically appear between the ages of 5 and 25. CMT2D is one of 31 Charcot-Marie-Tooth type 2 forms 1 and is only diagnosed if sensory deficits (such as loss of sensation due to the degradation of sensory axons) are observed along with motor deficits; otherwise, distal hereditary motor neuropathy type V is diagnosed. It is unknown why sensory involvement is so varied between GARS1 neuropathy patients. Symptoms of CMT2D include foot deformity, muscle weakness and cramping, compromised reflexes, loss of sensation, and muscle atrophy and are similar to the symptoms of other both CMT1 and CMT2 types. Symptoms and severity vary from patient to patient.Mice are often used to model CMT2D and typically demonstrate aberrant neuromuscular function at the neuromuscular junction (NMJ). The neuromuscular junction is abnormal in CMT2D mice, with subjects showing neuromuscular junction degeneration in hind muscles. The dorsal root ganglia (DRG) is also affected via aberrant sensory neuron fate, meaning that sensory neuron cell fates are abnormally determined. CMT2D mice have fewer proprioceptive and mechanosensitive neurons, but have more nociceptive neurons, possibly due to mutant GlyRS aberrantly interacting with the extracellular region of tropomyosin receptor kinase, or Trk, receptors.  Trk receptors are crucial to the survival and development of sensory neurons; when disrupted, nerve development and survival is disrupted as well, possibly leading to the abnormal sensory neuron counts observed in CMT2D mice.CMT2D is a result of autosomal dominant mutations in the human GARS1 gene located at 7p14.3  and is thought to be caused by aberrant gain-of-function missense mutations. The GARS1 gene is a protein-coding gene responsible for the encoding of glycyl-tRNA synthetase (GlyRS). Glycyl-tRNA synthetase is a class II aminoacyl-tRNA synthetase and acts as the catalyst for the synthesis of glycyl-tRNA by covalently bonding amino acids with their corresponding cognate tRNAs for protein translation. Glycyl-tRNA is integral to protein translation and attaches glycine to its cognate RNA.Many different mutations have been found in CMT2D patients and it remains unclear how mutations in GARS1 cause CMT2D. However, it is thought that mutant glycyl-tRNA synthetase (GlyRS) interferes with transmembrane receptors, causing motor disease and that mutations in the gene could disrupt the ability of GlyRS to interact with its cognate RNA, disrupting protein production. The GARS1 mutations present in CMT2D cause a deficient amount of glycyl-tRNA in cells, preventing the elongation phase of protein synthesis. Because elongation is a key step in protein production, ribosomes are unable to continue protein synthesis at glycine sites. GARS1 mutations also stall initiation of translation. Glycine addition failure causes a stress response that further stalls protein production, preventing initiation of translation. By stalling elongation and initiation of translation, CMT2D mutations in the GARS1 gene cause translational repression, meaning that overall translation is inhibited.GARS1-associated axonal neuropathy is progressive, meaning that it worsens over time. Unknown mechanisms are thought to cause the chronic neurodegeneration resulting from the aberrant GlyRS; however, one theory for disease is VEGF-deficiency. Mutant GlysRS interferes with neuronal transmembrane receptors, including neuropilin 1 (Nrp1) and vascular endothelial growth factor (VEGF), causing neuropathy. GARS-CMT2D mutations alter GlyRS and allow it to bind to the Nrp1 receptor, interfering with the normal binding of Nrp1 to VEGF. While enhanced expression of VEGF improves motor function, reduced expression of Nrp1 worsens CMT2D; because Nrp1 binds to mutant GlyRS in mutant GARS1-CMT2D individuals, Nrp1 expression is reduced, in turn worsening motor function. Mice with deficient VEGF demonstrate motor-neuron disease over time. Thus, the VEGF/Nrp1 pathway is considered to be targetable for CMT2D treatment.

Diagnosis
CMT can be diagnosed through three different forms of tests: measurement of the speed of nerve impulses (nerve conduction studies), a biopsy of the nerve, and DNA testing. DNA testing can give a definitive diagnosis, but not all the genetic markers for CMT are known.  CMT is first most noticed when someone develops lower leg weakness, such as foot drop, or foot deformities, including hammertoes and high arches, but signs alone do not lead to diagnosis.  Patients must be referred to a physician specialising in neurology or rehabilitation medicine. To see signs of muscle weakness, the neurologist may ask patients to walk on their heels or to move part of their leg against an opposing force.  To identify sensory loss, the neurologist tests for deep-tendon reflexes, such as the knee jerk, which are reduced or absent in CMT. The doctor may also ask the patients family history since CMT is hereditary.  The lack of family history does not rule out CMT, but is helpful to rule out other causes of neuropathy, such as diabetes or exposure to certain chemicals or drugs.In 2010, CMT was one of the first diseases where the genetic cause of a particular patients disease was precisely determined by sequencing the whole genome of an affected individual.  This was done by the scientists employed by the Charcot Marie Tooth Association (CMTA). Two mutations were identified in a gene, SH3TC2, known to cause CMT.  Researchers then compared the affected patients genome to the genomes of the patients mother, father, and seven siblings with and without the disease. The mother and father each had one normal and one mutant copy of this gene, and had mild or no symptoms. The offspring who inherited two mutant genes presented fully with the disease.

Histology
The constant cycle of demyelination and remyelination, which occurs in CMT, can lead to the formation of layers of myelin around some nerves, termed an "onion bulb".  These are also seen in chronic inflammatory demyelinating polyneuropathy.  Muscles show fiber type grouping, a similarly nonspecific finding that indicates a cycle of denervation/reinnervation.  Normally, type I and type II muscle fibers show a checkerboard-like random distribution.  However, when reinnervation occurs, the group of fibers associated with one nerve are of the same type.  The standard for indicating fiber type is histoenzymatic adenosine triphosphatase (ATPase at pH 9.4).

Management
Often, the most important goal for patients with CMT is to maintain movement, muscle strength, and flexibility. Therefore, an interprofessional team approach with occupational therapy (OT), physical therapy (PT), orthotist, podiatrist, and or orthopedic surgeon is recommended. PT typically focuses on muscle-strength training, muscle stretching, and aerobic exercise, while OT can provide education on energy conservation strategies and activities of daily living. Physical therapy should be involved in designing an exercise program that fits a persons personal strengths and flexibility. Bracing can also be used to correct problems caused by CMT. An orthotist may address gait abnormalities by prescribing the use of orthotics.Appropriate footwear is also very important for people with CMT, but they often have difficulty finding well-fitting shoes because of their high arched feet and hammertoes. Due to the lack of good sensory reception in the feet, CMT patients may also need to see a podiatrist for assistance in trimming nails or removing calluses that develop on the pads of the feet. Lastly, patients can also decide to have surgery performed by a podiatrist or an orthopedic surgeon. Surgery may help to stabilize the patients feet or correct progressive problems. These procedures include straightening and pinning the toes, lowering the arch, and sometimes, fusing the ankle joint to provide stability. CMT patients must take extra care to avoid falling as fractures take longer to heal in someone with an underlying disease process. Additionally, the resulting inactivity may cause the CMT to worsen. The Charcot–Marie–Tooth Association classifies the chemotherapy drug vincristine as a "definite high risk" and states, "vincristine has been proven hazardous and should be avoided by all CMT patients, including those with no symptoms." Several corrective surgical procedures  can be done to improve the physical condition of the affected individuals.

Orthotics
If the muscles of the lower extremities are weak, it makes sense to prescribe custom-fabricated orthotics. Depending on which muscle groups are affected, the correct orthoses with appropriate functional elements should be prescribed. A weakness of the Musculus tibialis anterior, which lifts the feet, is usually accompanied by an atrophy of the Musculus gastrocnemius which, together with the Musculus soleus, forms the Musculus triceps surae (distal calf muscles), occurs causing the known "stork leg deformity". In most cases, ankle-foot orthoses that have functional elements for the foot lifting and adjustable control of the lowering of the forefoot make sense </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Bad breath and explain in detail? [/INST] Bad breath, also known as halitosis, is a symptom in which a noticeably unpleasant breath odour is present. It can result in anxiety among those affected. It is also associated with depression and symptoms of obsessive compulsive disorder.The concerns of bad breath may be divided into genuine and non-genuine cases. Of those who have genuine bad breath, about 85% of cases come from inside the mouth. The remaining cases are believed to be due to disorders in the nose, sinuses, throat, lungs, esophagus, or stomach. Rarely, bad breath can be due to an underlying medical condition such as liver failure or ketoacidosis. Non-genuine cases occur when someone complains of having bad breath but other people cannot detect it. This is estimated to make up between 5% and 72% of cases.The treatment depends on the underlying cause. Initial efforts may include tongue cleaning, mouthwash, and flossing. Tentative evidence supports the use of mouthwash containing chlorhexidine or cetylpyridinium chloride. While there is tentative evidence of benefit from the use of a tongue cleaner it is insufficient to draw clear conclusions. Treating underlying disease such as gum disease, tooth decay, tonsil stones, or gastroesophageal reflux disease may help. Counselling may be useful in those who falsely believe that they have bad breath.Estimated rates of bad breath vary from 6% to 50% of the population. Concern about bad breath is the third most common reason people seek dental care, after tooth decay and gum disease. It is believed to become more common as people age. Bad breath is viewed as a social taboo and those affected may be stigmatized. People in the United States spend more than $1 billion per year on mouthwash to treat it.

Signs and symptoms
Bad breath is when a noticeably unpleasant odour is believed to be present on the breath. It can result in anxiety among those affected. It is also associated with depression and symptoms of obsessive compulsive disorder.

Causes
Mouth
In about 90% of genuine halitosis cases, the origin of the odour is in the mouth itself. This is known as intra-oral halitosis, oral malodour or oral halitosis.
The most common causes are odour producing biofilm on the back of the tongue or other areas of the mouth due to poor oral hygiene. This biofilm results in the production of high levels of foul odours. The odours are produced mainly due to the breakdown of proteins into individual amino acids, followed by the further breakdown of certain amino acids to produce detectable foul gases. Volatile sulfur compounds are associated with oral malodour levels, and usually decrease following successful treatment. Other parts of the mouth may also contribute to the overall odour, but are not as common as the back of the tongue. These locations are, in order of descending prevalence, inter-dental and sub-gingival niches, faulty dental work, food-impaction areas in between the teeth, abscesses, and unclean dentures. Oral based lesions caused by viral infections like herpes simplex and HPV may also contribute to bad breath.
The intensity of bad breath may differ during the day, due to eating certain foods (such as garlic, onions, meat, fish, and cheese), smoking, and alcohol consumption. Since the mouth is exposed to less oxygen and is inactive during the night, the odour is usually worse upon awakening ("morning breath"). Bad breath may be transient, often disappearing following eating, drinking, tooth brushing, flossing, or rinsing with specialized mouthwash. Bad breath may also be persistent (chronic bad breath), which affects some 25% of the population in varying degrees.

Tongue
The most common location for mouth-related halitosis is the tongue. Tongue bacteria produce malodourous compounds and fatty acids, and account for 80 to 90% of all cases of mouth-related bad breath. Large quantities of naturally occurring bacteria are often found on the posterior dorsum of the tongue, where they are relatively undisturbed by normal activity. This part of the tongue is relatively dry and poorly cleansed, and the convoluted microbial structure of the tongue dorsum provides an ideal habitat for anaerobic bacteria, which flourish under a continually-forming tongue coating of food debris, dead epithelial cells, postnasal drip and overlying bacteria, living and dead. When left on the tongue, the anaerobic respiration of such bacteria can yield either the putrescent smell of indole, skatole, polyamines, or the "rotten egg" smell of volatile sulfur compounds (VSCs) such as hydrogen sulfide, methyl mercaptan, allyl methyl sulfide, and dimethyl sulfide. The presence of halitosis-producing bacteria on the back of the tongue is not to be confused with tongue coating. Bacteria are invisible to the naked eye, and degrees of white tongue coating are present in most people with and without halitosis. A visible white tongue coating does not always equal the back of the tongue as an origin of halitosis, however a "white tongue" is thought to be a sign of halitosis. In oral medicine generally, a white tongue is considered a sign of several medical conditions. Patients with periodontal disease were shown to have sixfold prevalence of tongue coating compared with normal subjects. Halitosis patients were also shown to have significantly higher bacterial loads in this region compared to individuals without halitosis.

Gums
Gingival crevices are the small grooves between teeth and gums, and they are present in health, although they may become inflamed when gingivitis is present. The difference between a gingival crevice and periodontal pocket is that former is <3mm in depth and the latter is >3mm. Periodontal pockets usually accompany periodontal disease (gum disease). There is some controversy over the role of periodontal diseases in causing bad breath. However, advanced periodontal disease is a common cause of severe halitosis. People with uncontrolled diabetes are more prone to have multiple gingival and periodontal abscess. Their gums are evident with large pockets, where pus accumulation occurs. This nidus of infection can be a potential source for bad breath. Removal of the subgingival calculus (i.e. tartar or hard plaque) and friable tissue has been shown to improve mouth odour considerably.  This is accomplished by subgingival scaling and root planing and irrigation with an antibiotic mouth rinse. The bacteria that cause gingivitis and periodontal disease (periodontopathogens) are invariably gram negative and capable of producing VSC. Methyl mercaptan is known to be the greatest contributing VSC in halitosis that is caused by periodontal disease and gingivitis. The level of VSC on breath has been shown to positively correlate with the depth of periodontal pocketing, the number of pockets, and whether the pockets bleed when examined with a dental probe. Indeed, VSC may themselves have been shown to contribute to the inflammation and tissue damage that is characteristic of periodontal disease. However, not all patients with periodontal disease have halitosis, and not all patients with halitosis have periodontal disease. Although patients with periodontal disease are more likely to develop halitosis than the general population, the halitosis symptom was shown to be more strongly associated with degree of tongue coating than with the severity of periodontal disease. Another possible symptom of periodontal disease is a bad taste, which does not necessarily accompany a malodour that is detectable by others.

Other causes
Other less common reported causes from within the mouth include:
Deep carious lesions (dental decay) – which cause localized food impaction and stagnation
Recent dental extraction sockets – fill with blood clot, and provide an ideal habitat for bacterial proliferation
Interdental food packing – (food getting pushed down between teeth) - this can be caused by missing teeth, tilted, spaced or crowded teeth, or poorly contoured approximal dental fillings. Food debris becomes trapped, undergoes slow bacterial putrefaction and release of malodourous volatiles. Food packing can also cause a localized periodontal reaction, characterized by dental pain that is relieved by cleaning the area of food packing with interdental brush or floss.
Acrylic dentures (plastic false teeth) – inadequate denture hygiene practises such as failing to clean and remove the prosthesis each night, may cause a malodour from the plastic itself or from the mouth as microbiota responds to the altered environment. The plastic is actually porous, and the fitting surface is usually irregular, sculpted to fit the edentulous oral anatomy. These factors predispose to bacterial and yeast retention, which is accompanied by a typical smell.
Oral infections
Oral ulceration
Fasting
Stress/anxiety
Menstrual cycle – at mid cycle and during menstruation, increased breath VSC were reported in women.
Smoking – Smoking is linked with periodontal disease, which is the second most common cause of oral maloduor. Smoking also has many other negative effects on the mouth, from increased rates of dental decay to premalignant lesions and even oral cancer.
Alcohol
Volatile foods  – e.g. onion, garlic, durian, cabbage, cauliflower and radish. Volatile foodstuffs may leave malodourous residues in the mouth, which are the subject to bacterial putrefaction and VSC release. However, volatile foodstuffs may also cause halitoisis via the blood borne halitosis mechanism.
Medication – often medications can cause xerostomia (dry mouth) which results in increased microbial growth in the mouth.

Nose and sinuses
In this occurrence, the air exiting the nostrils has a pungent odour that differs from the oral odour. Nasal odour may be due to sinus infections or foreign bodies.Halitosis is often stated to be a symptom of chronic rhinosinusitis, however gold standard breath analysis techniques have not been applied. Theoretically, there are several possible mechanisms of both objective and subjective halitosis that may be involved.

Tonsils
There is disagreement as to the proportion of halitosis cases which are caused by conditions of the tonsils. Some claim that the tonsils are the most significant cause of halitosis after the mouth. According to one report, approximately 3% of halitosis cases were related to the tonsils. Conditions of the tonsils which may be associated with halitosis include chronic caseous tonsillitis (cheese-like material can be exuded from the tonsillar crypt orifi), tonsillolithiasis (tonsil stones), and less commonly peritonsillar abscess, actinomycosis, fungating malignancies, chondroid choristoma and inflammatory myofibroblastic tumor.

Esophagus
The lower esophageal sphincter, which is the valve between the stomach and the esophagus, may not close properly due to a hiatal hernia or GERD, allowing acid to enter the esophagus and gases to escape to the mouth. A Zenkers diverticulum may also result in halitosis due to aging food retained in the esophagus.

Stomach
The stomach is considered by most researchers as a very uncommon source of bad breath. The esophagus is a closed and collapsed tube, and continuous flow of gas or putrid substances from the stomach indicates a health problem—such as reflux serious enough to be bringing up stomach contents or a fistula between the stomach and the esophagus—which will demonstrate more serious manifestations than just foul odour.In the case of allyl methyl sulfide (the byproduct of garlics digestion), odour does not come from the stomach, since it does not get metabolized there.

Systemic diseases
There are a few systemic (non-oral) medical conditions that may cause foul breath odour, but these are infrequent in the general population. Such conditions are:
Fetor hepaticus: an example of a rare type of bad breath caused by chronic liver failure.
Lower respiratory tract infections (bronchial and lung infections).
Kidney infections and kidney failure.
Carcinoma.
Trimethylaminuria ("fish odour syndrome").
Diabetes mellitus.
Metabolic conditions, e.g. resulting in elevated blood dimethyl sulfide.Individuals affected by the above conditions often show additional, more diagnostically conclusive symptoms than bad breath alone.

Delusional halitosis
One quarter of the people seeking professional advice on bad breath have an exaggerated concern of having bad breath, known as halitophobia, delusional halitosis, or as a manifestation of olfactory reference syndrome. They are sure that they have bad breath, although many have not asked anyone for an objective opinion. Bad breath may severely affect the lives of some 0.5–1.0% of the adult population.

Diagnosis
Self diagnosis
Scientists have long thought that smelling ones own breath odour is often difficult due to acclimatization, although many people with bad breath are able to detect it in others.  Research has suggested that self-evaluation of halitosis is not easy because of preconceived notions of how bad we think it should be. Some people assume that they have bad breath because of bad taste (metallic, sour, fecal, etc.), however bad taste is considered a poor indicator.
Patients often self-diagnose by asking a close friend.One popular home method to determine the presence of bad breath is to lick the back of the wrist, let the saliva dry for a minute or two, and smell the result. This test results in overestimation, as concluded from research, and should be avoided. A better way would be to lightly scrape the posterior back of the tongue with a plastic disposable spoon and to smell the drying residue. Home tests that use a chemical reaction to test for the presence of polyamines and sulfur compounds on tongue swabs are now available, but there are few studies showing how well they actually detect the odour. Furthermore, since breath odour changes in intensity throughout the day depending on many factors, multiple testing sessions may be necessary.

Testing
If bad breath is persistent, and all other medical and dental factors have been ruled out, specialized testing and treatment is required. Hundreds of dental offices and commercial breath clinics now claim to diagnose and treat bad breath.  They often use some of several laboratory methods for diagnosis of bad breath:

Halimeter: a portable sulfide monitor used to test for levels of sulfur emissions (to be specific, hydrogen sulfide) in the mouth air. When used properly, this device can be very effective at determining levels of certain VSC-producing bacteria. However, it has drawbacks in clinical applications. For example, other common sulfides (such as mercaptan) are not recorded as easily and can be misrepresented in test results. Certain foods such as garlic and onions produce sulfur in the breath for as long as 48 hours and can result in false readings. The Halimeter is also very sensitive to alcohol, so one should avoid drinking alcohol or using alcohol-containing mouthwashes for at least 12 hours prior to being tested. This analog machine loses sensitivity over time and requires periodic recalibration to remain accurate.
Gas chromatography: portable machines are being studied. This technology is designed to digitally measure molecular levels of major VSCs in a sample of mouth air (such as hydrogen sulfide, methyl mercaptan, and dimethyl sulfide). It is accurate in measuring the sulfur components of the breath and produces visual results in graph form via computer interface.
BANA test: this test is directed to find the salivary levels of an enzyme indicating the presence of certain halitosis-related bacteria.
β-galactosidase test: salivary levels of this enzyme were found to be correlated with oral malodour.Although such instrumentation and examinations are widely used in breath clinics, the most important measurement of bad breath (the gold standard) is the actual sniffing and scoring of the level and type of the odour carried out by trained experts ("organoleptic measurements"). The level of odour is usually assessed on a six-point intensity scale.

Classification
Two main classification schemes exist for bad breath, although neither are universally accepted.The Miyazaki et al. classification was originally described in 1999 in a Japanese scientific publication,  and has since been adapted to reflect North American society, especially with regards halitophobia.  The classification assumes three primary divisions of the halitosis symptom, namely genuine halitosis, pseudohalitosis and halitophobia. This classification has been suggested to be most widely used, but it has been criticized because it is overly simplistic and is largely of use only to dentists rather than other specialties.

Genuine halitosis
A. Physiologic halitosis
B. Pathologic halitosis
(i) Oral
(ii) Extra-oral
Pseudohalitosis
HalitophobiaThe Tangerman and Winkel classification was suggested in Europe in 2002. This classification focuses only on those cases where there is genuine halitosis, and has therefore been criticized for being less clinically useful for dentistry when compared to the Miyazaki et al. classification.

Intra-oral halitosis
Extra-oral halitosis
A. Blood borne halitosis
(i) Systemic diseases
(ii) Metabolic diseases
(iii) Food
(iv) Medication
B. Non-blood borne halitosis
(i) Upper respiratory tract
(ii) Lower respiratory tractThe same authors also suggested that halitosis can be divided according to the character of the odour into 3 groups:
"Sulfurous or fecal" caused by volatile sulfur compounds (VSC), most notably methyl mercaptan, hydrogen sulfide and dimethyl sulfide.
"Fruity" caused by acetone, present in diabetes.
"Urine-like or ammoniacal" caused by ammonia, dimethyl amine and trimethylamine (TMA), present in trimethylaminuria and uremia.Based on the strengths and weaknesses of previous attempts at classification, a cause based classification has been proposed:
Type 0 (physiologic)
Type 1 (oral)
Type 2 (airway)
Type 3 (gastroesophageal)
Type 4 (blood-borne)
Type 5 (subjective)Any halitosis symptom is potentially the sum of these types in any combination, superimposed on the physiologic odour present in all healthy individuals.

Management
Approaches to improve bad breath may include physical or chemical means to decrease bacteria in the mouth, products to mask the smell, or chemicals to alter the odour creating molecules. Many different interventions have been suggested and trialed such as toothpastes, mouthwashes, lasers, tongue scraping, and mouth rinses. There is no strong evidence to indicate which interventions work and which are more effective. It is recommended that in those who use tobacco products stop. Evidence does not support the benefit of dietary changes or chewing gum.

Mechanical measures
Brushing the teeth may help. While there is evidence of tentative benefit from tongue cleaning it is insufficient to draw clear conclusions. A 2006 Cochrane review found tentative evidence that it might decrease levels of odour molecules. Flossing may be useful.

Mouthwashes
A 2008 systematic review found that antibacterial mouthrinses may help. Mouthwashes often contain antibacterial agents including cetylpyridinium chloride, chlorhexidine, zinc gluconate, zinc chloride, zinc lactate, hydrogen peroxide, chlorine dioxide, amine fluorides, stannous fluoride, hinokitiol, and essential oils. Listerine is one of the well-known mouthwash products composed of different essential oils. Other formulations containing herbal products and probiotics have also been proposed. Cetylpyridinium chloride and chlorhexidine can temporarily stain teeth.

Underlying disease
If gum disease and cavities are present, it is recommended that these be treated.If diseases outside of the mouth are believed to be contributing to the problem, treatment may result in improvements.Counselling may be useful in those who falsely believe that they have bad breath.

Epidemiology
It is difficult for researchers to make estimates of the prevalence of halitosis in the general population for several reasons. Firstly, halitosis is subject to societal taboo and stigma, which may impact individuals willingness to take part in such studies or to report accurately their experience of the condition. Secondly, there is no universal agreement about what diagnostic criteria and what detection methods should be used to define which individuals have halitosis and which do not. Some studies rely on self reported estimation of halitosis, and there is contention as to whether this is a reliable predictor of actual halitosis or not. In reflection of these problems, reported epidemiological data are widely variable.

History, society and culture
The earliest known mention of bad breath occurs in ancient Egypt, where detailed recipes for toothpaste are made before the Pyramids are built. The 1550 BC Ebers Papyrus describes tablets to cure bad breath based on incense, cinnamon, myrrh and honey. Hippocratic medicine advocated a mouthwash of red wine and spices to cure bad breath.  Alcohol-containing mouthwashes are now thought to exacerbate bad breath as they dry the mouth, leading to increased microbial growth. The Hippocratic Corpus also describes a recipe based on marble powder for females with bad breath. The Ancient Roman physician Pliny wrote about methods to sweeten the breath.Ancient Chinese emperors required visitors to chew clove before an audience. The Talmud describes bad breath as a disability, which could be grounds for legal breaking of a marriage license. Early Islamic theology stressed that the teeth and tongue should be cleaned with a siwak, a stick from the plant Salvadora persica tree. This traditional chewing stick is also called a Miswak, especially used in Saudi Arabia, an essentially is like a natural toothbrush made from twigs. During the Renaissance era, Laurent Joubert, doctor to King Henry III of France states bad breath is "caused by dangerous miasma that falls into the lungs and through the heart, causing severe damages".In B. G. Jefferis and J. L. Nichols "Searchlights on Health" (1919), the following recipe is offered: "[One] teaspoonful of the following mixture after each meal: One ounce chloride of soda, one ounce liquor of potassa, one and one-half ounces phosphate of soda, and three ounces of water."
In the present day, bad breath is one of the biggest social taboos. The general population places great importance on the avoidance of bad breath, illustrated by the annual $1 billion that consumers in the United States spend on deodorant-type mouth (oral) rinses, mints, and related over-the-counter products. Many of these practices are merely short term attempts at masking the odour. Some authors have suggested that there is an evolutionary basis to concern over bad breath. An instinctive aversion to unpleasant odours may function to detect spoiled food sources and other potentially invective or harmful substances. Body odours in general are thought to play an important role in mate selection in humans, and unpleasant odour may signal disease, and hence a potentially unwise choice of mate. Although reports of bad breath are found in the earliest medical writings known, the social stigma has likely changed over time, possibly partly due to sociocultural factors involving advertising pressures. As a result, the negative psychosocial aspects of halitosis may have worsened, and psychiatric conditions such as halitophobia are probably more common than historically. There have been rare reports of people committing suicide because of halitosis, whether there is genuine halitosis or not.

Etymology
The word halitosis is derived from the Latin word halitus, meaning breath, and the Greek suffix -osis meaning diseased or a condition of. With modern consumerism, there has been a complex interplay of advertising pressures and the existing evolutionary aversion to malodour. Contrary to the popular belief that Listerine coined the term halitosis, its origins date to before the products existence, being coined by physician Joseph William Howe in his 1874 book The Breath, and the Diseases Which Give It a Fetid Odor, although it only became commonly used in the 1920s when a marketing campaign promoted Listerine as a solution for "chronic halitosis". The company was the first to manufacture mouth washes in the United States. According to Freakonomics: Listerine "...was invented in the nineteenth century as powerful surgical antiseptic. It was later sold, in distilled form, as both a floor cleaner and a cure for gonorrhea. But it wasnt a runaway success until the 1920s, when it was pitched as a solution for "chronic halitosis"— a then obscure medical term for bad breath </s>