Mylodysplasia

The myelodysplastic syndromes (MDS, formerly known as "preleukemia") are a diverse collection of hematological conditions united by ineffective production of blood cells and varying risks of transformation to acute myelogenous leukemia. Anemia requiring chronic blood transfusion is frequently present. Although not truly malignant, MDS is nevertheless classified within the haematological neoplasms.

Signs and symptoms
Abnormalities include:

neutropenia, anemia and thrombocytopenia (low cell counts of white and red blood cells, and platelets, respectively)
abnormal granules in cells, abnormal nuclear shape and size
chromosomal abnormalities, including chromosomal translocations and abnormal chromosome number.
Symptoms of myelodysplastic conditions:

Anemia—chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain
Neutropenia (low neutrophil count) —increased susceptibility to infection
Thrombocytopenia (low platelet count) —increased susceptibility to bleeding
Although there is some risk for developing acute myelogenous leukemia, about 50% of deaths occur as a result of bleeding or infection. Leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment.

Diagnosis
Investigation:

Full blood count and examination of blood film
Bone marrow examination by an experienced hematopathologist
Cytogenetics or chromosomal studies. This is performed on the bone marrow aspirate.

Pathophysiology
MDS is thought to arise from mutations in the multi-potent bone marrow stem cell, but the specific defects responsible for these diseases remain poorly understood. Differentiation of blood precursor cells is impaired, and there is a significant increase in levels of cell death apoptosis in bone marrow cells. Clonal expansion of the abnormal cells results in the production of cells which have lost the ability to differentiate. If the overall percentage of bone marrow blasts rises over a particular cutoff (20% for WHO and 30% for FAB) then transformation to leukemia (specifically acute myelogenous leukemia or AML) is said to have occurred. The progression of MDS to leukemia is a good example of the multi-step theory of carcinogenesis in which a series of mutations occur in an initially normal cell and transform it into a cancer cell.

While recognition of leukemic transformation was historically important (see History), a significant proportion of the morbidity and mortality attributable to MDS results not from transformation to AML but rather from the cytopenias seen in all MDS patients. While anemia is the most common cytopenia in MDS patients, given the ready availability of blood transfusion MDS patients rarely suffer injury from severe anemia. However, if an MDS patient is fortunate enough to suffer nothing more than anemia over several years, they then risk iron overload. The two most serious complications in MDS patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells).


Types and classification
French-American-British (FAB) classification
In 1974 and 1975 a group of pathologists from France, the United States, and Britain met and deliberated and derived the first widely used classification of these diseases. This French-American-British (FAB) classification was published in 1976 and revised in 1982. Cases were classified into 5 categories: (ICD-O codes are provided where available)

(M9980/3) Refractory anemia (RA) - characterized by less than 5% primitive blood cells (myeloblasts) in the bone marrow and pathological abnormalities primarily seen in red cell precursors;
(M9982/3) Refractory anemia with ringed sideroblasts (RARS) - also characterized by less than 5% myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts";
(M9983/3) Refractory anemia with excess blasts (RAEB) - characterized by 5-19% myeloblasts in the marrow;
(M9984/3) Refractory anemia with excess blasts in transformation (RAEB-T) - characterized by 20-29% myeloblasts in the marrow (30% blasts is defined as acute myeloid leukemia);
(M9945/3) Chronic myelomonocytic leukemia (CMML) - not to be confused with chronic myelogenous leukemia or CML - characterized by less than 20% myeloblasts in the bone marrow and greater than 1000 * 109/uL monocytes (a type of white blood cell) circulating in the peripheral blood.
A table comparing these is available from the Cleveland Clinic.

The best prognosis is seen with refractory anemia with ringed sideroblasts and refractory anemia, where some non-transplant patients live more than a decade (the average is on the order of 3-5 years, although long term remission is possible if a bone marrow transplant is successful); the worst outlook is with RAEB-T, where the mean life expectancy is less than 1 year. About 1/4 of patients develop overt leukemia. The others die of complications of low blood count or unrelated disease. The International Prognostic Scoring System is another tool for determining the prognosis of MDS, published in Blood in 1997. This system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias.

The FAB classification was used by pathologists and clinicians for almost 20 years.

WHO classification
In the late 1990s a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others.

One new category was refractory cytopenia with multilineage dysplasia (RCMD), which includes patients with pathological changes not restricted to red cells (i.e., prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia. See below for morphologic definitions of dysplasia.

The list of dysplastic syndromes under the new WHO system includes:

Refractory anemia (RA)
Refractory anemia with ringed sideroblasts (RARS)
Refractory cytopenia with multilineage dysplasia (RCMD)
Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS)
Refractory anemia with excess blasts I and II
5q- syndrome
Myelodysplasia unclassifiable (seen in those cases of megakaryocyte dysplasia with fibrosis and others)
RAEB was divided into *RAEB-I (5-10% blasts) and RAEB-II (11-19%) blasts, which has a poorer prognosis than RAEB-I. Auer rods may be seen in RAEB-II which may be difficult to distinguish from acute myeloid leukemia.

The category of RAEB-T was eliminated; such patients are now considered to have acute leukemia. 5q- syndrome, typically seen in older women with normal or high platelet counts and isolated deletions of the long arm of chromosome 5 in bone marrow cells, was added to the classification.

CMML was removed from the myelodysplastic syndromes and put in a new category of myelodysplastic-myeloproliferative overlap syndromes. Not all physicians concur with this reclassification. This is because the underlying pathology of the diseases is not well understood. It is difficult to classify things that are not well understood.

Diagnosis
The average age at diagnosis for MDS is about 65 years, but pediatric cases have been reported. Some patients have a history of exposure to chemotherapy (especially alkylating agents such as melphalan, mustard, cyclophosphamide, busulfan, and chlorambucil) or radiation (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons such as the petroleum industry have a slightly higher risk of contracting the disease than the general population. Males are slightly more frequently affected than females. Xylene and benzene exposure has been associated with myelodysplasia. Vietnam Veterans that were exposed to Agent Orange are at risk of developing MDS.

Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains (PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:

Granulocytic series
Hypersegmented neutrophils (also seen in Vit B12/Folate deficiency)
Hyposegmented neutrophils (Pseudo-Pelger Huet)
Hypogranular neutrophils or pseudo Chediak Higashi large granules
Dimorphic granules (basophilic and eosinophilic granules) within eosinophils
Erythroid series
Binucleated erythroid percursors and karyorrhexis
Erythroid nuclear budding
Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias)
PAS (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin fixed bone marrow biopsy). Note: One can see PAS vacuolar positivity in L1 and L2 blasts (AFB classification; the L1 and L2 nomenclature is not used in the WHO classification)
Ringed sideroblasts seen on Prussian blue iron stain (10 or more iron granules encircling 1/3 or more of the nucleus and >15% ringed sideroblasts when counted amongst red cell precursors)
Megakaryocytic series (can be the most subjective)
Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation)
Hypersegmented (osteoclastic appearing) megakaryocytes
Ballooning of the platelets (seen with interference contrast microscopy)
Other stains can help in special cases (PAS and napthol ASD chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy.

On the bone marrow biopsy high grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors (ALIPs) which are islands of immature cells clustering together. This morphology can be difficult to recognize from treated leukemia and recovering immature normal marrow elements. Also topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia (RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands.

Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, vitamin deficiencies, and nutrient deficiencies are ruled out. Also congenital diseases such as congenital dyserthropoietic anemia (CDA I through IV) has been recognized, Pearson's syndrome (sideroblastic anemia), Jacobson's syndrome, ALA (aminolevulinic acid) enzyme deficiency, and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines, however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity and other poisons.

All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood (red cells, white cells other than lymphocytes and platelets or their progenitor cells, megakaryocytes).

Epidemiology

The exact number of people with MDS is not known because it can go undiagnosed and there is no mandated tracking of the syndrome. Some estimates are on the order of 10,000 to 20,000 new cases each year in the United States alone. The incidence is probably increasing as the age of the population increases

Therapy

The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to acute myelogenous leukemia.

The IPSS scoring system can help triage patients for more aggressive treatment (i.e. bone marrow transplant) as well as help determine the best timing of this therapy. Supportive care with blood product support and hematopoeitic growth factors (e.g. erythropoietin) is the mainstay of therapy.

Three agents have been approved by the US FDA for the treatment of MDS: 5-azacytidine, decitabine, and lenalidomide. Chemotherapy with the hypomethylating agents 5-azacytidine and decitabine has been shown to decrease blood transfusion requirements and to retard the progression of MDS to AML. Lenalidomide was approved by the FDA in December 2005 only for use in the 5q- syndrome.

Bone marrow transplant, particularly in younger patients (ie less than 40 years of age), more severely affected patients, offers the potential for curative therapy. Success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having a more favorable IPSS score tending to have a more favorable outcome with transplantation.

History
Since the early 20th century it began to be recognized that some people with acute myelogenous leukemia had a preceding period of anemia and abnormal blood cell production. These conditions were lumped with other diseases under the term "refractory anemia". The first description of "preleukemia" as a specific entity was published in 1953 by Block et al. The early identification, characterization and classification of this disorder were problematical, and the syndrome went by many names until the 1976 FAB classification was published and popularized the term MDS.

Mylodysplasia

Fibrocystic Breast Disease in Spanish

Mastitis is the inflammation of the mammalian breast. It is called puerperal mastitis when it occurs to breastfeeding mothers and non-puerperal otherwise. Mastitis can rarely occur in men. Inflammatory breast cancer has symptoms very similar to mastitis and must be ruled out.

Popular usage of the term mastitis varies by geographic region. Outside the US it is commonly used for puerperal and nonpuerperal cases, in the US the term nonpuerperal mastitis is rarely used.

Chronic cystic mastitis, also called fibrocystic disease, a condition rather than a disease, is characterized by noncancerous lumps in the breast.

American slang: here mastitis usually refers to puerperal (occurring to breastfeeding mothers) mastitis with symptoms of systemic infection. Lighter cases of puerperal mastitis are often called breast engorgement.

Names for non-puerperal mastitis are not used very consistently and include Mastitis, Subareolar Abscess, Duct Ectasia, Periductal Inflammation, Zuska's Disease and others.

In this wikipedia article mastitis is used in the original sense of the definition as inflammation of the breast with additional qualifiers where appropriate.

Mastitis is also a very common condition in Veterinary medicine.

Puerperal mastitis
Caused by the blocking of the milk ducts while the mother is lactating (see breastfeeding). It can cause painful areas on the breasts or nipples and may lead to a fever or flu-like symptoms. Except in heavy cases it is not necessary to wean a nursling because of mastitis; in fact, nursing is the most effective way to remove the blockage and alleviate the symptoms, and is not harmful to the baby. Sudden weaning can cause or exacerbate mastitis symptoms.

Mastitis can be discerned from simple blockages by the intensity of pain, heat emanating from the area, redness and fever in the mother. In some cases the fever can become severe, requiring antibiotics; ten percent of cases develop into abscesses that need to be drained surgically.

Treatment
Massage and the application of heat can help prior to feeding as this will aid the opening of the ducts and passageways. A cold compress may be used to ease the pain when not wanting to lose the milk, though it is most appropriate to reduce the levels of milk contained. For this reason it is also advised that the baby should frequently feed from the inflamed breast. However, the content of the milk may be slightly altered, sometimes being more salty, and the taste may make the baby reject the breast at the first instance.

The presence of cracks or sores on the nipples increases the likelihood of infection. Tight clothing or ill-fitting bras may also cause problems as they compress the breasts. The most common infecting organism is Staph. aureus, and babies carrying the organism in their noses are more likely to give it to their mothers;[1] the clinical significance of this finding is still unknown, but theoretically, removing carriage from the nursing infant's nose may help prevent recurrence.

In severe cases it may be required to stop lactation and use lactation inhibiting medication.

Nonpuerperal mastitis
The term Nonpuerperal mastitis describes all inflammatory lesions of the breast except inflammatory breast cancer and skin related conditions like dermatitis and foliculitis. This article includes description of mastitis as well as various kinds of mammary abscesses.

Most patients are women of reproductive age but mastitis beyond the age of 60 is not uncommon. Rarely occurs in newborn children (Mastitis neonatorum) or prepubertal children.

So called pre-pubertal mastitis can occur shortly before or during the first stages of puberty of both boys and girls with very mild symptoms and resolves without intervention.

Symptoms of nonpuerperal mastitis
in most cases local to a part of breast, often close to the nipple and areola, more often the upper inner side of the breast. Rarely whole breast affected, mostly only one breast.
redness of the area
pain local to affected area
diffuse density/palpable mass of varying volume
local overwarming, hotspots (thermographically detectable)
swollen lymph nodes on the affected side, rarely both sides
inflammation intensity can be repeatedly flaring up and down
abscess
Systemic (flu like) symptoms like in puerperal mastitis are rare.

Special forms of mastitis like subareolar abscess can show rare symptoms like nipple retraction and skin dimpling.

Mammography and symptoms allone never allow reliable exclusion of breast cancer. Mastitis may also mimic several typical signs of malignancy on mammography.


Terminology
Depending on appearance, symptoms, aetiological assumptions and histopathological findings a variety of terms has been used to describe mastitis and various related aspects.

galactopoiesis: milk production
secretory disease: aberrant secretory activity in the lobular and lactiferous duct system, believed to be the most frequent factor causing galactophoritis. The secretions may be milk like or apocrine luminal fluid.
retention syndrome (aka retention mastitis): accumulation of secretions in the ducts with mainly intraductal inflammation.
galactostasis: like retention syndrome where the secret is known to be milk.
galactophoritis: inflammation of the lobular and lactiferous duct system, mainly resulting from secretory disease and retention syndrome.
plasma cell mastitis: plasma cells from the intraductal inflammation infiltrate surrounding tissue.
duct ectasia: literally widening of lactiferous ducts - relatively common finding in breast exams, increase with age. Strongly correlated with cyclic and very strongly with noncyclic breast pain. Correlation with mastitis is of anecdotal quality and has been questioned by recent research.
duct ectasia syndrome: in older literature this was used as synonym for nonpuerperal mastitis with recurring breast abscess, nipple discharge and possibly associated fibrocystic condition with blue dome cysts. Recent research shows that duct ectasia is only very weakly correlated with mastitis symptomes (inflammation, breast abscess). The use of the terms Duct Ectasia and Duct Ectasia Syndrome is inconsistent throughout the literature.
squamous metaplasia of lactiferous ducts: cuboid cells in the epithelial lining of the lactiferous ducts transform (squamous metaplasia) to squamous epithelial cells. Present in many cases of subareolar abscesses.
subareolar abscess: abscess bellow or in close vicinity of the areola. Mostly resulting from galactophoritis.
retroareolar abscess: deeper (closer to chest) than the lobular ductal system and thus deeper than a subareolar abscess.
periductal inflammation (aka periductal mastitis): inflammation infiltrated tissue surrounding lactiferous ducts. Almost synonym for subaerolar abscess. May be just a different name for plasma cell mastitis.
fistula: fine channel draining an abscess cavity
Zuska's disease: periareolar abscess associated with squamous metaplasia of lactiferous ducts. Some authors also associate this with nipple discharge.

Aetiology and Pathogenesis
Most clinically significant cases present as inflammation of the ductal and lobular system (galactophoritis) and possibly the immediately surrounding tissue.

Secretory stasis is the cause of nonpuerperal mastitis in about 80% of cases (Lanyi 2003). The retained secretions can get infected or cause inflammation by causing mechanical damage or leaking the lactiferous ducts. Autoimmune reaction to the secretions may be also a factor.

Several mechanisms are discussed throughout literature that may cause or predispose this (Lanyi 2003, Peters & Schuth 1989, Goepel & Pahnke 1991, Krause et al 1994).

secretory disease or galactorrhea
changes in permeability of lactiferous ducts (retention syndrome)
blockage of lactiferous ducts, for example duct plugging caused by squamous metaplasia of lactiferous ducts
trauma, injury
mechanical irritation caused by retention syndrome or Fibercystic Condition
infection
autoimmune reaction to luminal fluid
About 25% of patients may be hyperprolactinemic and significant coincidence with Fibercystic Condition and thyroid anomalies has been documented (Peters & Schuth 1989, Goepel & Pahnke 1991). Up to 50% of patientes experience transient hyperprolactinemia possibly caused by the inflammation or treatment and most had abnormally high Prolactin reserve (Goepel & Pahnke 1991).

Prolactin, IGF-1 and TSH are important sytemic factors in galactopoesis, their significance in secretory disease is not documented but it has been asserted that the mechanisms of secretory disease and galactopiesis are closely related (Lanyi 2003).

Permeability the of the alveolar and ductal epithelia is mostly controlled by tight junction regulation and is closely linked to galactopoiesis and possibly secretory disease. The tight junctions are regulated by a multitude of systemic (prolactin, progesterone, glucocorticoids) and local (intramammary pressure, TGF-beta, osmotic balance) factors (Nguyen & Neville 1998)

Tobacco smoking appears to be an important factor in the aetiology of squamous metaplasia of lactiferous ducts, around 90% of patients with this condition are smokers. Current smokers have the worst prognosis and highest rate of recurrent abscesses.

Acromegaly may present with symptoms of nonpuerperal mastitis.

Diabetes and many conditions with suppressed immune system can cause various infections of the breast and mastitis. Such conditions often present with inflammation of peripheral tissue and exotic infections.

Nipple piercings pose a risk due to bacterial infection following the injury and hormonal stimulation by the piercing (Jacobs et al 2003, Modest & Fangman 2002, Demirtas et al 2003).

Treatment
Treatment according to presumed cause, diagnosis and treatment of underlying condition is very important.

Prolactin inhibiting medication has been shown to be most effective and reduce risk of recurrence (Goepel & Pahnke 1991, Krause et al 1994, Stauber & Weyerstrahl 2005, Petersen 2003, Goerke et al 2003).

Antibiotics should be given in addition to prolactin inhibiting medication if there are clear signs of infection.

Granulomatous mastitis has been treated with some success by a combination of steroids and Prolactin inhibiting medication (Krause et al 1994).

More exotic treatments for nonpuerperal mastitis that have been mentioned to show at least some efficiacy include local and systemic Progestins or Progesteron (Goepel & Pahnke 1991), antidiuretics, Vitex Agnus Castus extract and Danazol.

NSAIDs are being used to treat symptoms of the inflammation, however it must be considered that these medicaments also affect pituitary function and tend to increase Prolactin and IGF-1 levels (Caviezel et al 1983).

Many variants of surgical procedures such as duct resection have been tried to reduce the risk of recurrent subareolar abscesses. So far the success rates are limited and conservative treatment seems preferable where possible (Petersen 2003, Hannavadi et al 2005).

Approximately 30% of cases develop chronic or recurring mastitis requiring long term or indefinite treatment with Prolactin inhibiting medication (Goerke et al 2003).

Breast cancer and mastitis
Lifetime risk for breast cancer is significantly reduced for women who were pregnant and breastfeeding. Mastitis episodes do not appear to influence lifetime risk of breast cancer.

Mastitis does however cause great difficulties in diagnosis of breast cancer and delayed diagnosis and treatment can result in worse outcome.

Breast cancer may coincide with mastitis or develop shortly afterwards. All suspicious symptoms that do not completely disappear within 5 weeks must be investigated.

Breast cancer incidence during lactation is assumed to be the same like in controls. Diagnosis during lactation is particularly problematic, often leading to delayed diagnosis.

Some data suggests that breast cancer incidence is increased following episodes of nonpuerperal mastitis and special care is required for followup cancer prevention screening.

A very serious type of breast cancer called inflammatory breast cancer presents with similar symptoms as mastitis. It is the most aggressive type of breast cancer with the highest mortality rate. Case reports indicate that inflammatory breast cancer symptoms can flare up following injury or inflammation making it even more likely to be mistaken for mastitis. Because inflammatory breast cancer is mostly EGF positive this may be a reaction of a preexisting asymptomatic cancer to local cytokine stimulation following the normal injury or inflammatory response.

Fibrocystic Breast Disease in Spanish

Inpetigo

Impetigo is a superficial skin infection most common among children age 2–6 years. People who play close contact sports such as rugby, American football and wrestling are also susceptible, regardless of age. The name derives from the Latin impetere ("assail"). It is also known as school sores.

Causes
Impetigo is usually caused by Staphylococcus aureus, it may also be caused by the same streptococcus strain that causes strep throat, Streptococcus pyogenes.

According to the American Academy of Family Physicians - "Nonbullous impetigo was previously thought to be a group A streptococcal process and bullous impetigo was primarily thought to be caused by S. aureus. Studies now indicate that both forms of impetigo are primarily caused by S. aureus with Streptococcus usually being involved in the nonbullous form"

Scratching may spread the lesions.

Transmission
The infection is spread by direct contact with lesions or with nasal carriers. The incubation period is 1–3 days. Dried streptococci in the air are not infectious to intact skin.

Signs and symptoms
One or more pimple-like lesions surrounded by reddened skin. Lesions fill with pus, then break down over 4–6 days and form a thick crust. Impetigo is often associated with insect bites, cuts, and other forms of trauma to the skin. Itching is common.

People who suffer from cold sores have shown higher chances of suffering from impetigo. Those who normally suffer from cold sores should consult a doctor if normal treatment has no effect.

Diagnosis
The diagnosis is made based on the typical appearance of the skin lesion.

Treatment
Topical or oral antibiotics are usually prescribed.

Treatment may involve washing with soap and water and letting the impetigo dry in the air.

Many general practitioners choose to treat impetigo with bactericidal ointment, such as fusidic acid (Fucidin) or mupirocin (Bactroban), but in more severe cases oral antibiotics, such as flucloxacillin (e.g. Floxapen) or erythromycin (e.g. Erythrocin) or Dicloxacillin are necessary.

It is very important to remove the crusts before applying ointment, because the bacteria that cause the disease live underneath them.

Inpetigo

Graves Diseas

Graves disease is a thyroid disorder characterized by goiter, exophthalmos, "orange-peel" skin, and hyperthyroidism. It is caused by an antibody-mediated auto-immune reaction, but the trigger for this reaction is still unknown. It is the most common cause of hyperthyroidism in the world, and the most common cause of general thyroid enlargement in developed countries.

In some parts of Europe the term Basedow’s disease or Graves-Basedow disease is preferred to Graves' disease.

History
Graves disease owes its name to the Irish doctor Robert James Graves, who described a case of goiter with exophthalmos in 1835. However, the German Karl Adolph von Basedow independently reported the same constellation of symptoms in 1840. As a result, on the European Continent the term Basedow's disease is more common than Graves' disease.

Several earlier reports exist but were not widely circulated. For example, cases of goiter with exophthalmos were published by the Italians Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810 respectively.[4] Prior to these, Caleb Hillier Parry, a notable provincial physician in England of the late 18th-century (and a friend of Edward Jenner), described a case in 1786. This case was not published until 1825, but still ten years ahead of Graves

However, fair credit for the first description of Graves disease goes to the 12th-century Persian physician Sayyid Ismail Al-Jurjani, who noted the association of goiter and exophthalmos in his Thesaurus of the Shah of Khwarazm, the major medical dictionary of its time.

Diagnosis
Graves' disease may present clinically with one of the following characteristic signs:

goiter (an enlarged thyroid gland, sometimes detectable as a swelling in the neck)
exophthalmos (protuberance of one or both eyes)
a non-pitting edema with thickening of the skin, described as "peau d'orange" or "orange peel", usually found on the lower extremities
fatigue, weight loss with increased appetite, and other symptoms of hyperthyroidism
The two signs that are truly diagnostic of Graves' disease (i.e. not seen in other hyperthyroid conditions) are exophthalmos and nonpitting edema. Goiter, which is caused by an enlarged thyroid gland, can be present with other forms of hyperthyroidism, although Graves' disease is the most common cause. A large goiter is visible to the naked eye, but a smaller goiter may not be clinically detectable, though X-rays or ultrasound can assist in detecting it.

Another sign of Graves' disease is hyperthyroidism, i.e. over-production of the thyroid hormones T3 and T4. Although, hypothyroidism has also been associated and may be the causating factor in some patients. Hyperthyroidism can be confirmed by measuring elevated blood levels levels of free (unbound) T3 and T4. Other useful laboratory measurements include thyroid-stimulating hormone (TSH, low in Graves' disease due to negative feedback from the elevated T3 and T4), and protein-bound iodine (elevated). Thyroid-stimulating antibodies may also be detected serologically.

Definitive diagnosis requires a biopsy.

Other Graves' Disease Symptoms
Some of the most typical symptoms of Graves' Disease are the following:

Palpitations
Tachycardia (rapid heart rate: 100-120 beats per minute, or higher)
Arrhythmia (irregular heart beat)
Raised blood pressure (Hypertension)
Tremor (usually fine shaking eg. hands)
Excessive sweating
Heat intolerance
Increased appetite
Unexplained weight loss despite increased appetite
Shortness of breath
Muscle weakness (especially in the large muscles of the arms and legs) and degeneration
Diminished/Changed sex drive
Insomnia (inability to get enough sleep)
Increased energy
Fatigue
Mental impairment, memory lapses, diminished attention span
Decreased concentration
Nervousness, agitation
Irritability
Restlessness
Erratic behavior
Emotional liability
Brittle nails
Abnormal breast enlargement (men)
Goiter (enlarged thyroid gland)
Protruding eyeballs (Graves' disease only
Double vision
Eye pain, irritation, or the feeling of grit or sand in the eyes
Swelling or redness of eyes or eyelids/eyelid retraction
Sensitivity to light
Decrease in menstrual periods (oligomenorrhea), Irregular and scant menstrual flow (Amenorrhea)
Difficulty conceiving/infertility/recurrent miscarriage
Hair loss
Itchy skin, hives
Chronic sinus infections
Lumpy, reddish skin of the lower legs (pretibial myxedema)
Smooth, velvety skin
Increased bowel movements or Diarrhea

Incidence and epidemiology

The disease occurs most frequently in women (7:1 compared to men). It occurs most often in middle age (most commonly in the third to fifth decades of life), but is not uncommon in adolescents, during pregnancy, at the time of menopause and in people over age 50. There is a marked family preponderance, which has led to speculation that there may be a genetic component. To date, no clear genetic defect has been found that would point at a monogenic cause. Tissue behind the eye can become swollen or fibrous, causing the characteristic symptom of bulging eyes.

Pathophysiology
Graves' disease is an autoimmune disorder, in which the body produces antibodies to the receptor for thyroid-stimulating hormone (TSH). (Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced.)

These antibodies cause hyperthyroidism because they bind to the TSH receptor and chronically stimulate it. The TSH receptor is expressed on the follicular cells of the thyroid gland (the cells that produce thyroid hormone), and the result of chronic stimulation is an abnormally high production of T3 and T4. This in turn causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland visible as goiter.

The infiltrative exophthalmos that is frequently encountered has been explained by postulating that the thyroid gland and the extraocular muscles share a common antigen which is recognized by the antibodies. Antibodies binding to the extraocular muscles would cause swelling behind the eyeball.

The "orange peel" skin has been explained by the infiltration of antibodies under the skin, causing an inflammatory reaction and subsequent fibrous plaques.

There are 3 types of autoantibodies to the TSH receptor currently recognized:

TSI, Thyroid stimulating immunoglobulins: these antibodies (mainly IgG) act as LATS (Long Acting Thyroid Stimulants), activating the cells in a longer and slower way than TSH, leading to an elevated production of thyroid hormone.
TGI, Thyroid growth immunoglobulins: these antibodies bind directly to the TSH receptor and have been implicated in the growth of thyroid follicles.
TBII, Thyrotrophin Binding-Inhibiting Inmunoglobulins: these antibodies inhibit the normal union of TSH with its receptor. Some will actually act as if TSH itself is binding to its receptor, thus inducing thyroid function. Other types may not stimulate the thyroid gland, but will prevent TSI and TSH from binding to and stimulating the receptor.

Etiology
The trigger for auto-antibody production is not known. There appears to be a genetic predisposition for Graves' disease, suggesting that some people are more prone than others to develop TSH receptor activating antibodies due to a genetic cause. HLA DR (especially DR3) appears to play a significant role.

Since Graves' disease is an autoimmune disease which appears suddenly, often quite late in life, it is thought that a viral or bacterial infection may trigger antibodies which cross-react with the human TSH receptor (a phenomenon known as antigenic mimicry, also seen in some cases of type I diabetes).

One possible culprit is the bacterium Yersinia enterocolitica (a cousin of Yersinia pestis, the agent of bubonic plague). However, although there is indirect evidence for the structural similarity between the bacteria and the human thyrotropin receptor, direct causative evidence is limited. Yersinia seems not to be a major cause of this disease, although it may contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals.It has also been suggested that Y. enterocolitica infection is not the cause of auto-immune thyroid disease, but rather is only an associated condition; with both having a shared inherited susceptibility. More recently the role for Y. enterocolitica has been disputed.

The ocular manifestations of Graves disease are more common in smokers and tend to worsen (or develop for the first time) following radioiodine treatment of the thyroid condition. Thus, they are not caused by hyperthyroidism per se; this common misperception may result from the fact that hyperthyroidism from other causes may cause eyelid retraction or eyelid lag (so-called hyperthyroid stare) which can be confused with the general appearance of proptosis/exophthalmos, despite the fact that the globes do not actually protrude in other causes of hyperthyroidism. Also, both conditions (globe protrusion and hyperthyroid lid retraction) may exist at the same time in the hyperthyroid patient with Graves disease.

Treatment
Medical treatment of Graves' disease includes antithyroid drugs, radioactive iodine and thyroidectomy (surgical excision of the gland).

Treatment of the hyperthyroidism of Graves disease may be with medications such as carbimazole, methimazole or propylthiouracil (PTU), which reduce the production of thyroid hormone, or with radioactive iodine. Surgical removal of the thyroid is another option, but still requires preoperative treatment with methimazole or PTU. This is done to render the patient "euthyroid" (i.e. normothyroid) before the surgery since operating on a frankly hyperthyroid patient is dangerous. Therapy with radioactive iodine (I-131) is the most common treatment in the United States and in many other parts of the world. Thyroid blocking drugs and/or surgical thyroid removal is used more often than radioactive iodine as definitive treatment in Japan, perhaps because of general fear of radioactivity among many Japanese.

The development of radioactive iodine (I-131) in the early 1940s at the Mallinckrodt General Clinical Research Center and its widespread adoption as treatment for Graves' Disease has led to a progressive reduction in the use of surgical thyroidectomy for this problem. In general, RAI therapy is effective, less expensive, and avoids the small but definite risks of surgery. Treatment with antithyroid medications must be given for six months to two years, in order to be effective. Even then, upon cessation of the drugs, the hyperthyroid state may recur. Side effects of the antithyroid medications include a potentially fatal reduction in the level of white blood cells.

Antithyroid drugs
The main antithyroid drugs are methimazole (US), carbimazole (UK) and propylthiouracil. These drugs block the binding of iodine and coupling of iodotyrosines. The most dangerous side-effect is agranulocytosis (1/250, more in PTU); this is an idiosyncratic reaction which does not stop on cessation of drug. Others include granulocytopenia (dose dependent, which improves on cessation of the drug) and aplastic anemia. Patients on these medications should see a doctor if they develop sore throat or fever. The most common side effects are rash and peripheral neuritis. These drugs also cross the placenta and are secreted in breast milk.

Radioiodine
This modality is suitable for most patients, although some prefer to use it mainly for older patients. Indications for radioiodine are: failed medical therapy or surgery and where medical or surgical therapy are contraindicated.

Contraindications to RAI are pregnancy (absolute), ophthalmopathy (relative- it can aggravate thyroid eye disease), solitary nodules. Disadvantages of this treatment are a high incidence of hypothyroidism (up to 80%) requiring hormone supplementation. It acts slowly and has a relapse rate that depends on the dose administered.

Surgery
This modality is suitable for young patients and pregnant patients. Indications are: a large goiter (especially when compressing the trachea), suspicious nodules or suspected cancer (to pathologically examine the thyroid) and patients with ophthalmopathy.

Both bilateral subtotal thyroidectomy and the Hartley-Dunhill procedure (hemithyroidectomy on 1 side and partial lobectomy on other side) are possible.

Advantages are: immediate cure and potential removal of carcinoma. Its risks are injury of the recurrent laryngeal nerve, hypoparathyroidism (due to removal of the parathyroid glands), hematoma (which can be life-threatening if it compresses the trachea) and scarring.

Herbal
For treating Graves disease, along with many other thyroid disorders, one can use the herb bugleweed. This herb has a profound effect on thyroid function and regulation of thyroid hormones.

Eye disease
Thyroid-associated ophthalmopathy is one of the most typical symptom of Graves Disease. It is known by a variety of terms, the commonest being Graves ophthalmopathy. Thyroid eye disease is an inflammatory condition which affects the orbital contents including the extraocular muscles and orbital fat. It is almost always associated with Graves' disease but may rarely be seen in Hashimoto's thyroiditis, primary hypothyroidism, or thyroid cancer.

The ocular manifestations include soft tissue inflammation, eyelid retraction, proptosis, corneal exposure, and optic nerve compression. The signs and symptoms of the disease are characteristic. These include lid retraction, lid lag, and a delay in the downward excursion of the upper eyelid in down gaze that is specific to thyroid-associated ophthalmopathy.

For mild disease - artificial tears, steroid eyedrops, oral steroids (to reduce chemosis)
For moderate disease - lateral tarsorrhaphy
For severe disease - orbital decompression or retro-orbital radiation

No treatment
If left untreated, more serious complications could result, including birth defects in pregnancy, increased risk of a miscarriage, and in extreme cases, death. Graves-Basedow disease is often accompanied by an increase in heart rate, which may lead to further heart complications. If the eyes are proptotic (bulging) severely enough that the lids do not close completely at night, severe dryness will occur with a very high risk of a secondary corneal infection which could lead to blindness. Pressure on the optic nerve behind the globe can lead to visual field defects and vision loss as well.

Graves Diseas

Encepalitis

Encephalitis is an acute inflammation of the brain, commonly caused by a viral infection. Sometimes, encephalitis can result from a bacterial infection, such as bacterial meningitis, or it may be a complication of other infectious diseases like rabies (viral) or syphilis (bacterial). Certain parasitic protozoal infestations, like by toxoplasma or Naegleria fowleri, can also cause encephalitis in people with compromised immune systems. Brain damage occurs as the inflamed brain pushes against the skull, and can lead to death.

Symptoms
Patients with encephalitis suffer from fever, headache and photophobia with weakness and seizures also common. Less commonly, stiffness of the neck can occur with rare cases of patients also suffering from stiffness of the limbs, slowness in movement and clumsiness depending on which specific part of the brain is involved. The symptoms of encephalitis are caused by the brain's defense mechanisms activating to get rid of the infection. Another symptomn of Encephalitis is hallucination.


Etiology
Encephalitis may be caused by a variety of afflictions. One such affliction is rabies.


Diagnosis
Adult patients with encephalitis present with acute onset of fever, headache, confusion, and sometimes seizures. Younger children or infants may present with irritability, anorexia and fever.

Neurological examinations usually reveal a drowsy or confused patient. Stiff neck, due to the irritation of the meninges covering the brain, indicates that the patient has either meningitis or meningeoncephalitis. Examination of the cerebrospinal fluid obtained by a lumbar puncture procedure usually reveals increased amounts of protein and white blood cells with normal glucose, though in a significant percentage of patients, the cerebrospinal fluid may be normal. CT scan often is not helpful, as cerebral abscess is uncommon. Cerebral abscess is more common in patients with meningitis than encephalitis. Bleeding is also uncommon except in patients with herpes simplex type 1 encephalitis. Magnetic resonance imaging offers better resolution. In patients with herpes simplex encephalitis, electroencephalograph may show sharp waves in one or both of the temporal lobes. Lumbar puncture procedure is performed only after the possibility of prominent brain swelling is excluded by a CT scan examination. Diagnosis is often made with detection of antibodies against specific viral agent (such as herpes simplex virus) or by polymerase chain reaction that amplifies the RNA or DNA of the virus responsible.

Treatment
Treatment is usually symptomatic. Reliably tested specific antiviral agents are available only for a few viral agents (e.g. acyclovir for herpes encephalitis) and are used with limited success for most infection except herpes simplex encephalitis. In patients who are very sick, supportive treatment, such as mechanical ventilation, is equally important.

Encephalitis lethargica
Main article: Encephalitis lethargica
Encephalitis lethargica is an atypical form of encephalitis which caused an epidemic from 1917 to 1928. There have only been a small number of isolated cases since, though in recent years a few patients have shown very similar symptoms. The cause is now thought to be either a bacterial agent or an autoimmune response following infection.

Limbic system encephalitis
In a small number of cases, called limbic encephalitis, the pathogens responsible for encephalitis attack primarily the limbic system (a collection of structures at the base of the brain responsible for basic autonomic functions).

Encepalitis

Alchohol and Chemical Detox

Detox, short for detoxification, in general is the removal of toxic substances from the body. It is one of the major functions of the liver, lower gastrointestinal tract and kidneys, but can also be achieved artificially by techniques such as dialysis and (in a very limited number of cases) chelation therapy.

Types of detoxification

Alcohol detoxification
Alcohol detoxification is used as a form of drug rehabilitation to treat alcoholism or other drug addiction. The process involves abstinence to clear the drug from the body, accompanied by social and environmental support during the associated physiological and psychological changes.

Metabolic detoxification
An animal's metabolism can produce harmful substances which it can then make less toxic through oxidation, conjugation and excretion of molecules from cells or tissues. Enzymes that are important in detoxification metabolism include cytochrome P450 oxidases, UDP-glucuronosyltransferasess, and glutathione S-transferases. These processes are particularly well-studied as part of drug metabolism, as they influence the pharmacokinetics of a drug in the body.

Alternative medicine
Certain approaches in alternative medicine claim to remove toxins from the body through herbal, electrical or electromagnetic treatments (such as the Aqua Detox treatment). These toxins are undefined and have little scientific basis, making the validity of such techniques questionable. There is no evidence for toxic accumulation in these cases, as the liver and kidneys automatically detoxify and excrete many toxic materials including metabolic wastes. Under this theory if toxins are too rapidly released without being safely eliminated (such as burning fat that stores toxins) they can damage the body and cause malaise.

Diet detoxification
Main article: Detox diet
Certain diets have an underlying assumption that the body accumulates toxins that must be removed, especially after periods of over-eating or the consumption of non-nutritious and processed foods. As with alternative medicine, the 'toxins' removed are undefined and are ascribed to foods, the environment and the body's own wastes.

Evian and marketing
In 2004, Evian began to use the term 'detox' to market and sell their bottled water. Taglines included "Detox with Evian," "Evian. Detox," "Evian - Your natural detox," and "Drink at least 1.5L of Evian every day to help cleanse your system inside out." The marketing campaign has included a five-step process aimed at personal health. Although the first step advocates drinking any kind of water, the company claimed their particular water was particularly efficacious because it was filtered through a "mineral-rich Alpine region." There is no consensus among health experts that Evian is healthier than any other type of processed potable water.

Methods of detoxification
Drug detox is performed in many different ways depending on where one decides to receive treatment. Most drug detox centers simply provide treatment to avoid physical withdrawal to alcohol & other drugs. Ideally, a trained detox facility will incorporate counseling and therapy during detox to help with the psychological distress that the individual may experience as well. Less conventional methods for eliminating toxic substances from the body include the modification of the diet and addition of certain herbs and rituals such as colon hydrotherapy, body cleansing, juice fasting, and saunas. All of these methods are claimed to assist the body's natural detoxification process, but none have been proven.

Alchohol and Chemical Detox

Archaebacteria Found in Black Smokers

The Archaea ,or archaebacteria, are a major group of microorganisms. Like bacteria, archaea are single-celled organisms that lack nuclei and are therefore prokaryotes, classified in kingdom Monera in the traditional five-kingdom taxonomy. Although there is still uncertainty in the phylogeny, Archaea, Eukaryota and Bacteria are the fundamental classifications of what is called the three-domain system. Although their prokaryotic features are diagnostic of that clade, archaea are more closely related to eukaryotes than to bacteria. To account for this, archaeans and eukaryotes are grouped together in the clade Neomura, which is thought to have arisen from gram-positive bacteria. Archaea were originally described in extreme environments, but have since been found in all habitats and may contribute up to 20% of total biomass.

A single individual or species from this domain is called an archaeon, while the adjectival form is archaeal or archaean. The etymology is Greek, from αρχαία meaning "ancient ones".

Habitats

Yellowstone geysers harbour archaeaMany archaeans are extremophiles, and some would say this is their ecological niche. They can survive high temperatures, often above 100°C, as found in geysers, black smokers, and oil wells. Some are found in very cold habitats and others in highly saline, acidic, or alkaline water. Mesophiles favour milder conditions in marshland, sewage and soil. Many methanogenic archaea are found in the digestive tracts of animals such as ruminants, termites, and humans. As of 2007, no clear examples of archaeal pathogens are known, although a relationship has been proposed between the presence of some methanogens and human periodontal disease.

Archaea are commonly placed into three physiological groups. These are the halophiles, thermophiles and acidophiles. These groups are not necessarily comprehensive or monophyletic, nor even mutually exclusive. Nonetheless, they are a useful starting point for ecological studies. Halophiles, including the genus Halobacterium, live in extremely saline environments and start outnumbering their bacterial counterparts at salinities greater than 20-25%. These can be found in sediments or in the intestines of animals. Thermophiles live in places that have high temperatures, such as hot springs. Where optimal growth occurs at greater than 80°C, the archaeon is a hyperthermophyle, and the highest recorded temperature survived was 121°C. Although thermophilic bacteria predominate at some high temperatures, archaea generally have the edge when acidity exceeds pH 5. True acidophiles withstand pH 0 and below.

Recently, several studies have shown that archaea exist not only in mesophilic and thermophilic environments but are also present, sometimes in high numbers, at low temperatures as well. It is increasingly becoming recognised that methanogens are commonly present in low-temperature environments such as cold sediments. Some studies have even suggested that at these temperatures the pathway by which methanogenesis occurs may change due to the thermodynamic constraints imposed by low temperatures. Perhaps even more significant are the large numbers of archaea found throughout most of the world's oceans, a predominantly cold environment. These archaea, which belong to several deeply branching lineages unrelated to those previously known, can be present in extremely high numbers (up to 40% of the microbial biomass) although almost none have been isolated in pure culture. Currently we have almost no information regarding the physiology of these organisms, meaning that their effects on global biogeochemical cycles remain unknown. One recent study has shown, however, that one group of marine crenarchaeota are capable of nitrification, a trait previously unknown among the archaea.

History of archaean microbiology
Archaea were identified in 1977 by Carl Woese and George E. Fox as being a separate branch based on their separation from other prokaryotes on 16S rRNA phylogenetic trees. These two groups were originally named the Archaebacteria and Eubacteria, treated as kingdoms or subkingdoms, which Woese and Fox termed Urkingdoms. Woese argued that they represented fundamentally different branches of living things. He later renamed the groups Archaea and Bacteria to emphasize this, and argued that together with Eukarya they compose three Domains of living organisms.

Origin and early evolution
The Archaea should not be confused with the geological term Archean eon, also known as the Archeozoic era. This refers to the primordial period of earth history when Archaea and Bacteria were the only cellular organisms living on the planet. Probable fossils of these microbes have been dated to almost 3.5 billion years ago, and the remains of lipids that may be either archaean or eukaryotic have been detected in shales dating from 2.7 billion years ago.

The last common ancestor of Bacteria and Archaea was probably a non-methanogenic thermophile, raising the possibility that lower temperatures are extreme environments in archaeal terms, and organisms that can survive in cooler environments evolved later on.

Comparison of Archaean, Bacterial and Eukaryotic cells
Archaea are similar to other prokaryotes in most aspects of cell structure and metabolism. However, their genetic transcription and translation — the two central processes in molecular biology — do not show many typical bacterial features, and are in many aspects similar to those of eukaryotes. For instance, archaean translation uses eukaryotic-like initiation and elongation factors, and their transcription involves TATA Binding Proteins and TFIIB as in eukaryotes. Many archaeal tRNA and rRNA genes harbor unique archaeal introns which are neither like eukaryotic introns, nor like bacterial (type I and type II etc which can "home") introns.

Several other characteristics also set the Archaea apart. Like bacteria and eukaryotes, archaea possess glycerol-based phospholipids. However, three features of the archaeal lipids are unusual:

The archaeal lipids are unique because the stereochemistry of the glycerol is the reverse of that found in bacteria and eukaryotes. This is strong evidence for a different biosynthetic pathway.
Most bacteria and eukaryotes have membranes composed mainly of glycerol-ester lipids, whereas archaea have membranes composed of glycerol-ether lipids. Even when bacteria have ether-linked lipids, the stereochemistry of the glycerol is the bacterial form. These differences may be an adaptation on the part of Archaea to hyperthermophily. However, it is worth noting that even mesophilic archaea have ether-linked lipids.
Archaeal lipids are based upon the isoprenoid sidechain. This is a five-carbon unit that is also common in rubber and as a component of some bacterial and eukaryotic vitamins. However, only the archaea incorporate these compounds into their cellular lipids, frequently as C-20 (four monomers) or C-40 (eight monomers) side-chains. In some archaea, the C-40 isoprenoid side-chain is long enough to span the membrane, forming a monolayer for a cell membrane with glycerol phosphate moieties on both ends. Although dramatic, this adaptation is most common in the extremely thermophilic archaea.
Although not unique, archaeal cell walls are also unusual. For instance, the in most archaea they are formed by surface-layer proteins or an S-layer. S-layers are common in bacteria, where they serve as the sole cell-wall component in some organisms (like the Planctomyces) or an outer layer in many organisms with peptidoglycan. With the exception of one group of methanogens, archaea lack a peptidoglycan wall (and in the case of the exception, the peptidoglycan is very different from the type found in bacteria). Archaeans also have flagella that are notably different in composition and development from the superficially similar flagella of bacteria. The bacterial flagellum is a modified type III secretion system, while archeal flagella resemble type IV pilli which use a sec dependent secretion system somewhat similar to but different from type II secretion system.

The sizes of prokaryotes relative to other organisms and biomolecules.
Morphology
Individual archaeans range from 0.1 μm to over 15 μm in diameter, and some form aggregates or filaments up to 200 μm in length. They occur in various shapes, such as spherical, rod-shape, spiral, lobed, or rectangular. Archaea have no murein in their cell walls. Recently, a species of flat, square archaean that lives in hypersaline pools has been discovered.

Metabolism
Archaea exhibit a variety of different types of metabolism; there are nitrifiers, methanogens and anaerobic methane oxidisers. Methanogens live in anaerobic environments and produce methane. Of note are the halobacteria, which use light to produce energy. Although no archaea conduct photosynthesis with an electron transport chain, light-activated ion pumps like bacteriorhodopsin and halorhodopsin play a role in generating ion gradients, which are harnessed into adenosine triphosphate (ATP).

Genetics and propagation
Archaea have one circular chromosome although up to 30% of their genetic material may be contained in plasmids, as evidenced by comparisons of GC content. Archaea can reproduce by binary and multiple fission, fragmentation, and budding.

Archaebacteria Found in Black Smokers