Myloma

Multiple myeloma (also known as MM, myeloma, plasma cell myeloma, or as Kahler's disease after Otto Kahler) is a type of cancer of plasma cells which are immune system cells in bone marrow that produce antibodies. Its prognosis, despite therapy, is generally poor, and treatment may involve chemotherapy and stem cell transplant. It is part of the broad group of diseases called hematological malignancies.

Clinical features
Because many organs can be affected by myeloma, the symptoms and signs vary greatly. A mnemonic sometimes used to remember the common tetrad of multiple myeloma is CRAB - C = Calcium (elevated), R =Renal failure, A = Anemia, B = Bone lesions. Myeloma has many possible symptoms, and all symptoms may be due to other causes. They are presented here in decreasing order of incidence.

Bone pain
Myeloma bone pain usually involves the spine and ribs, and worsens with activity. Persistent localized pain may indicate a pathological fracture. Involvement of the vertebrae may lead to spinal cord compression. Myeloma bone disease is due to proliferation of tumor cells and release of IL-6, also known as osteoclast activating factor (OAF), which stimulates osteoclasts to break down bone. These bone lesions are lytic in nature and are best seen in plain radiographs, which may show a "punched-out" resorptive lesions. The breakdown of bone also leads to release of calcium into the blood, leading to hypercalcemia and its associated symptoms.

Infection
The most common infections are pneumonias and pyelonephritis. Common pneumonia pathogens include S pneumoniae, S aureus, and K pneumoniae, while common pathogens causing pyelonephritis include E coli and other gram-negative organisms. The increased risk of infection is due to immune deficiency resulting from diffuse hypogammaglobulinemia, which is due to decreased production and increased destruction of normal antibodies.

Renal failure
Renal failure may develop both acutely and chronically. It is commonly due to hypercalcemia. It may also be due to tubular damage from excretion of light chains, which can manifest as the Fanconi syndrome (type II renal tubular acidosis). Other causes include glomerular deposition of amyloid, hyperuricemia, recurrent infections (pyelonephritis), and local infiltration of tumor cells.

Anemia
The anemia found in myeloma is usually normocytic and normochromic. It results from the replacement of normal bone marrow by infiltrating tumor cells and inhibition of normal red blood cell production (hematopoiesis) by cytokines.

Neurological symptoms
Common problems are weakness, confusion and fatigue due to hypercalcemia. Headache, visual changes and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein. Finally, there may be radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome and other neuropathies (due to infiltration of peripheral nerves by amyloid). It may give rise to paraplegia in late presenting cases.

Diagnosis

Investigations
The presence of unexplained anemia, kidney dysfunction, a high erythrocyte sedimentation rate (ESR) and a high serum protein (especially raised immunoglobulin) may prompt further testing. A doctor will request protein electrophoresis of the blood and urine, which might show the presence of a paraprotein (monoclonal protein, or M protein) band, with or without reduction of the other (normal) immunoglobulins (known as immune paresis). One type of paraprotein is the Bence Jones protein which is a urinary paraprotein composed of free light chains (see below). Quantitative measurements of the paraprotein are necessary to establish a diagnosis and to monitor the disease. The paraprotein is an abnormal immunoglobulin produced by the tumor clone. Very rarely, the myeloma is nonsecretory (not producing immunoglobulins).

In theory, multiple myeloma can produce all classes of immunoglobulin, but IgG paraproteins are most common, followed by IgA and IgM. IgD and IgE myeloma are very rare. In addition, light and or heavy chains (the building blocks of antibodies) may be secreted in isolation: κ- or λ-light chains or any of the five types of heavy chains (α-, γ-, δ-, ε- or μ-heavy chains).

Additional findings include: a raised calcium (when osteoclasts are breaking down bone, releasing calcium into the bloodstream), raised serum creatinine due to reduced renal function, which may be due to paraprotein deposition in the kidney.

Workup
The workup of suspected multiple myeloma includes a skeletal survey. This is a series of X-rays of the skull, axial skeleton and proximal long bones. Myeloma activity sometimes appear as "lytic lesions" (with local disappearance of normal bone due to resorption), and on the skull X-ray as "punched-out lesions" (pepper pot skull). Magnetic resonance imaging (MRI) is more sensitive than simple X-ray in the detection of lytic lesions, and may supersede skeletal survey, especially when vertebral disease is suspected. Occasionally a CT scan is performed to measure the size of soft tissue plasmacytomas.

A bone marrow biopsy is usually performed to estimate the percentage of bone marrow occupied by plasma cells. This percentage is used in the diagnostic criteria for myeloma. Immunohistochemistry (staining particular cell types using antibodies against surface proteins) can detect plasma cells which express immunoglobulin in the cytoplasm but usually not on the surface; myeloma cells are typically CD56, CD38, CD138 positive and CD19 and CD45 negative. Cytogenetics may also be performed in myeloma for prognostic purposes.

Other useful laboratory tests include quantitative measurement of IgA, IgG, IgM (immunoglobulins) to look for immune paresis, and β2-microglobulin which provides prognostic information.

The recent introduction of a commercial immunoassay for measurement of free light chains potentially offers an improvement in monitoring disease progression and response to treatment, particularly where the paraprotein is difficult to measure accurately by electrophoresis (for example in light chain myeloma, or where the paraprotein level is very low). Initial research also suggests that measurement of free light chains may also be used, in conjunction with other markers, for assessment of the risk of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma.[citation needed]

Diagnostic criteria
In 2003, the International Myeloma Working Group agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma and MGUS (monoclonal gammopathy of undetermined significance):

Symptomatic myeloma:
Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma)
A monoclonal protein (paraprotein) in either serum or urine
Evidence of end-organ damage (related organ or tissue impairment, ROTI):
Hypercalcemia (corrected calcium >2.75 mmol/L)
Renal insufficiency attributable to myeloma
Anemia (hemoglobin <10 g/dL)
Bone lesions (lytic lesions or osteoporosis with compression fractures)
Frequent severe infections (>2 a year)
Amyloidosis of other organs
Hyperviscosity syndrome
Asymptomatic myeloma:
Serum paraprotein >30 g/L AND/OR
Clonal plasma cells >10% on bone marrow biopsy AND
NO myeloma-related organ or tissue impairment
Monoclonal gammopathy of undetermined significance (MGUS):
Serum paraprotein <30 g/L AND/OR
Clonal plasma cells <10% on bone marrow biopsy AND
NO myeloma-related organ or tissue impairment
Related conditions include solitary plasmacytoma (a single tumor of plasma cells, typically treated with irradiation), plasma cell dyscrasia (where only the antibodies produce symptoms, e.g. AL amyloidosis), and POEMS syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes).

Staging
International Staging System
The International Staging System (ISS) for myeloma was published by the International Myeloma Working Group in 2003:

Stage I: β2-microglobulin (β2M) < 3.5 mg/L, albumin >= 3.5 g/dL
Stage II: β2M < 3.5 and albumin < 3.5; or β2M between 3.5 and 5.5
Stage III: β2M > 5.5
Durie-Salmon staging system
First published in 1975, the Durie-Salmon staging system [3] is still in use, but has largely been superseded by the simpler ISS:

stage 1: all of
Hb > 10g/dL
normal calcium
Skeletal survey: normal or single plasmacytoma or osteoporosis
Serum paraprotein level < 5 g/dL if IgG, < 3 g/dL if IgA
Urinary light chain excretion < 4 g/24h
stage 2: fulfilling the criteria of neither 1 nor 3
stage 3: one or more of
Hb < 8.5g/dL
high calcium > 12mg/dL
Skeletal survey: 3 or more lytic bone lesions
Serum paraprotein >7g/dL if IgG, > 5 g/dL if IgA
Urinary light chain excretion > 12g/24h
Stages 1, 2 and 3 of the Durie-Salmon staging system can be divided into A or B depending on serum creatinine:

A: serum creatinine < 2mg/dL (< 177 umol/L)
B: serum creatinine > 2mg/dL (> 177 umol/L)

Pathophysiology
Multiple myeloma develops in post-germinal center B lymphocytes.

A chromosomal translocation between the immunoglobulin heavy chain gene (on the fourteenth chromosome, locus 14q32) and an oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11[4]) is frequently observed in patients with multiple myeloma. This mutation results in dysregulation of the oncogene which is thought to be an important initiating event in the pathogenesis of myeloma. The result is proliferation of a plasma cell clone and genomic instability that leads to further mutations and translocations. The chromosome 14 abnormality is observed in about 50% of all cases of myeloma. Deletion of (parts of) the thirteenth chromosome is also observed in about 50% of cases.

Production of cytokines (especially IL-6) by the plasma cells causes much of their localised damage, such as osteoporosis, and creates a microenvironment in which the malignant cells thrive. Angiogenesis (the attraction of new blood vessels) is increased.

The produced antibodies are deposited in various organs, leading to renal failure, polyneuropathy and various other myeloma-associated symptoms.

Epidemiology
There are approximately 45,000 people in the United States living with multiple myeloma, and the American Cancer Society estimates that approximately 14,600 new cases of myeloma are diagnosed each year in the United States. It follows from here that the average survival at diagnosis is about three years.

Multiple myeloma is the second most prevalent blood cancer (10%) after non-Hodgkin's lymphoma. It represents approximately 1% of all cancers and 2% of all cancer deaths. Although the peak age of onset of multiple myeloma is 65 to 70 years of age, recent statistics indicate both increasing incidence and earlier age of onset.

Multiple myeloma affects slightly more men than women. African Americans and Native Pacific Islanders have the highest reported incidence of this disease in the United States and Asians the lowest. Results of a recent study found the incidence of myeloma to be 9.5 cases per 100,000 African Americans and 4.1 cases per 100,000 Caucasian Americans. Among African Americans, myeloma is one of the top 10 leading causes of cancer death.

Treatment
Treatment for multiple myeloma is focused on disease containment and suppression. If the disease is completely asymptomatic (i.e. there is a paraprotein and an abnormal bone marrow population but no end-organ damage), treatment may be deferred.

Although allogeneic stem cell transplant might cure the cancer, it is considered investigational given the high treatment-related mortality of 5-10% associated with the procedure. In addition to direct treatment of the plasma cell proliferation, bisphosphonates (e.g. pamidronate or zoledronic acid) are routinely administered to prevent fractures and erythropoietin to treat anemia.

Initial therapy
Initial treatment is aimed at treating symptoms and reducing disease burden. Commonly used induction regimens include dexamethasone with or without thalidomide and cyclophosphamide, and VAD (vincristine, adriamycin, and dexamethasone). Low-dose therapy with melphalan combined with prednisone can be used to palliate symptoms in patients who cannot tolerate aggressive therapy. Plasmapheresis can be used to treat symptomatic protein proliferation (hyperviscosity syndrome).

In younger patients, therapy may include high-dose chemotherapy, melphalan, and autologous stem cell transplantation. This can be given in tandem fashion, i.e. an autologous transplant followed by a second transplant. Nonmyeloablative (or "mini") allogeneic stem cell transplantation is being investigated as an alternative to autologous stem cell transplant, or as part of a tandem transplant following an autologous transplant (also known as an "auto-mini" tandem transplant).

Relapse
The natural history of myeloma is of relapse following treatment. Depending on the patient's condition, the prior treatment modalities used and the duration of remission, options for relapsed disease include re-treatment with the original agent, use of other agents (such as melphalan, cyclophosphamide, thalidomide or dexamethasone, alone or in combination), and a second autologous stem cell transplant.

Later in the course of the disease, "treatment resistance" occurs. This may be a reversible effect,and some new treatment modalities may re-sensitize the tumor to standard therapy. For patients with relapsed disease, bortezomib (or Velcade®) is a recent addition to the therapeutic arsenal, especially as second line therapy. Bortezomib is a proteasome inhibitor. Finally, lenalidomide (or Revlimid®), a less toxic thalidomide analog, is showing promise for treating myeloma.

Renal failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute renal failure typically resolves when the calcium and paraprotein levels are brought under control. Treatment of chronic renal failure is dependent on the type of renal failure and may involve dialysis.

Prognosis
The International Staging System can help to predict survival, with a median survival of 62 months for stage 1 disease, 45 months for stage 2 disease, and 29 months for stage 3 disease.

Cytogenetic analysis of myeloma cells may be of prognostic value, with deletion of chromosome 13, non-hyperdiploidy and the balanced translocations t(4;14) and t(14;16) conferring a poorer prognosis. The 11q13 and 6p21 cytogenetic abnormalities are associated with a better prognosis.

Prognostic markers such as these are always generated by retrospective analyses, and it is likely that new treatment developments will improve the outlook for those with traditionally 'poor-risk' disease.

Myloma

Lympoma

Lymphoma is a type of cancer that originates in lymphocytes. There are many types of lymphoma. Lymphomas are part of the broad group of diseases called hematological neoplasms.

In the 19th and 20th centuries the affliction was called Hodgkin's Disease, as it was discovered by Thomas Hodgkin in 1832. Colloquially, lymphoma is broadly categorized as Hodgkin's lymphoma and non-Hodgkin lymphoma (all other types of lymphoma). Scientific classification of the types of lymphoma is more detailed.

Although older classifications referred to histiocytic lymphomas, these are recognized in newer classifications as of B, T or NK cell lineage. Histiocytic malignancies are rare and are classified as sarcomas.

Prevalence
According to the U.S. National Institutes of Health, lymphomas account for about five percent of all cases of cancer in the United States, and Hodgkin's lymphoma in particular accounts for less than one percent of all cases of cancer in the United States.

Because the lymphatic system is part of the body's immune system, patients with weakened immune system, such as from HIV infection or from certain drugs or medication, also have a higher incidence of lymphoma.

Classification

WHO classification
The WHO Classification is the latest classification of lymphoma, published by the World Health Organization in 2001. It was based upon the "Revised European-American Lymphoma classification" (REAL).

This classification attempts to classify lymphomas by cell type, i.e. the normal cell type that most closely resembles the tumor. They are classified in three large groups: the B cell tumors, the T cell and natural killer cell tumors, Hodgkin lymphoma, and other minor groups: (ICD-O codes are provided where available)

Mature B cell neoplasms

DNA-microarray analysis of Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL) showing differences in gene expression patterns. Colors indicate levels of expression; green indicates genes that are overexpressed in normal cells compared to lymphoma cells and red indicates genes that are overexpressed in lymphoma cells compared to normal cells.
Chronic lymphocytic leukemia/small lymphocytic lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia
Splenic marginal zone lymphoma
Plasma cell neoplasms
Plasma cell myeloma
Plasmacytoma
Monoclonal immunoglobulin deposition diseases
Heavy chain diseases
Extranodal marginal zone B cell lymphoma (MALT lymphoma)
Nodal marginal zone B cell lymphoma
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B cell lymphoma
Mediastinal (thymic) large B cell lymphoma
Intravascular large B cell lymphoma
Primary effusion lymphoma
Burkitt lymphoma/leukemia
Lymphomatoid granulomatosis

Mature T cell and natural killer (NK) cell neoplasms

T cell prolymphocytic leukemia
T cell large granular lymphocytic leukemia
Aggressive NK cell leukemia
Adult T cell leukemia/lymphoma
Extranodal NK/T cell lymphoma, nasal type
Enteropathy-type T cell lymphoma
Hepatosplenic T cell lymphoma
Blastic NK cell lymphoma
Mycosis fungoides / Sezary syndrome
Primary cutaneous CD30-positive T cell lymphoproliferative disorders
Primary cutaneous anaplastic large cell lymphoma
Lymphomatoid papulosis
Angioimmunoblastic T cell lymphoma
Peripheral T cell lymphoma, unspecified
Anaplastic large cell lymphoma

Hodgkin Lymphoma

Nodular lymphocyte-predominant Hodgkin lymphoma
Classical Hodgkin lymphoma
Nodular sclerosis
Mixed cellularity
Lymphocyte-rich
Lymphocyte depleted or not depleted

Immunodeficiency-associated lymphoproliferative disorders

Associated with a primary immune disorder
Associated with the Human Immunodeficiency Virus (HIV)
Post-transplant
Associated with Methotrexate therapy

Working formulation
The Working Formulation, published in 1982, is primarily descriptive. It is still occasionally used, but has been superseded by the WHO classification, above.

Low grade
Malignant Lymphoma, small lymphocytic (chronic lymphocytic leukemia)
Malignant Lymphoma, follicular, predominantly small cleaved cell
Malignant Lymphoma, follicular, mixed (small cleaved and large cell)

High grade
Malignant Lymphoma, large cell, immunoblastic
Malignant Lymphoma, lymphoblastic
Malignant Lymphoma, small non-cleaved cells (Burkitt's lymphoma)

Miscellaneous
Composite
Mycosis fungoides
Histiocytic
Extramedullary plasmacytoma
Unclassifiable

Other classification systems
ICD-O (codes 9590-9999, details at) (archive link, was dead)
ICD-10 (codes C81-C96, details at)

For diagnosis, etiology, staging, prognosis, and treatment
Please see separate links to Hodgkin's lymphoma and non-Hodgkin's lymphoma.

Genetics
Enteropathy associated T-cell lymphoma (EATL) is environmentally induced as a result of the consumption of Triticeae glutens. In gluten sensitive individuals with EATL 68% are homozygotes of the DQB1*02 subtype at the HLA-DQB1 locus (serotype DQ2).

Lympoma

Ibuprofen Mode of Action

Ibuprofen (INN)(from the earlier nomenclature iso-butyl-propanoic-phenolic acid) is a non-steroidal anti-inflammatory drug (NSAID) originally marketed as Nurofen and since under various trademarks including Act-3, Advil, Brufen, Dorival, Herron Blue, Panafen, Motrin, Nuprin and Ipren or Ibumetin (Sweden), Ibuprom (Poland), IbuHEXAL, Moment (Italy), Ibux (Norway), Íbúfen (Iceland), Ibalgin (Czech Republic). It is used for relief of symptoms of arthritis, primary dysmenorrhoea, fever, and as an analgesic, especially where there is an inflammatory component. Ibuprofen has no antiplatelet effect.

History
Ibuprofen was developed by the research arm of Boots Group during the 1960s.

Clinical use
Low doses of ibuprofen (200 mg, and sometimes 400 mg) are available over the counter (OTC) in most countries. Ibuprofen has a dose-dependent duration of action of approximately 4–8 hours, which is longer than suggested by its short half-life. The recommended dose varies with body mass and indication. Generally, the oral dose is 200–400 mg (5–10 mg/kg in children) every 4–6 hours, adding up to a usual daily dose of 800–1200 mg. 1200 mg is considered the maximum daily dose for over-the-counter use, though under medical direction, a maximum daily dose of 3200 mg may sometimes be used in increments of 600--800 mg.

Off-Label and investigational use
As with other NSAIDs, ibuprofen may be useful in the treatment of severe orthostatic hypotension.
In some studies, ibuprofen showed superior results compared to placebo in the prophylaxis of Alzheimer's disease, when given in low doses over a long time.[2] Further studies are needed to confirm the results before ibuprofen can be recommended for this indication.
Ibuprofen has been associated with a lower risk of Parkinson's disease, and may delay or prevent Parkinson's disease. Aspirin, other NSAIDs, and paracetamol had no effect on the risk for Parkinson's. Further research is warranted before recommending ibuprofen for this use.

Ibuprofen lysine
In Europe, Australia, and New Zealand, ibuprofen lysine (ibuprofenlysinat, the lysine salt of ibuprofen) is licensed for treatment of the same conditions as ibuprofen. Ibuprofen lysine has been shown to have a more rapid onset of action compared to base ibuprofen.[4]

Mechanism of action
Ibuprofen is an NSAID which is believed to work through inhibition of cyclooxygenase (COX), thus inhibiting prostaglandin synthesis. There are at least 2 variants of cyclooxygenase (COX-1 and COX-2). Ibuprofen inhibits both COX-1 and COX-2. It appears that its analgesic, antipyretic, and anti-inflammatory activity are achieved principally through COX-2 inhibition; whereas COX-1 inhibition is responsible for its unwanted effects on platelet aggregation and the GI mucosa.

Side effects
Ibuprofen appears to have the lowest incidence of gastrointestinal adverse drug reactions (ADRs) of all the non-selective NSAIDs. However, this only holds true at lower doses of ibuprofen, so over-the-counter preparations of ibuprofen are generally labeled to advise a maximum daily dose of 1,200 mg.

Reported adverse drug reactions
Common adverse effects include: nausea, dyspepsia, gastrointestinal ulceration/bleeding, raised liver enzymes, diarrhea, headache, dizziness, priapism, salt and fluid retention, and hypertension.

Infrequent adverse effects include: oesophageal ulceration, heart failure, hyperkalaemia, renal impairment, confusion, bronchospasm, rash.

Very infrequent adverse effects include Stevens-Johnson syndrome.

Photosensitivity
As with other NSAIDs, ibuprofen has been reported to be a photosensitising agent. However, this only rarely occurs with ibuprofen and it is considered to be a very weak photosensitising agent when compared with other members of the 2-arylpropionic acids. This is because the ibuprofen molecule contains only a single phenyl moiety and no bond conjugation, resulting in a very weak chromophore system and a very weak absorption spectrum which does not reach into the solar spectrum.

Cardiovascular risk
Along with several other NSAIDs, ibuprofen has been implicated in elevating the risk of myocardial infarction, particularly among those chronically using high doses.

Pregnancy risks
Two studies have found an increased risk of miscarriage with the use of NSAIDs such as ibuprofen early in pregnancy; however, several other studies did not find this association. There are also concerns that drugs such as ibuprofen may interfere with implantation of the early fetus, although a clear risk has not been established.

When ibuprofen is used as directed in the first and second trimester of pregnancy, it is not associated with an increased risk for birth defects. However, ibuprofen is generally not the pain reliever of choice during pregnancy because there are concerns with the use of ibuprofen during the third trimester.

DOMS
A study has shown that athletes who take ibuprofen to treat delayed onset muscle soreness (DOMS) show less muscle gain than athletes who did not.[citation needed]

Stereochemistry

3D model of (R)-ibuprofenIbuprofen, like other 2-arylpropionate derivatives (including ketoprofen, flurbiprofen, naproxen, etc), contains a chiral carbon in the α-position of the propionate moiety. As such there are two possible enantiomers of ibuprofen with the potential for different biological effects and metabolism for each enantiomer.

Indeed it was found that (S)-(+)-ibuprofen (dexibuprofen) was the active form both in vitro and in vivo.

It was logical, then, that there was the potential for improving the selectivity and potency of ibuprofen formulations by marketing ibuprofen as a single-enantiomer product (as occurs with naproxen, another NSAID.).

Further in vivo testing, however, revealed the existence of an isomerase which converted (R)-ibuprofen to the active (S)-enantiomer(citation needed). Thus, due to the expense and futility that might be involved in marketing the single-enantiomer, most ibuprofen formulations currently marketed are racemic mixtures. A notable exception to this is Seractiv (Nordic Drugs).

Human toxicology
Ibuprofen overdose has become common since it was licensed for over-the-counter use. There are many overdose experiences reported in the medical literature. Human response in cases of overdose ranges from absence of symptoms to fatal outcome in spite of intensive care treatment. Most symptoms are an excess of the pharmacological action of ibuprofen and include abdominal pain, nausea, vomiting, drowsiness, dizziness, headache, tinnitus, and nystagmus. Rarely more severe symptoms such as gastrointestinal bleeding, seizures, metabolic acidosis, hyperkalaemia, hypotension, bradycardia, tachycardia, atrial fibrillation, coma, hepatic dysfunction, acute renal failure, cyanosis, respiratory depression, and cardiac arrest have been reported. The severity of symptoms varies with the ingested dose and the time elapsed, however, individual sensitivity also plays an important role. Generally, the symptoms observed with an overdose of ibuprofen are similar to the symptoms caused by overdoses of other NSAIDs.

There is little correlation between severity of symptoms and measured ibuprofen plasma levels. Toxic effects are unlikely at doses below 100 mg/kg but can be severe above 400 mg/kg; however, large doses do not indicate that the clinical course is likely to be lethal. It is not possible to determine a precise lethal dose, as this may vary with age, weight, and concomitant diseases of the individual patient.

Therapy is largely symptomatic. In cases presenting early, gastric decontamination is recommended. This is achieved using activated charcoal; charcoal absorbs the drug before it can enter the systemic circulation. Gastric lavage is now rarely used, but can be considered if the amount ingested is potentially life threatening and it can be performed within 60 minutes of ingestion. Emesis is not recommended. The majority of ibuprofen ingestions produce only mild effects and the management of overdose is straightforward. Standard measures to maintain normal urine output should be instituted and renal function monitored. Since ibuprofen has acidic properties and is also excreted in the urine, forced alkaline diuresis is theoretically beneficial. However, due to the fact ibuprofen is highly protein bound in the blood, there is minimal renal excretion of unchanged drug. Forced alkaline diuresis is therefore of limited benefit. Symptomatic therapy for hypotension, GI bleeding, acidosis, and renal toxicity may be indicated. Occasionally, close monitoring in an intensive care unit for several days is necessary. If a patient survives the acute intoxication, he/she will usually experience no late sequelae.

Ibuprofen Mode of Action

Colon Sugery

General surgery, despite its name, is a surgical specialty that focuses on surgical treatment of abdominal organs, e.g. intestines including esophagus, stomach, colon, liver, gallbladder and bile ducts, and often the thyroid gland (depending on the availability of head and neck surgery specialists) and hernias.

Scope

Breast disease
In Australia, Canada, the US and the UK, general surgeons are responsible for breast care, including the surgical treatment of breast cancer. In most other countries, breast care falls under Obstetrics and Gynecology and its sub-specialty of Mastology (or Senology).

Trauma
In the United States, the overall responsibility for trauma care falls under the auspices of general surgery, some general surgeons obtaining advanced training and specialty certification in this field alone.

Trends
In the last few years minimally invasive surgery has become more prevalent. Considerable enthusiasm has built around robotic surgery (also known as robotic-assisted surgery), despite a lack of data suggesting it has significant benefits that justify its cost.

Training
In Canada and the United States general surgery is a five-year residency and follows completion of medical school. Following high school, it takes approximately thirteen years to make a fully licensed general surgeon (four years undergraduate training, four years medical school and five years residency).

Subspecialization
In many countries general surgery is a prerequiste for subspecialization in:
vascular surgery,
thoracic surgery and
cardiac surgery.

Colon Sugery

Cause of Alchohol Poisoning

The effects of alcohol on the human body can take several forms.

Alcohol, specifically ethanol, is a potent central nervous system depressant, with a range of side effects. The amount and circumstances of consumption play a large part in determining the extent of intoxication; e.g., consuming alcohol after a heavy meal is less likely to produce visible signs of intoxication than consumption on an empty stomach. Hydration also plays a role, especially in determining the extent of hangovers. The concentration of alcohol in blood is usually measured in terms of the blood alcohol content.

Alcohol has a biphasic effect on the body, which is to say that its effects change over time. Initially, alcohol generally produces feelings of relaxation and cheerfulness, but further consumption can lead to blurred vision and coordination problems. Cell membranes are highly permeable to alcohol, so once alcohol is in the bloodstream it can diffuse into nearly every biological tissue of the body. After excessive drinking, unconsciousness can occur and extreme levels of consumption can lead to alcohol poisoning and death (a concentration in the blood stream of 0.55% will kill half of those affected). Death can also occur through asphyxiation by vomit. An appropriate first aid response to an unconscious, drunken person is to place them in the recovery position.

Intoxication frequently leads to a lowering of one's inhibitions, and intoxicated people will sometimes do things they would not do while sober, often overlooking social, moral, and legal considerations. However, it appears that intoxicated people have much greater control over their behavior than is generally recognized.

The image shows the brains of two six-week-old infants. The left brain is confirmed no alcohol exposure, while the right brain is of an infant with fetal alcohol syndrome.This article primarily covers the short-term effects of alcohol on the adult human body. For the potential long-term cumulative effects of alcohol on the adult human body, please refer to alcohol consumption and health, alcohol and cardiovascular disease, alcohol and cancer, alcohol and weight and alcoholic liver disease. The potential impact of alcohol consumption by pregnant women on their fetuses is discussed in the article fetal alcohol syndrome.

Metabolism of alcohol and action on the liver
The liver breaks down alcohols into acetaldehyde by the enzyme alcohol dehydrogenase, and then into acetic acid by the enzyme acetaldehyde dehydrogenase. Next, the acetate is converted into fats or carbon dioxide and water. Chronic drinkers, however, so tax this metabolic pathway that things go awry: fatty acids build up as plaques in the capillaries around liver cells and those cells begin to die, which leads to the liver disease cirrhosis. The liver is part of the body's filtration system which, if damaged, allows certain toxins to build up, leading to symptoms of jaundice.

The alcohol dehydrogenase of women is less effective than that of men[citation needed]. The percentage of water in women's bodies is less than that of men[citation needed]. Therefore, the alcohol has less volume to dissolve in, leading to a higher blood alcohol concentration when the same amount of alcohol is ingested. This contributes to the fact that women become intoxicated more quickly than men. Also contributing is the fact that men have a more active first-pass metabolism of alcohol in the stomach and small intestine.[citation needed]

Some people's DNA code for a different acetaldehyde dehydrogenase, resulting in more potent alcohol dehydrogenase. This leads to a buildup of acetaldehyde after alcohol consumption, causing the alcohol flush reaction with hangover-like symptoms such as flushing, nausea, and dizziness. These people are unable to drink much alcohol before feeling sick, and are therefore less susceptible to alcoholism. This adverse reaction can be artificially reproduced by drugs such as disulfiram, which are used to treat chronic alcoholism by inducing an acute sensitivity to alcohol.

Dehydration
Overconsumption can therefore lead to dehydration (the loss of water).

Hangover
A common after-effect of ethanol intoxication is the unpleasant sensation known as hangover, which is partly due to the dehydrating effect of ethanol. Hangover symptoms include dry mouth, headache, nausea, and sensitivity to light and noise. These symptoms are partly due to the toxic acetaldehyde produced from alcohol by alcohol dehydrogenase, and partly due to general dehydration. The dehydration portion of the hangover effect can be mitigated by drinking plenty of water between and after alcoholic drinks. Other components of the hangover are thought to come from the various other chemicals in an alcoholic drink, such as the tannins in red wine, and the results of various metabolic processes of alcohol in the body, but few scientific studies have attempted to verify this. Consuming water between drinks and before bed is the best way to prevent or lessen the effects of a hangover.

Beneficial effects of alcohol
The World Health Organization (WHO) reports that there is convincing evidence that "low to moderate alcohol intake" results in a decreased risk of coronary heart disease. However, the WHO cautions that "other cardiovascular and health risks associated with alcohol do not favour a general recommendation for its use."

Moderate alcohol consumption has been found to be associated with a lower risk of Alzheimer’s disease and other dementia, angina pectoris, bone fractures and osteoporosis, diabetes, duodenal ulcer, gallstones, hepatitis A, Hodgkin’s lymphoma, intermittent claudicating (IC), kidney stones, non-Hodgkin’s lymphoma, metabolic syndrome, pancreatic cancer, Parkinson's Disease, peripheral arterial disease (PAD), rheumatoid arthritis, and type B gastritis. Also it has been suggested that moderate consumption can reduce dementia risk, facilitate memory and learning, and even improve IQ scores.

However, a study of red wine published in the American Journal of Clinical Nutrition, found that alcohol-free red wine had the same health benefits as the alcoholic wine, and that the alcohol may actually shorten the benefits. Flavonoids believed to be protective against coronary heart disease and some types of cancer, are present in wine due to its fermentation from grapes. These left the blood more quickly when alcohol was consumed.

Moderate drinkers tend to have better health and live longer than those who abstain from alcohol or are heavy drinkers[citation needed], but this average difference may possibly be explained in part by the fact that a fraction of abstainers from alcohol are ex-alcoholics or those who have health problems or take drugs that preclude the use of alcohol. See Alcohol consumption and health.


Effects by dose
Different concentrations of alcohol in the human body have different effects on the subject. The following lists the effects of alcohol on the body, depending on the blood alcohol concentration or BAC. Also, tolerance varies considerably between individuals.

Please note: the BAC percentages provided below are just estimates and used for illustrative purposes only. They are not meant to be an exhaustive reference; please refer to a healthcare professional if more information is needed.
Euphoria (BAC = 0.03 to 0.12%)
Subject may experience an overall improvement in mood and possible euphoria.
They may become more self-confident or daring.
Their attention span shortens. They may look flushed.
Their judgment is not as good — they may express the first thought that comes to mind, rather than an appropriate comment for the given situation.
They have trouble with fine movements, such as writing or signing their name.
Lethargy (BAC = 0.09 to 0.25%)
Subject may become sleepy
They have trouble understanding or remembering things, even recent events. They do not react to situations as quickly.
Their body movements are uncoordinated; they begin to lose their balance easily, stumbling; walking is not stable.
Their vision becomes blurry. They may have trouble sensing things (hearing, tasting, feeling, etc.).
Confusion (BAC = 0.18 to 0.30%)
Profound confusion — uncertain where they are or what they are doing. Dizziness and staggering occur.
Heightened emotional state — aggressive, withdrawn, or overly affectionate. Vision, speech, and awareness are impaired.
Poor coordination and pain response. Nausea and vomiting often occur.
Stupor (BAC = 0.25 to 0.40%)
Movement severely impaired; lapses in and out of consciousness.
Subjects can slip into a coma; will become completely unaware of surroundings, time passage, and actions.
Risk of death is very high due to alcohol poisoning and/or pulmonary aspiration of vomit while unconscious.
Coma (BAC = 0.35 to 0.50%)
Unconsciousness sets in.
Reflexes are depressed (i.e., pupils do not respond appropriately to changes in light).
Breathing is slower and more shallow. Heart rate drops. Death usually occurs at levels in this range.
Death (BAC more than 0.50%)
Can cause central nervous system to fail, resulting in death.

Moderate doses
Although alcohol is typically thought of purely as a depressant, at low concentrations it can actually stimulate certain areas of the brain. Alcohol sensitises the N-methyl-D-aspartate (NMDA) system of the brain, making it more receptive to the neurotransmitter glutamate. Stimulated areas include the cortex, hippocampus and nucleus accumbens, which are responsible for thinking and pleasure seeking. Another one of alcohol's agreeable effects is body relaxation, possibly caused by heightened alpha brain waves surging across the brain. Alpha waves are observed (with the aid of EEGs) when the body is relaxed. Heightened pulses are thought to correspond to higher levels of enjoyment.

A well-known side effect of alcohol is lowering inhibitions. Areas of the brain responsible for planning and motor learning are dulled. A related effect, caused by even low levels of alcohol, is the tendency for people to become more animated in speech and movement. This is due to increased metabolism in areas of the brain associated with movement, such as the nigrostriatal pathway. This causes reward systems in the brain to become more active, and combined with reduced understanding of the consequences of their behavior, can induce people to behave in an uncharacteristically loud and cheerful manner.

Behavioural changes associated with drunkenness are, to some degree, contextual. A scientific study found that people drinking in a social setting significantly and dramatically altered their behavior immediately after the first sip of alcohol, well before the chemical itself could have filtered through to the nervous system. Likewise, people consuming non-alcoholic drinks often exhibit drunk-like behaviour on a par with their alcohol-drinking companions even though their own drinks contained no alcohol whatsoever. [citation needed]

Excessive doses
The effect alcohol has on the NMDA receptors, earlier responsible for pleasurable stimulation, turns from a blessing to a curse if too much alcohol is consumed. NMDA receptors start to become unresponsive, slowing thought in the areas of the brain they are responsible for. Contributing to this effect is the activity which alcohol induces in the gamma-aminobutyric acid system (GABA). The GABA system is known to inhibit activity in the brain. GABA could also be responsible for the memory impairment that many people experience. It has been asserted that GABA signals interfere with the registration and consolidation stages of memory formation. As the GABA system is found in the hippocampus, (among other areas in the CNS), which is thought to play a large role in memory formation, this is thought to be possible.

Blurred vision is another common symptom of drunkenness. Alcohol seems to suppress the metabolism of glucose in the brain. The occipital lobe, the part of the brain responsible for receiving visual inputs, has been found to become especially impaired, consuming 29% less glucose than it should. With less glucose metabolism, it is thought that the cells aren't able to process images properly.

Often, after much alcohol has been consumed, it is possible to experience vertigo, the sense that the room is spinning (sometimes referred to as 'The Spins'). This is associated with abnormal eye movements called nystagmus, specifically positional alcohol nystagmus. In this case, alcohol has affected the organs responsible for balance (vestibular system), present in the ears. Balance in the body is monitored principally by two systems: the semicircular canals, and the utricle and saccule pair. Inside both of these is a flexible blob called a cupula, which moves when the body moves. This brushes against hair cells in the ear, creating nerve impulses that travel through the vestibulocochlear nerve (Cranial nerve VIII) in to the brain. However, when alcohol gets in to the bloodstream it distorts the shape of the cupola, causing it to keep pressing on to the hairs. The abnormal nerve impulses tell the brain that the body is rotating, causing disorientation and making the eyes spin round to compensate. When this wears off (usually taking until the following morning) the brain has adjusted to the spinning, and interprets not spinning as spinning in the opposite direction causing further disorientation. This is often a common symptom of the hangover.

Anterograde amnesia, colloquially referred to as "blacking out", is another symptom of heavy drinking.

Another classic finding of alcohol intoxication is ataxia, in its appendicular, gait, and truncal forms. Appendicular ataxia results in jerky, uncoordinated movements of the limbs, as though each muscle were working independently from the others. Truncal ataxia results in postural instability; gait instability is manifested as a disorderly, wide-based gait with inconsistent foot positioning. Ataxia is responsible for the observation that drunk people are clumsy, sway back and forth, and often fall down. It is probably due to alcohol's effect on the cerebellum.

Extreme overdoses can lead to alcohol poisoning and death due to respiratory depression.

A rare complication of acute alcohol ingestion is Wernicke encephalopathy, a disorder of thiamine metabolism. If not treated with thiamine, Wernicke encephalopathy can progress to Korsakoff psychosis, which is irreversible.

Chronic alcohol ingestion over many years can produce atrophy of the vermis, which is the part of the cerebellum responsible for coordinating gait; vermian atrophy produces the classic gait findings of alcohol intoxication even when its victim is not inebriated.

Severe drunkenness and hypoglycemia can be mistaken for each other on casual inspection, with potentially serious medical consequences for diabetics. Measurement of the serum glucose and ethanol concentrations in comatose individuals is routinely performed in the emergency department or by properly-equipped prehospital providers and easily distinguishes the two conditions.

Cause of Alchohol Poisoning

Osseous Surgery

Dental surgery is any of a number of medical procedures which involve artificially modifying the dentition.

Types
Some of the more common are:

Endodontic (surgery involving the pulp or root of the tooth)
Root canal
Pulpotomy The opening of the pulp chamber of the tooth to allow an infection to drain; Usually a precursor to a root canal
Pulpectomy - The removal of the pulp from the pulp chamber to temporarily relieve pain; Usually a precursor to a root canal.
Apicoectomy - A root-end resection. Occasionally a root canal alone will not be enough to relieve pain and the end of the tooth, called the apex, will be removed by entering through the gingiva and surgically extracting the diseased material.
Prosthodontic (dental prosthetics)
Crowns (caps) — artificial coverings of the tooth made from a variety of materials, including CMC/PMC (ceramic/porcelain metal composite), gold or a tin/aluminum mixture. The underlying tooth must be reshaped to accommodate these
Veneers — artificial coverings similar to above, except that they only cover the forward (labial or buccal) surface of the tooth. Usually for aesthetic purposes only.
Bridges — a set of two or more fused crowns which bridge a missing tooth (teeth). Typically used after an extraction.
Implants — a procedure in which a base is set into the bone (mandible or maxilla), allowed to heal, and months later an artificial tooth is screwed into place.
Dentures (false teeth) — a partial or complete set of dentition which either attach to neighboring teeth by use of metal or plastic grasps or to the gingival or palatial surface by use of adhesive.
Implant-supported prosthesis — a combination of dentures and implants, bases are placed into the bone, allowed to heal, and metal appliances are fixed to the gingival surface, following which dentures are placed atop and fixed into place.
Orthodontic treatment
Implants and implant-supported prosthesis — also an orthodontic treatment as it involves bones
Apiectomy — also an orthodontic treatment as part of the underlying bone structure must be removed.
Extraction — a procedure in which a diseased, redundant, or problematic tooth is removed, either by pulling or cutting out. This procedure can be done under local or general anesthesia and is very common — many people have their wisdom teeth removed before they become problematic.
Fiberotomy — a procedure to sever the fibers around a tooth, preventing it from relapsing.

Dental anesthesia
Dentists inject anesthetic to block sensory transmission by the alveolar nerves. The superior alveolar nerves are not usually anesthetized directly because they are difficult to approach with a needle. For this reason, the maxillary teeth are usually anesthetized locally by inserting the needle beneath the oral mucosa surrounding the teeth. The inferior alveolar nerve probably is anesthetized more often than any other nerve in the body. To anesthetize this nerve, the dentist inserts the needle somewhat posterior to the patient’s last molar.

Several nondental nerves are usually anesthetized during an inferior alveolar block. The mental nerve, which supplies cutaneous innervation to the anterior lip and chin, is a distal branch of the inferior alveolar nerve. When the inferior alveolar nerve is blocked, the mental nerve is blocked also, resulting in a numb lip and chin. Nerves lying near the point where the inferior alveolar nerve enters the mandible often are also anesthetized during inferior alveolar anesthesia. For example, the lingual nerve can be anesthetized to produce a numb tongue. The facial nerve lies some distance from the inferior alveolar nerve, but in rare cases anesthetic can diffuse far enough posteriorly to anesthetize that nerve. The result is a temporary facial palsy (paralysis or paresis), with the injected side of the face drooping because of flaccid muscles, which disappears when the anesthesia wears off. If the facial nerve is cut by an improperly inserted needle, permanent facial palsy may occur.

Agents
Forms of dental anesthesia are similar to general medical anesthesia except for the use of nitrous oxide, relatively uncommon outside of the dental field in the U.S.

Nitrous oxide (N2O), also known as "laughing gas", binds to the hemoglobin in the lungs, where it travels to the brain, leaving a disassociated and euphoric feeling for most patients. N2O is typically used in conjunction with Procaine.
Local anesthetics used are lidocaine or xylocaine (a modern replacement for novocaine, procaine), septocaine (a numbing medication which can overpower infection, which can make it difficult to get numb), and marcaine (a long-acting anesthetic). A combination of these may be used depending on the situation. Also, most agents come in two forms: with and without epinephrine.
Eugenol — made from clove oil, this is a topical anesthetic also used in the common dental material ZOE (zinc oxide eugenol).
Topical anastethics — benzocaine, eugenol, and forms of xylocaine are used topically to numb various areas before injections or other minor procedures
General anesthesia — drugs such as versed, ketamine, and fentynyl are used to put the patient in a twilight sleep or render them completely unconscious and unaware of pain.

Blocks
Electrical nerve blocks — a technology that involves using electrical current to block the reception or generation of pain signals.
Branch block — a common form of local dental anesthesia, blocks the reception of pain for one quadrant of the mouth at a time. Typically given in the buccal surface (cheek). (IAB, MNB are types of this block)
Dental block — given below the tooth in question. Used usually for minor procedures such as fillings.
Palatal block— given into the hard palate, useful in numbing the upper teeth.
Intraosseous — an injection of local anesthetic given directly into the osseous (bone) structure of the tooth.
Intrapulpal — an injection of local anesthetic given directly into the pulp of the tooth to completely desensitize the tooth.
An alternative to chemical or electrical blocks, acupuncture or acupressure is rarely used.

Osseous Surgery

Amoxicillian

Amoxicillin (INN) or amoxycillin (former BAN) is a moderate-spectrum β-lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms. It is usually the drug of choice within the class because it is better absorbed, following oral administration, than other beta-lactam antibiotics. Amoxicillin is susceptible to degradation by β-lactamase-producing bacteria, and so may be given with clavulanic acid to decrease its susceptibility (see below). It was developed by Beecham in 1972 and is currently marketed by GlaxoSmithKline (the inheritor company) under the original trade name Amoxil.

Mode of action
Main article: Beta-lactam antibiotic
Amoxicillin acts by inhibiting the synthesis of bacterial cell walls. It inhibits cross-linkage between the linear peptidoglycan polymer chains that make up a major component of the cell wall of Gram-positive bacteria.

Microbiology
Amoxicillin is a moderate-spectrum antibiotic active against a wide range of Gram-positive, and a limited range of Gram-negative organisms. Some examples of susceptible and resistant organisms, from the Amoxil® Approved Product Information (GSK, 2003), are listed below.

Susceptible Gram-positive organisms
Streptococcus spp., penicillin-susceptible Streptococcus pneumoniae, non β-lactamase-producing Staphylococcus spp., and Enterococcus faecalis.

Susceptible Gram-negative organisms
Non-β-lactamase producing strains of the following bacteria: Haemophilus influenzae, Neisseria gonorrhoeae, Neisseria meningitidis, Escherichia coli, Proteus mirabilis and Salmonella spp.

Resistant organisms
Penicillinase-producing organisms, particularly penicillinase-producing Staphylococcus spp. Penicillinase-producing N. gonorrhoeae and H. influenzae are also resistant.

All strains of Pseudomonas spp., Klebsiella spp., Enterobacter spp., indole-positive Proteus spp., Serratia marcescens, and Citrobacter spp. are resistant.

The incidence of β-lactamase-producing resistant organisms, including E. coli, appears to be increasing.

Doubling the routinely given concentration (in pediatrics) of amoxicillin has been shown to eradicate intermediately resistant Streptococcus pneumoniae in selected infections.[1]

Formulations
Amoxicillin in trihydrate form is available as capsules, tablets, or syrup for oral use, and as the sodium salt for intravenous administration. It is one of the most common antibiotics issued to children.

Amoxicillin and clavulanic acid
Amoxicillin (in either trihydrate or sodium salt forms) may be combined with Clavulanic acid (as potassium clavulanate), a β-lactamase inhibitor, to increase the spectrum of action against Gram-negative organisms, and to overcome bacterial antibiotic resistance mediated through β-lactamase production. This formulation is referred to as Co-amoxiclav (British Approved Name), but commonly by proprietary names such as Amoksiklav (×2 or SOLVO), Augmentin and Clamoxyl, Augclav (VHB Life Science inc.-CRONUS).

Side effects
Side effects are as those for other beta-lactam antibiotics. Side effects include nausea, vomiting and easy fatigue.

Proprietary preparations
The patent for amoxicillin has expired. Thus amoxicillin is marketed under many trade names including: Actimoxi, Amoxiclav Sandoz, Amoxil, Amoksiklav, Amoxibiotic, Amoxicilina, Apo-Amoxi, Bactox, Betalaktam, Cilamox, Curam, Dedoxil, Dispermox, Duomox, Isimoxin, Lamoxy, Moxypen, Moxyvit, Novamoxin, Ospamox, Panklav, Pamoxicillin, Polymox, Samthongcillin, Sinacilin, Trimox, Tolodina, Wymox, Zerrsox and Zimox.

Amoxicillian

Catarac

A cataract is an opacity that develops in the crystalline lens of the eye or in its envelope. Early on in the development of age-related cataract the power of the crystalline lens may be increased, causing near-sightedness (myopia), and the gradual yellowing and opacification of the lens may reduce the perception of blue colours. Cataracts typically progress slowly to cause vision loss and are potentially blinding if untreated. Moreover, with time the cataract cortex liquefies to form a milky white fluid in a Morgagnian Cataract, and can cause severe inflammation if the lens capsule ruptures and leaks. Untreated, the cataract can cause phacomorphic glaucoma. Very advanced cataracts with weak zonules are liable to dislocation anteriorly or posteriorly. Such spontaneous posterior dislocations (akin to the earliest surgical procedure of couching) in ancient times were regarded as a blessing from the heavens, because it restored some perception of light in the bilaterally affected patients.

Cataract derives from the Latin cataracta meaning "waterfall" and the Greek kataraktes and katarrhaktes, from katarassein meaning "to dash down" (kata-, "down"; arassein, "to strike, dash"[2]). As rapidly running water turns white, the term may later have been used metaphorically to describe the similar appearance of mature ocular opacities. In Latin, cataracta had the alternate meaning, "portcullis", so it is also possible that the name came about through the sense of "obstruction".

Causes

Normal vision. Courtesy National Institutes of Health, USA (NIH).
Hazy view as seen by a person with a cataract, Courtesy NIHCataracts develop from a variety of reasons, including long-term ultraviolet exposure, exposure to radiation, secondary effects of diseases such as diabetes, and advanced age; they are usually a result of denaturation of lens proteins. Genetic factors are often a cause of congenital cataracts and positive family history may also play a role in predisposing someone to cataracts at an earlier age, a phenomenon of "anticipation" in pre-senile cataracts. Cataracts may also be produced by eye injury or physical trauma. A study among Icelandair pilots showed commercial airline pilots as three times more likely to develop cataracts than people with non-flying jobs. This is thought to be caused by excessive exposure to radiation coming from outer space. Cataracts are also unusually common in persons exposed to infrared radiation, such as glassblowers who suffer from "exfoliation syndrome". Exposure to microwave radiation can cause cataracts.

Cataracts may be partial or complete, stationary or progressive, hard or soft.

Some drugs can induce cataract development, such as Corticosteroids and Ezetimibe

There are various types of cataracts, e.g. nuclear, cortical, mature, hypermature. Cataracts are also classified by their location, e.g. posterior (classically due to steroid use) and anterior (common (senile) cataract related to aging).

Epidemiology
Cataracts are the leading cause of blindness in the world.

In the United States, age-related lenticular changes have been reported in 42% of those between the ages of 52 to 64, 60% of those between the ages 65 and 74, and 91% of those between the ages of 75 and 85.

Catarac

Ways to Prevent Wilson Disease

Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative disease that, in its most common form, is found in people over age 65. Approximately 24 million people worldwide are living with Alzheimer’s.

Clinical signs of Alzheimer's disease are characterized by progressive cognitive deterioration, together with declining activities of daily living and by neuropsychiatric symptoms or behavioral changes. It is the most common type of dementia. Plaques which contain misfolded proteins called beta amyloid form in the brain many years before the clinical signs of Alzheimer's are observed. Together, these plaques and neurofibrillary tangles form the pathological hallmarks of the disease. These features can only be discovered at autopsy and help to confirm the clinical diagnosis. Medications can help reduce the symptoms of the disease, but they cannot change the course of the underlying pathology.

The ultimate cause of Alzheimer's is unknown. Genetic factors are suspected, and dominant mutations in three different genes have been identified that account for the small number of cases of familial, early-onset AD. For the more common form of late onset AD (LOAD), ApoE is the only repeatedly confirmed susceptibility gene.

History

Auguste D.In 1901, Dr. Alois Alzheimer, a German psychiatrist, identified the first case of what became known as Alzheimer's disease, in a 50 year-old patient Auguste D and followed her to her death in 1906, when he first reported the case publicly.

For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of presenile dementia. Senile dementia, as a set of symptoms, was considered to be a relatively normal outcome of the ageing process, and thought to be due to age-related brain arterial "hardening."

In the 1970s and early-1980s, because the symptoms and brain pathology were identical for any age, the name "Alzheimer's disease" became used equally for afflicted individuals of all ages; however, the term senile dementia of the Alzheimer type (SDAT) was often used to describe the condition in those over 65. Eventually, the term Alzheimer's disease was formally adopted in medical nomenclature to describe individuals of all ages with the characteristic common symptom pattern, disease course, and neuropathology. The term Alzheimer disease (without the apostrophe and s) is also sometimes used in literature for learning.

Clinical features
The first readily identified symptoms of Alzheimer's disease are usually short-term memory loss and visual-spatial confusion. These initial symptoms progress from seemingly simple and often fluctuating forgetfulness and difficulty orienting oneself in space such as in a traffic lane while driving, to a more pervasive loss of short-term memory and difficulty navigating through familiar areas such as one's neighborhood, then to loss of other familiar and well-known skills as well as recognition of objects and persons.

Since family members are often the first to notice changes that might indicate the onset of Alzheimer's they should learn the early warning signs and serve as informants during initial evaluation of patients clinically. Aphasia, disorientation and disinhibition often accompany the loss of memory. Alzheimer's disease (AD) may also include behavioral changes, such as outbursts of violence or excessive passivity in people who have no previous history of such behavior.

In the later stages of the disease, deterioration of musculature and mobility, leading to bedfastness, inability to feed oneself, and incontinence, will be seen if death from some external cause (e.g. heart attack or pneumonia) does not intervene. Once identified, the average lifespan of patients living with Alzheimer's disease is approximately 7-10 years, although cases are known where reaching the final stage occurs within 4-5 years or at the other extreme they may survive up to 21 years.

Stages and symptoms
Mild — In the early stage of the disease, patients have a tendency to become less energetic or spontaneous, though changes in their behavior often go unnoticed even by the patients' immediate family. This stage of the disease has also been termed Minor Cognitive Impairment (MCI), when the patient does not meet the criteria for a diagnosis of dementia.
Moderate — As the disease progresses to the middle stage, patients might still be able to perform tasks independently (such as using the bathroom), but may need assistance with more complicated activities (such as paying bills).
Severe — As the disease progresses from the middle to the late stage, patients will not be able to perform even simple tasks independently and will require constant supervision. They become incontinent of bladder and then incontinent of bowel. They will eventually lose the ability to walk and eat without assistance. Language becomes severely disorganized, and then is lost altogether. They may eventually lose the ability to swallow food and fluid, and this can ultimately lead to death.

Diagnosis
Alzheimer's disease (AD) is primarily a clinically diagnosed condition based on the presence of characteristic neurological and neuropsychological features and the absence of alternative diagnoses. Determination of neurological characteristics is made utilizing patient history and clinical observation, while neuropsychological evaluation includes memory testing and assessment of intellectual functioning over a series of weeks or months. Supplemental physical testing, including blood tests and neuroimaging, is utilized to rule out other diagnoses. Psychological testing, to include screening for depression and a mini mental state examination, can be helpful in establishing the presence and severity of dementia. Although certain clues from history may suggest a diagnosis of vascular dementias instead of, or in addition to, AD (for example, see the Hachinski scale [9]), the ability of certain neuroimaging modalities such as SPECT to differentiate vascular type from Alzheimer disease types of dementias, appears to be superior to clinical exam (PMID 15545324).

Interviews with family members and/or caregivers are also utilized in the initial assessment of the disease, as a patient with Alzheimer's may tend to minimize his or her symptoms, or may undergo evaluation at a time when his or her symptoms are less apparent, as quotidian fluctuations ("good days and bad days") are a common feature of the disease. Observations noting that a patient's good memory function decreases over time plays a critical role in the diagnosis of Alzheimer's.

No medical tests are available to diagnose Alzheimer's disease conclusively pre-mortem. Expert clinicians who specialize in memory disorders can now diagnose AD with an accuracy of 85 - 90%. However, a definitive diagnosis of Alzheimer's disease must await microscopic examination of brain tissue which generally occurs at autopsy.

Pathology
Main article: Biochemistry of Alzheimer's disease

Biochemical characteristics
Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded amyloid beta protein and tau protein in the brains of AD patients. Amyloid beta, also written Aβ, is a short peptide that is a proteolytic byproduct of the transmembrane protein amyloid precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation. Although amyloid beta monomers are soluble and harmless, they undergo a dramatic conformational change at sufficiently high concentration to form a beta sheet-rich tertiary structure that aggregates to form amyloid fibrils that deposit outside neurons in dense formations known as senile plaques or neuritic plaques, in less dense aggregates as diffuse plaques, and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy or congophilic angiopathy.

AD is also considered a tauopathy due to abnormal aggregation of the tau protein, a microtubule-associated protein expressed in neurons that normally acts to stabilize microtubules in the cell cytoskeleton. Like most microtubule-associated proteins, tau is normally regulated by phosphorylation; however, in AD patients, hyperphosphorylated tau accumulates as paired helical filaments that in turn aggregate into masses inside nerve cell bodies known as neurofibrillary tangles and as dystrophic neurites associated with amyloid plaques.

Neuropathology
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains. At an anatomical level, AD is characterized by gross diffuse atrophy of the brain and loss of neurons, neuronal processes and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.[13] Levels of the neurotransmitter acetylcholine are reduced. Levels of the neurotransmitters serotonin, norepinephrine, and somatostatin are also often reduced. Glutamate levels are usually elevated.

Disease mechanism
Three major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is known as the "cholinergic hypothesis" and suggests that AD is due to reduced biosynthesis of the neurotransmitter acetylcholine. The medications that treat acetylcholine deficiency have served to only treat symptoms of the disease and have neither halted nor reversed it. The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholingeric effects have been proposed to initiate large-scale aggregation leading to generalized neuroinflammation.

Research after 2000 includes hypotheses centered on the effects of the misfolded and aggregated proteins, amyloid beta and tau. The two positions differ with one stating that the tau protein abnormalities initiate the disease cascade, while the other believes that beta amyloid deposits are the causative factor in the disease. The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques do not correlate well with neuron loss; however, a majority of researchers support the alternative hypothesis that amyloid is the primary causative agent.

The amyloid hypothesis is initially compelling because the gene for the amyloid beta precursor APP is located on chromosome 21, and patients with trisomy 21 - better known as Down syndrome - who thus have an extra gene copy almost universally exhibit AD-like disorders by 40 years of age. The traditional formulation of the amyloid hypothesis points to the cytotoxicity of mature aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis and thus inducing apoptosis. A more recent and widely supported hypothesis suggests that the cytotoxic species is an intermediate misfolded form of amyloid beta, neither a soluble monomer nor a mature aggregated polymer but an oligomeric species. Relevantly, much early development work on lead compounds has focused on the inhibition of fibrillization, but the toxic-oligomer theory would imply that prevention of oligomeric assembly is the more important process or that a better target lies upstream, for example in the inhibition of APP processing to amyloid beta.

It should be noted further that ApoE4, the major genetic risk factor for AD, leads to excess amyloid build up in the brain before AD symptoms arise. Thus, beta-amyloid deposition precedes clinical AD. Another strong support for the amyloid hypothesis, which looks at the beta-amyloid as the common initiating factor for the Alzheimer's disease, is that transgenic mice solely expressing a mutant human APP gene develop first diffuse and then fibrillar beta-amyloid plaques, associated with neuronal and microglial damage.

Genetics
Rare cases of Alzheimer's are caused by dominant genes that run in families. These cases often have an early age of onset. Mutations in presenilin-1 or presenilin-2 genes have been documented in some families. Mutations of presenilin 1 (PS1) lead to the most aggressive form of familial Alzheimer's disease (FAD). Evidence from rodent studies suggests that the FAD mutation of PS1 results in impaired hippocampal-dependent learning which is correlated with reduced adult neurogenesis in the dentate gyrus. Mutations in the APP gene on chromosome 21 can also cause early onset disease. The presenilins have been identified as essential components of the proteolytic processing machinery that produces beta amyloid peptides through cleavage of APP.

Most cases identified are "sporadic" with no clear family history. Environmental factors sometimes claimed to increase risk of Alzheimer's including prior head injury, paticularly repeated trauma, previous incidents of migraine headaches, exposure to defoliants, low activity levels during adulthood. owever, with the exception of previous concussion, none of these environmental risk factors are widely accepted.

Inheritance of the ε4 allele of the ApoE gene is regarded as a risk factor for development of disease, but large-scale genetic association studies raise the possibility that even this does not indicate susceptibility so much as how early one is likely to develop Alzheimer's. There is speculation among genetic experts that there are other risk and protective factor genes that may influence the development of late onset Alzheimer's disease (LOAD). Researchers are investigating the possibility that the regulatory regions of various Alzheimer's associated genes could be important in sporadic Alzheimer's, especially inflammatory activation of these genes. These hypotheses include the amyloid-β precursor protein (APP), e beta secretase enzymes nsulin-degrading enzyme endothelin-converting enzymes nd inflammatory 5-lipoxygenase gene.

Genetic linkage
Alzheimer's disease is definitely linked to the 1st, 14th, and 21st chromosomes, but other linkages are controversial and not yet confirmed. While some genes predisposing to AD have been identified , such as ApoE4 on chromosome 19, sporadic AD also involves other risk and protective genes still awaiting confirmation.

Ways to Prevent Wilson Disease

Acromegly

Acromegaly (from Greek akros "extreme" or "extremities" and megalos "large" - extremities enlargement) is a hormonal disorder that results when the pituitary gland produces excess growth hormone (hGH). Most commonly it is a benign hGH producing tumor derived from a distinct type of cells (somatotrophs) and called pituitary adenoma.

Acromegaly most commonly affects middle-aged adults and can result in serious illness and premature death. Because of its insidious pathogenesis and slow progression, the disease is hard to diagnose in the early stages and is frequently missed for many years.

Symptoms
Features that result from high level of hGH or expanding tumor include:

Soft tissue swelling of the hands and feet
Brow and lower jaw protrusion
Enlarging hands
Enlarging feet
Arthritis and carpal tunnel syndrome
Teeth spacing increase
Macroglossia [enlarged tongue]
Heart failure
Kidney failure
Compression of the optic chiasm leading to loss of vision in the outer visual fields (typically bitemporal hemianopia)
Headache
Diabetes mellitus
Hypertension
Enlarging heart
Increased palmar sweating and sebum production over the face (seborrhea) are clinical indicators of active growth hormone (GH) producing pituitary tumours. These symptoms can also be used to monitor the activity of the tumour after surgery although biochemical monitoring is confirmatory.

Causes

Pituitary adenoma
In over 90 percent of acromegaly patients, the overproduction of GH is caused by a benign tumor of the pituitary gland, called an adenoma. These tumors produce excess GH and, as they expand, compress surrounding brain tissues, such as the optic nerves. This expansion causes the headaches and visual disturbances that are often symptoms of acromegaly. In addition, compression of the surrounding normal pituitary tissue can alter production of other hormones, leading to changes in menstruation and breast discharge in women and impotence in men because of reduced testosterone production.

There is a marked variation in rates of GH production and the aggressiveness of the tumor. Some adenomas grow slowly and symptoms of GH excess are often not noticed for many years. Other adenomas grow rapidly and invade surrounding brain areas or the sinuses, which are located near the pituitary. In general, younger patients tend to have more aggressive tumors.

Most pituitary tumors arise spontaneously and are not genetically inherited. Many pituitary tumors arise from a genetic alteration in a single pituitary cell which leads to increased cell division and tumor formation. This genetic change, or mutation, is not present at birth, but is acquired during life. The mutation occurs in a gene that regulates the transmission of chemical signals within pituitary cells; it permanently switches on the signal that tells the cell to divide and secrete GH. The events within the cell that cause disordered pituitary cell growth and GH oversecretion currently are the subject of intensive research.

Other tumors
In a few patients, acromegaly is caused not by pituitary tumors but by tumors of the pancreas, lungs, and adrenal glands. These tumors also lead to an excess of GH, either because they produce GH themselves or, more frequently, because they produce GHRH, the hormone that stimulates the pituitary to make GH. In these patients, the excess GHRH can be measured in the blood and establishes that the cause of the acromegaly is not due to a pituitary defect. When these non-pituitary tumors are surgically removed, GH levels fall and the symptoms of acromegaly improve.

In patients with GHRH-producing, non-pituitary tumors, the pituitary still may be enlarged and may be mistaken for a tumor. Therefore, it is important that physicians carefully analyze all "pituitary tumors" removed from patients with acromegaly in order not to overlook the possibility that a tumor elsewhere in the body is causing the disorder.

Diagnosis
If acromegaly is suspected, medical imaging and medical laboratory investigations are generally used together to confirm or rule out the presence of this condition.

Hormonal
IGF1 provides the most sensitive and useful lab test for the diagnosis of acromegaly. A single value of the Growth hormone (GH) is not useful in view of its pulsatality (levels in the blood vary greatly even in healthy individuals). GH levels taken 2 hours after a 75 or 100 gram glucose tolerance test are helpful in the diagnosis: GH levels are suppressed below 1 μg/L in normal people, and levels higher than this cutoff are confirmatory of acromegaly.

Other pituitary hormones have to be assessed to address the secretory effects of the tumour as well as the mass effect of the tumor on the normal pituitary gland. They include TSH (thyroid stimulating hormone), gonadotropic hormones (FSH,LH), ACTH (adrenocorticotropic hormone), prolactin.

Radiological
An MRI of the brain focussing on the sella turcica after gadolinium administration allows for clear delineation of the pituitary and the hypothalamus and the location of the tumour.

Treatment
The goals of treatment are to reduce GH production to normal levels, to relieve the pressure that the growing pituitary tumor exerts on the surrounding brain areas, to preserve normal pituitary function, and to reverse or ameliorate the symptoms of acromegaly. Currently, treatment options include surgical removal of the tumor, drug therapy, and radiation therapy of the pituitary.

Surgery
Surgery is a rapid and effective treatment, of which there are two alternative methods. The first method, a procedure known as transsphenoidal surgery, involves the surgeon reaching the pituitary through an incision in the nose and, with special tools, removing the tumor tissue. The second method is the removal of the tumor via a craniotomy, during which a bone flap is removed from the patient's skull to allow access to the tumor from the front and side. Once the tumor has been removed, the section of bone is replaced. Transsphenoidal surgery is a less invasive procedure with a shorter recovery time than a craniotomy, yet the likelihood of successfully removing the entire tumor is lower. Consequently, transsphenoidal surgery is often used as a first option, with craniotomy and other treatments being used to remove any remaining tumor.

These procedures promptly relieve the pressure on the surrounding brain regions and lead to a lowering of GH levels. If the surgery is successful, facial appearance and soft tissue swelling improve within a few days. Surgery is most successful in patients with blood GH levels below 40 ng/ml before the operation and with pituitary tumors no larger than 10 mm in diameter. Success depends on the skill and experience of the surgeon. The success rate also depends on what level of GH is defined as a cure. The best measure of surgical success is normalization of GH and IGF-1 levels. Ideally, GH should be less than 2 ng/ml after an oral glucose load. A review of GH levels in 1,360 patients worldwide immediately after surgery revealed that 60 percent had random GH levels below 5 ng/ml. Complications of surgery may include cerebrospinal fluid leaks, meningitis, or damage to the surrounding normal pituitary tissue, requiring lifelong pituitary hormone replacement.

Even when surgery is successful and hormone levels return to normal, patients must be carefully monitored for years for possible recurrence. More commonly, hormone levels may improve, but not return completely to normal. These patients may then require additional treatment, usually with medications.

Drug therapy
Two medications currently are used to treat acromegaly. These drugs reduce both GH secretion and tumor size. Medical therapy is sometimes used to shrink large tumors before surgery. Bromocriptine (Parlodel) in divided doses of about 20 mg daily reduces GH secretion from some pituitary tumors. Side effects include gastrointestinal upset, nausea, vomiting, light-headedness when standing, and nasal congestion. These side effects can be reduced or eliminated if medication is started at a very low dose at bedtime, taken with food, and gradually increased to the full therapeutic dose. Because bromocriptine can be taken orally, it is an attractive choice as primary drug or in combination with other treatments. However, bromocriptine lowers GH and IGF-1 levels and reduces tumor size in less than half of patients with acromegaly. Some patients report improvement in their symptoms although their GH and IGF-1 levels still are elevated.

The second medication used to treat acromegaly is octreotide (Sandostatin) and lanreotide (Somatulin). Both are synthetic forms of a brain hormone, somatostatin, that stops GH production. The long-acting forms of these drugs must be injected every 2 to 4 weeks for effective treatment. Most patients with acromegaly respond to this medication. In many patients, GH levels fall within one hour and headaches improve within minutes after the injection. Several studies have shown that octreotide and lanreotide are effective for long-term treatment. Octreotide and lanreotide have also been used successfully to treat patients with acromegaly caused by non-pituitary tumors.

Because octreotide inhibits gastrointestinal and pancreatic function, long-term use causes digestive problems such as loose stools, nausea, and gas in one third of patients. In addition, approximately 25 percent of patients develop gallstones, which are usually asymptomatic. In rare cases, octreotide treatment can cause diabetes. On the other hand, scientists have found that in some acromegaly patients who already have diabetes, octreotide can reduce the need for insulin and improve blood sugar control.

The latest development in the medical treatment of acromegaly is the use of growth hormone receptor antagonists. The only available member of this family is pegvisomant (Somavert). By blocking the action of the endogenous growth hormone molecules, this compound is able to control disease activity of acromegaly in virtually all patients. Pegvisomant has to be administered subcutaneously by daily injections. Combinations of long-acting somatostatin analogues and weekly injections of pegvisomant seem to be equally effective as daily injections of pegvisomant.

Radiation therapy
Radiation therapy has been used both as a primary treatment and combined with surgery or drugs. It is usually reserved for patients who have tumor remaining after surgery. These patients often also receive medication to lower GH levels. Radiation therapy is given in divided doses over four to six weeks. This treatment lowers GH levels by about 50 percent over 2 to 5 years. Patients monitored for more than 5 years show significant further improvement. Radiation therapy causes a gradual loss of production of other pituitary hormones with time. Loss of vision and brain injury, which have been reported, are very rare complications of radiation treatments.

No single treatment is effective for all patients. Treatment should be individualized depending on patient characteristics, such as age and tumor size. If the tumor has not yet invaded surrounding brain tissues, removal of the pituitary adenoma by an experienced neurosurgeon is usually the first choice. After surgery, a patient must be monitored for a long time for increasing GH levels. If surgery does not normalize hormone levels or a relapse occurs, a doctor will usually begin additional drug therapy. The first choice should be bromocriptine because it is easy to administer; octreotide is the second alternative. With both medications, long-term therapy is necessary because their withdrawal can lead to rising GH levels and tumor re-expansion. Radiation therapy is generally used for patients whose tumors are not completely removed by surgery; for patients who are not good candidates for surgery because of other health problems; and for patients who do not respond adequately to surgery and medication.

Pituitary gigantism in children
This condition of growth hormone excess is rare in children and is referred to as pituitary gigantism, because the excessive growth hormone produces excessive growth of bones and the child can achieve excessive height. As an affected child becomes an adult, many of the adult problems can gradually develop. The distinction between gigantism (occurring in children) and acromegaly (occurring in adults) can be made by the occurrence of the adenoma in relation to the closure of the epiphyses. If elevated growth hormone levels occur before the closure of the epiphyses (i.e. in prepubertal children), then gigantism ensues. If it occurs after the closure of the epiphyses (i.e., in adults) then acromegaly ensues.

Notable sufferers
Famous patients, all but two (Tony Robbins, Maurice Tillet) standing in excess of 2.00 metres:

Actor Richard Kiel ('Jaws' in the James Bond movies), 7'2" tall
Actor Carel Struycken (known for playing Lurch in the Addams Family movies, and for his other giant roles), 7' tall
Actor Matthew McGrory (listed in the Guinness Book of World Records for having the largest feet - size 29 1/2), 7'6" tall (died at the age of 32)
Actor Rondo Hatton
Wrestler and actor André the Giant, 7' tall after back surgery; his original wrestling stats listed him at 7'4". He died at the age of 46, when most sufferers weren't expected to live past the age of 40. (He chose not to be treated and died from disease)
Wrestler Paul Wight (The Big Show), had surgery on his pituitary gland in the 1990s to fix the condition, his height peaking at 7'1" tall
Wrestler Maurice Tillet ( 1903?- August 4, 1954 ), 5'10", 276 Ibs.
Wrestler and bodybuilder Daliph Singh (The Great Khali), 7'3" tall
Wrestler and mixed martial artist Paulo César da Silva (Giant Silva), 7'5" tall
Wrestler Jorge Gonzalez (El Gigante), 7'6" tall
Former NBA player Gheorghe Mureşan (star of My Giant), 7'7" tall
Aspiring basketball player Sun Ming Ming, 7'9" tall
Makeup artist Kevyn Aucoin
Composer Sergei Rachmaninoff
Life coach, writer, and professional speaker Tony Robbins, 6'7" tall
It has been suggested that the character 'Punch' from Punch and Judy was originally a caricature of an Acromegaly sufferer.

The actor Paul Benedict had an arrested case of acromegaly. After his performance in a stage production, a member of the audience came backstage and introduced himself as an endocrinologist; he had diagnosed Benedict's condition during the performance and was ultimately able to cure him before the disease reached its later stages.

Acromegly