Duchenne muscular dystrophy (DMD) is a recessive X-linked ...



Duchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy, which results in muscle degeneration, difficulty walking, breathing, and death. The incidence is 1 in 3,000.[1] Females and males are affected, though females are rarely affected and are more often carriers. The disorder is caused by a mutation in the dystrophin gene, located in humans on the X chromosome (Xp21). The dystrophin gene codes for the protein dystrophin, an important structural component within muscle tissue. Dystrophin provides structural stability to the dystroglycan complex (DGC), located on the cell membrane.

Symptoms usually appear in male children before age 5 and may be visible in early infancy. Progressive proximal muscle weakness of the legs and pelvis associated with a loss of muscle mass is observed first. Eventually this weakness spreads to the arms, neck, and other areas. Early signs may include pseudohypertrophy (enlargement of calf and deltoid muscles), low endurance, and difficulties in standing unaided or inability to ascend staircases. As the condition progresses, muscle tissue experiences wasting and is eventually replaced by fat and fibrotic tissue (fibrosis). By age 10, braces may be required to aid in walking but most patients are wheelchair dependent by age 12. Later symptoms may include abnormal bone development that lead to skeletal deformities, including curvature of the spine. Due to progressive deterioration of muscle, loss of movement occurs, eventually leading to paralysis. Intellectual impairment may or may not be present but if present, does not progressively worsen as the child ages. The average life expectancy for patients afflicted with DMD varies from late teens to early to mid 20s. 

Pathogenesis

Duchenne muscular dystrophy is caused by a mutation of the dystrophin gene at locus Xp21. Dystrophin is responsible for connecting thecytoskeleton of each muscle fiber to the underlying basal lamina (extracellular matrix) through a protein complex containing many subunits. The absence of dystrophin permits excess calcium to penetrate the sarcolemma (cell membrane).[4] Alterations in these signalling pathways cause water to enter into the mitochondria which then burst. In skeletal muscle dystrophy, mitochondrial dysfunction gives rise to an amplification of stress-induced cytosolic calcium signals and an amplification of stress-induced reactive-oxygen species (ROS) production. In a complex cascading process that involves several pathways and is not clearly understood, increased oxidative stress within the cell damages the sarcolemma and eventually results in the death of the cell. Muscle fibers undergo necrosis and are ultimately replaced withadipose and connective tissue.

In medicine, Aschoff bodies are nodules found in the hearts of individuals with rheumatic fever. They result from inflammation in the heart muscle and are characteristic of rheumatic heart disease. 

Appearance

Microscopically, Aschoff bodies are areas of inflammation of the connective tissue of the heart, or focal interstitial inflammation. Fully developed Aschoff bodies are granulomatous structures consisting of fibrinoid change, lymphocytic infiltration, occasional plasma cells, and characteristically abnormal macrophages surrounding necrotic centres. Some of these macrophages may fuse to form multinucleated giant cells. Others may become Anitschkow cellsor "caterpillar cells", so named because of the appearance of their chromatin.

A psammoma body is a round collection of calcium, seen microscopically. 

Etiology

Psammoma bodies are associated with the papillary (nipple-like) histomorphologyand are thought to arise from (1) the infarction and calcification of papillae tips and (2) calcification of intralymphatic tumor thrombi.[1]

Association with malignant lesions

Psammoma bodies are commonly seen in certain tumors such

▪ Papillary thyroid carcinoma

▪ Papillary renal cell carcinoma

▪ Ovarian papillary serous cystadenocarcinoma[2]

▪ endometrial adenocarcinomas (Papillary serous carcinoma ~3%-4%)

▪ meningioma

▪ mesothelioma

▪ somatostatinoma (pancreas)[3]

▪ Prolactinoma of the pituitary [4]

Benign lesions

Psammoma bodies may be seen in:

▪ Endosalpingiosis[5]

▪ Psammomatous melanotic schwannoma

Appearance

Psammoma bodies usually have a laminar appearance, are circular, acellular and eosinophilic.

Reed-Sternberg cells (also known as lacunar histiocytes for certain types) are different giantcells found with light microscopy in biopsies from individuals with Hodgkin's lymphoma (aka Hodgkin's disease; a type of lymphoma) primarily due to EBV, and certain other disorders. They are usually derived from B lymphocytes.[1]

They are named after Dorothy Reed Mendenhall (1874-1964) and Carl Sternberg (1872-1935), who provided the first definitive microscopic descriptions of Hodgkin's disease.[2][3]

Reed-Sternberg cells are large and are either multinucleated or have a bilobed nucleus (thus resembling an "owl's eye" appearance) with prominent eosinophilic inclusion-like nucleoli. Reed-Sternberg cells are CD30 and CD15 positive, usually negative for CD20 and CD45. The presence of these cells is necessary in the diagnosis of Hodgkin's lymphoma - absence of Reed-Sternberg cells has very high negative predictive value. They can also be found in reactive lymphadenopathy(such as infectious mononucleosis, carbamazepine associated lymphadenopathy) and very rarely non-Hodgkin lymphomas.

A special type of Reed-Sternberg cells are lacunar histiocytes, whose cytoplasm retracts when fixed in formalin, so the nuclei give the appearance of cells that lie with empty spaces (calledlacunae) between them.[4] These are characteristic of the nodular sclerosis subtype of Hodgkin's lymphoma.[4]

A paraneoplastic syndrome is a disease or symptom that is the consequence of the presence of cancer in the body, but is not due to the local presence of cancer cells. These phenomena are mediated by humoral factors (by hormones or cytokines) excreted by tumor cells or by animmune response against the tumor. Paraneoplastic syndromes are typical among middle aged to older patients, and they most commonly present with cancers of the lung, breast, ovaries or lymphatic system (a lymphoma).[1] Sometimes the symptoms of paraneoplastic syndromes show even before the diagnosis of a malignancy.

Ghon's complex is a lesion seen in the lung that is caused by tuberculosis. [1][2] The lesions consist of a calcified focus of infection and an associated lymph node. These lesions are particularly common in children and can retain viable bacteria, so are sources of long-term infection and may be involved in reactivation of the disease in later life.[3]

In countries where infected milk has been eliminated, primary tuberculosis almost always begins in the lungs. Typically, the inhaled bacilli implant in the distal airspaces of the lower part of the upper lobe or the upper part of the lower lobe, usually close to the pleura. As sensitization develops, a 1- to 1.5-cm area of gray-white inflammation with consolidation emerges, known as the Ghon focus. In most cases, the center of this focus undergoes caseous necrosis. Tubercle bacilli, either free or within phagocytes, drain to the regional nodes, which also often caseate. This combination of parenchymal lung lesion and nodal involvement is referred to as the Ghon complex. During the first few weeks there is also lymphatic and hematogenous dissemination to other parts of the body. In approximately 95% of cases, development of cell-mediated immunity controls the infection. Hence, the Ghon complex undergoes progressive fibrosis, often followed by radiologically detectable calcification (Ranke complex), and despite seeding of other organs, no lesions develop.[4]

Note: Although they are often confused, Ranke complex and Ghon complex are not synonymous. The Ranke complex is an evolution of the Ghon complex (resulting from further healing and calcification of the lesion).[5]

A Ghon focus is a primary lesion caused by mycobacterium bacilli (tuberculosis) developed in the lung of a previously uninfected individual. It is named for Anton Ghon (1866-1936), an Austrian pathologist.

It is a small area of granulomatous inflammation, only detectable by chest X-ray if it calcifies or grows substantially (see tuberculosis radiology)[1]. Typically these will heal, but in some cases, especially inimmunosuppressed patients, it will progress to miliary tuberculosis (so named due to the granulomas resembling millet seeds on a chest X-ray)[1].

The classical location for primary infection is surrounding the lobar fissures, either in the upper part of the lower lobe or lower part of the upper lobe[1].

If the Ghon focus also involves infection of adjacent lymphatics and hilar lymph nodes, it is known as the Ghon's complex or primary complex. When a Ghon's complex undergoes fibrosis and calcification it is called a Ranke complex.[1][2].

Carcinoid syndrome refers to the array of symptoms that occur secondary to carcinoid tumors.[1] The syndrome includes flushing and diarrhea, and, less frequently, heart failure andbronchoconstriction.[2] It is caused by endogenous secretion of mainly serotonin and kallikrein.

Pathophysiology

Carcinoid tumors produce the vasoactive substance, serotonin. It is commonly, but incorrectly, thought that serotonin is the cause of the flushing. The flushing results from secretion of kallikrein, the enzyme that catalyzes the conversion of kininogen to lysyl-bradykinin. The latter is further converted to bradykinin, one of the most powerful vasodilators known. Other components of the carcinoid syndrome are diarrhea (probably caused by serotonin), a pellagra-like syndrome (probably caused by diversion of large amounts of tryptophan from synthesis of the vitamin B3, niacin, to the synthesis of 5-hydroxyindoles including serotonin), fibrotic lesions of the endocardium, particularly on the right side of the heart resulting in insufficiency of the tricuspid valve and, less frequently, the pulmonary valve and, uncommonly, bronchoconstriction. The pathogenesis of the cardiac lesions and the bronchoconstriction is unknown, but the former probably involves activation of serotonin 5-HT2B receptors by serotonin. When the primary tumor is in the gastrointestinal tract, as it is in the great majority of cases, the serotonin and kallikrein are inactivated in the liver; manifestations of carcinoid syndrome do not occur until there are metastases to the liver or when the cancer is accompanied by liver failure (cirrhosis). Carcinoid tumors arising in the bronchi may be associated with manifestations of carcinoid syndrome without liver metastases because their biologically active products reach the systemic circulation before passing through the liver and being metabolized.

In most patients, there is an increased urinary excretion of 5-HIAA (5-hydroxyindoleacetic acid), a degradation product of serotonin.

MULTIPLE MYELOMA OVERVIEW

Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Normally, plasma cells produce antibodies and play a key role in immune function. However, uncontrolled growth of these cells leads to bone pain and fractures, anemia, infections, and other complications.

In the United States, about 4 people per 100,000 are diagnosed with MM each year. This condition is slightly more common among men than women, and almost twice as common among blacks as among whites. The average age at diagnosis is 65 to 70 years.

The current treatment options for MM include watchful waiting (for asymptomatic or smoldering multiple myeloma), chemotherapy, treatment with immune modulating medications, and stem cell transplantation. Multiple myeloma is seldom cured, although treatment can relieve symptoms, induce remission, and prolong life.

The cause of MM is unknown. Exposure to radiation, organic chemicals (such as benzene), herbicides, and insecticides may play a role. Genetic factors and viral infection may also influence the risk of developing multiple myeloma.

This topic review discusses the signs and symptoms, diagnostic tests, and staging system used for people with multiple myeloma. The treatment of multiple myeloma is discussed in a separate topic review. (See "Patient information: Multiple myeloma treatment".)

MULTIPLE MYELOMA FEATURES

Multiple myeloma can produce a wide variety of symptoms.

Bone symptoms — Most individuals develop bone pain in the back or chest, or less commonly, the arms and legs, at the time of diagnosis. The pain is usually triggered by movement and is absent at night, except when changing positions.

MM causes both generalized bone loss throughout the body as well as areas of bone destruction (called "lytic lesions" on x-ray) in specific areas. The bone loss and erosions can lead to osteoporosis and fractures. Many individuals with multiple myeloma experience fractures of the vertebrae (the bones of the spine), which can lead to a loss of height; about 30 percent of individuals experience fractures in other bones, often with little or no preceding trauma. For this reason they are called "pathologic fractures."

High blood calcium levels — Because bones contain large amounts of calcium, the breakdown of bone in MM can lead to high blood calcium levels (called hypercalcemia). High blood calcium levels occur in 10 to 15 percent of individuals, and the symptoms may include loss of appetite, nausea, vomiting, frequent urination, increased thirst, constipation, weakness, confusion, stupor, or coma.

Anemia — About two-thirds of individuals have anemia (low red cell count) at the time of diagnosis, and anemia eventually occurs in almost all individuals. The signs and symptoms of anemia include paleness, weakness, and fatigue.

Impaired kidney function — The excess proteins and high blood calcium levels associated with MM can damage the kidneys. Kidney function is abnormal at diagnosis in about half of individuals with multiple myeloma. Occasionally, kidney failure is the first sign of MM.

Thickened blood — The excessive production of proteins by the malignant plasma cells in MM can cause a thickening of the blood (called hyperviscosity syndrome). The symptoms may include bleeding from the nose and mouth, blurred vision, neurologic symptoms, and heart failure.

Neurologic symptoms — Fractures of the vertebrae can lead to increased pressure on the nerve roots where they exit the spine, causing neurologic symptoms (called radiculopathy). This complication of multiple myeloma most commonly affects the chest, lower back, or legs, and the symptoms may include odd sensations (numbness or tingling), pain, or muscle weakness.

Occasionally, neurologic symptoms occur because plasma cells grow within the spinal canal and press on the spinal cord. The symptoms may include severe back pain, muscle weakness, especially of the legs, numbness or tingling, and loss of control of bowel or bladder function (incontinence). Spinal cord compression is a medical emergency and requires immediate treatment to relieve the pressure and prevent permanent damage.

Generalized symptoms — The generalized symptoms of MM include an increased susceptibility to infections (especially during chemotherapy) and weight loss. Occasionally, it causes increased bleeding or tumors of the ribs. In individuals with advanced MM, tumor cells may accumulate beneath the skin, causing large purple-colored bumps.

MULTIPLE MYELOMA TESTING

The diagnosis of MM is based upon the presence of characteristic signs and symptoms of the disease and on the results of tests of the blood and bone marrow. Several tests are used to determine the presence and severity of MM. In some individuals with early MM or related conditions, it may be necessary to repeat these tests periodically until the diagnosis is certain.

After MM is confirmed, additional tests are used to check for the presence of impaired kidney function, anemia, thickening of the blood, and other complications of multiple myeloma.

Blood and urine tests for monoclonal protein — An abnormal protein produced by the plasma cells, called a monoclonal (M) protein (sometimes called a "paraprotein"), can be found in the blood or urine of almost all patients with MM, which helps establish the diagnosis. M proteins serve no useful function, and may be responsible for increases in the thickness of the blood, kidney damage, or bleeding problems.

However, it is important to remember that not everyone with a monoclonal protein has MM. The diagnosis also requires one or more abnormalities such as anemia, bone lesions (see 'X-rays' below), kidney failure, or high calcium levels in the blood (see 'Criteria for diagnosis' below).

Bone marrow examination — In most individuals with MM, a bone marrow aspiration and biopsy (a collection of a small sample of bone marrow for laboratory analysis, usually taken from the hip) shows that plasma cells comprise an abnormally high percentage of bone marrow cells (more than 10 percent). It may be necessary to collect samples from different areas because MM can affect the marrow of some bones but not others.

X-rays — In about 80 percent of individuals, routine x-rays show distinct, round (lytic) areas of bone erosion; generalized thinning of the bones; and/or fractures at the time of diagnosis. The bones most commonly involved are the vertebrae, the ribs, the pelvic bones, and the bones of the thigh and upper arm.

Genetic and chromosomal tests — Specialized tests may reveal genetic or chromosomal abnormalities of the plasma cells in individuals with MM. The results of these tests are helpful for predicting the response to treatment and survival.

Plasma cell labeling index — The plasma cell labeling index (PCLI) determines how rapidly the abnormal plasma cells are growing and dividing. Patients in whom the labeling index is low tend to have slower disease progression than those with high values. This test is also useful for distinguishing MM from related conditions that generally have a better prognosis. A normal plasma cell labeling index suggests that MM is less likely, while an elevated index suggests that multiple myeloma is more likely. Although this test is not readily available in many centers, PLCI is a reliable marker of high risk disease. Thus, if it is available, it is recommended to help differentiate between high risk and standard risk MM.

Criteria for diagnosis — The diagnosis of multiple myeloma requires the following:

• A bone marrow aspirate or biopsy showing that at least 10 percent of the cells are plasma cells or the presence of a plasma cell tumor (called a plasmacytoma), plus

• M protein in the blood or urine, plus

• Evidence of damage to the body as a result of the plasma cell growth, such as destructive bone lesions, kidney failure, anemia, or high calcium in the blood

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 is mainly due to casts of paraprotein deposition in the kidney, although the cast may also contain complete immunoglobulins, Tamm-Horsfall protein and albumin.[5]

A Bence Jones protein is a monoclonal globulin protein found in the blood or urine, with a molecular weight of 22-24 kDa.[1]

Finding this protein is often suggestive of multiple myeloma or Waldenstrom's macroglobulinemia.

Bence Jones Proteins are particularly diagnostic of multiple myeloma in the context of end-organ manifestations such as malignant bone marrow cancer, renal failure, lytic bone disease, oranemia, or large numbers of plasma cells in the bone marrow of patients. Bence Jones Proteins are present in 2/3 of multiple myeloma cases.[2]

The proteins are immunoglobulin light chains (paraproteins) and are produced by neoplasticplasma cells. They can be kappa (most of the time) or lambda.[2] The light chains can be immunoglobulin fragments or single homogeneous immunoglobulins. They are found in urine due to the kidneys' decreased filtration capabilities due to renal failure, often induced by hypercalcemia from the calcium released as the bones are destroyed.[citation needed] The light chains have traditionally been detected by heating or electrophoresis of concentrated urine. More recently serum free light chain assays have been utilised in a number of published studies which have indicated superiority over the urine tests, particularly for patients producing low levels of monoclonal free light chains, as seen in nonsecretory multiple myeloma[3][4][5] and AL amyloidosis.[5][6][7][8] This is primarily because of the re-absorption of free light chains in the kidneys, creating a "threshold" of light chain production which must be exceeded before measurable quantities overflow into the urine. As such, urinalysis is a fickle witness to changing free light chain production.

There are various rarer conditions that can produce Bence Jones proteins, such as Waldenström's macroglobulinemia and other malignances.

Bence Jones proteins are small proteins (light chains of immunoblobulin) found in the urine. Testing for these proteins is done to diagnose and monitor multiple myeloma and other similar diseases.

Purpose

Bence Jones proteins are considered the first tumor marker. A tumor marker is a substance, made by the body, that is linked to a certain cancer, or malignancy. Bence Jones proteins are made by plasma cells, a type of white blood cell. The presence of these proteins in a person's urine is associated with a malignancy of plasma cells.

Multiple myeloma, a tumor of plasma cells, is the disease most often linked with Bence Jones proteins. The amount of Bence Jones proteins in the urine indicates how much tumor is present. Physicians use Bence Jones proteins testing to diagnose the disease as well as to check how well the disease is responding to treatment.

These proteins are dimers of immunoglobulin light chains, normally produced by plasma cells. Bence Jones proteins are sufficiently small to be excreted by the kidney. ... It is a characteristic protein found in the urine of most patients with multiple myeloma.

Mallory bodies are classically found in the livers of people suffering from alcoholicliver disease and were once thought to be specific for that.

They are most common in alcoholic hepatitis (prevalence of 65%) and alcoholic cirrhosis (prevalence of 51%).[2]

They are a recognized feature of Wilson's disease (25%), primary biliary cirrhosis(24%), non-alcoholic cirrhosis (24%), hepatocellular carcinoma (23%) and morbid obesity (8%), among other conditions.[2]

[edit]Appearance

Mallory bodies are highly eosinophilic and thus appear pink on H&E stain. The bodies themselves are made up of intermediate keratinfilament proteins that have been ubiquinated, or bound by other proteins such as heat shock proteins, or p62.

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