ITP Treatment

      The goal of treating ITP is to ensure a safe platelet count and prevent bleeding complications while minimizing treatment side effects.

       In children, idiopathic thrombocytopenic purpura usually runs its course without the need for treatment. About 80 percent of children with idiopathic thrombocytopenic purpura recover completely within six months. Even in children who develop chronic ITP, complete recovery may still occur, even years later.

Adults with mild cases of ITP may require nothing more than regular monitoring and platelet checks. But if your symptoms are troublesome and your platelet count remains low, you and your doctor may opt for treatment. Treatment usually consists of medications and sometimes surgery (splenectomy). Your doctor may also have you discontinue certain drugs that can further inhibit platelet function, such as aspirin, ibuprofen (Advil, Motrin IB, others) and the blood-thinning medication warfarin (Coumadin).

Common medications used to treat idiopathic thrombocytopenic purpura include:

• Corticosteroids. The first line of therapy for ITP is a corticosteroid, usually prednisone, which can help raise your platelet count by decreasing the activity of your immune system. Once your platelet count is back to a safe level, you can gradually discontinue taking the drug under the direction of your doctor. In general, this takes about two to six weeks.
  The problem is that many adults experience a relapse after discontinuing corticosteroids. A new course of corticosteroids may be pursued, but long-term use of these medications isn't recommended because of the risk of serious side effects, including weight gain, cataracts, high blood sugar, increased risk of infections and loss of calcium from your bones (osteoporosis). You and your doctor will want to weigh the benefits of the medication against these risks. If you need to take corticosteroids long term, your doctor will likely recommend that you take calcium and vitamin D supplements to help maintain your bone density.
  
• Intravenous immune globulin (IVIG). If you have critical bleeding or need to quickly increase your blood count before surgery, you may receive medications, such as immune globulin, given intravenously. These medications are quick and effective, but the effect usually wears off in a couple of weeks. Possible side effects include headache, nausea and fever. In certain people, Rho (D) immune globulin (WinRho) may be an option. This medication may cause fewer side effects than IVIG.
• Thrombopoietin receptor agonists. The newest medications approved to treat ITP are romiplostim (Nplate) and eltrombopag (Promacta). These drugs help your bone marrow produce more platelets, which helps prevent bruising and bleeding. Possible side effects include headache, joint or muscle pain, dizziness, nausea or vomiting, and an increased risk of blood clots.
• Biologic therapy. Rituximab (Rituxan) helps reduce the immune system response. It's generally used for people with severe ITP, and in those who corticosteroids don't help. Possible side effects include low blood pressure, fever, sore throat and rash.

Removal of your spleen (splenectomy)

        If you have severe ITP and an initial course of prednisone hasn't helped, surgical removal of your spleen (splenectomy) may be an option. This quickly eliminates the main source of platelet destruction in your body and improves your platelet count, though it doesn't work for everyone. Splenectomy for ITP is not as routinely performed as it once was, however. Serious post-surgical complications sometimes occur, and not having a spleen permanently increases your susceptibility to infection.

       Splenectomy is rarely performed in children because of their high rate of spontaneous remission.

Emergency treatment

     Although rare, severe bleeding can occur with ITP, regardless of age or platelet count. Severe or widespread bleeding is life-threatening and demands emergency care. This usually includes transfusions of platelet concentrates, intravenous methylprednisolone (a type of corticosteroid) and intravenous immune globulin.

Other treatments

       If neither the initial round of corticosteroids nor a splenectomy has helped you achieve remission and your symptoms are severe, your doctor may recommend another course of corticosteroids, usually at the lowest effective dose.

Other possible treatments include:

• Immunosuppressant drugs. Medications that suppress the immune system, such as cyclophosphamide (Cytoxan) and azathioprine (Imuran, Azasan), have been used to treat ITP, but they can cause significant side effects, and their effectiveness has yet to be proved. Possible side effects include fever, headache, nausea and vomiting, low blood pressure, hair loss, and dizziness.
• H. pylori treatment. Some people with ITP are also infected with Helicobacter pylori, the same bacteria that cause most peptic ulcers. Eliminating the bacteria has helped increase platelet count in some people, but the results for this therapy are inconsistent and need to be studied further.

         Because of the potential complications of both the disease and its treatment, it's important for you and your doctor to carefully weigh the benefits and risks of treatment. For example, some people find that the side effects of treatment are more burdensome than the effects of the disease itself. Other factors that might affect your decision include whether or not you have other medical conditions or take medications that could increase your risk of bleeding, and whether or not you have an active lifestyle that could increase the risk of injury and bleeding.

DIC Treatment

         Treatment of disseminated intravascular coagulation (DIC) is controversial, but treatment guidelines have been published. Treatment should primarily focus on addressing the underlying disorder. DIC can result from numerous clinical conditions, including sepsis, trauma, obstetric emergencies, and malignancy. Surgical management is limited to primary treatment of certain underlying disorders.

Management of the DIC itself has the following basic features:

• Monitor vital signs
• Assess and document the extent of hemorrhage and thrombosis
• Correct hypovolemia
• Administer basic hemostatic procedures when indicated

         Platelet and factor replacement should be directed not at simply correcting laboratory abnormalities but at addressing clinically relevant bleeding or meeting procedural needs. Heparin should be provided to those patients who demonstrate extensive fibrin deposition without evidence of substantial hemorrhage; it is usually reserved for cases of chronic DIC. Heparin is appropriate to treat the thrombosis that occurs with DIC. It also has a limited use in acute hemorrhagic DIC in a patient with a self-limited condition of acral cyanosis and digital ischemia.

         Administration of activated protein C (drotrecogin alfa) showed benefit in subgroups of patients with sepsis who have DIC, with consideration given to the anticoagulant effects of this agent. However, drotrecogin alfa was withdrawn from the worldwide market on October 25, 2011, after the PROWESS-SHOCK trial failed to show a survival benefit for patients with severe sepsis and septic shock^.

       Patients with DIC should be treated at hospitals with appropriate critical care and subspecialty expertise, such as hematology, blood bank, or surgery. Patients who present to hospitals without those capabilities and who are stable enough for transfer should be referred expeditiously to a hospital that has those resources. 

       The management of acute and chronic forms of disseminated intravascular coagulation (DIC) should primarily be directed at treatment of the underlying disorder. Often, the DIC component will resolve on its own once the underlying disorder is addressed.
For example, if infection is the underlying etiology, the appropriate administration of antibiotics and source control is the first line of therapy. As another example, in case of an obstetric catastrophe, the primary approach is to deliver appropriate obstetric care, in which case the DIC will rapidly subside. If the underlying condition causing DIC is not known, a diagnostic workup should be initiated. Most patients with acute DIC require critical care treatment appropriate for the primary diagnosis, occasionally including emergency surgery.
      A DIC scoring system has been proposed by Bick to assess the severity of the coagulopathy as well as the effectiveness of therapeutic modalities^. Clinical and laboratory parameters are measured with regularity.

MDGs (Millennium Development Goals)

        The Millennium Development Goals (MDGs) are the eight international development goals that were established following the Millennium Summit of the United Nations in 2000, following the adoption of the United Nations Millennium Declaration. All 189 United Nations member states at the time (there are 193 currently), and at least 23 international organizations, committed to help achieve the following Millennium Development Goals by 2015:

1. To eradicate extreme poverty and hunger
2. To achieve universal primary education
3. To promote gender equality
4. To reduce child mortality
5. To improve maternal health
6. To combat HIV/AIDS, malaria, and other diseases
7. To ensure environmental sustainability
8. To develop a global partnership for development

        Each goal has specific targets, and dates for achieving those targets. To accelerate progress, the G8 finance ministers agreed in June 2005 to provide enough funds to the World Bank, the International Monetary Fund (IMF) and the African Development Bank (AfDB) to cancel $40 to $55 billion in debt owed by members of the heavily indebted poor countries (HIPC) to allow them to redirect resources to programs for improving health and education and for alleviating poverty.

        Critics of the MDGs complained of a lack of analysis and justification behind the chosen objectives, and the difficulty or lack of measurements for some goals and uneven progress, among others. Although developed countries' aid for achieving the MDGs rose during the challenge period, more than half went for debt relief and much of the remainder going towards natural disaster relief and military aid, rather than further development.

        As of 2013, progress towards the goals was uneven. Some countries achieved many goals, while others  were not on track to realize any. A UN conference in September 2010 reviewed progress to date and concluded with the adoption of a global plan to achieve the eight goals by their target date. New commitments targeted women's and children's health, and new initiatives in the worldwide battle against poverty, hunger and disease.

         Among the non-governmental organizations assisting were the United Nations Millennium Campaign, the Millennium Promise Alliance, Inc., the Global Poverty Project, the Micah Challenge, The Youth in Action EU Programme, "Cartoons in Action" video project and the 8 Visions of Hope global art project.

Limfoma Hodgkin

      Hodgkin lymphoma is caused by a change (mutation) in the DNA of a type of white blood cell called B lymphocytes, although the exact reason why this happens is not known.

      The DNA gives the cells a basic set of instructions, such as when to grow and reproduce. The mutation in the DNA changes these instructions so that the cells keep growing. This causes them to multiply uncontrollably.

      The abnormal lymphocytes usually begin to multiply in one or more lymph nodes in a particular area of the body, such as your neck or groin. Over time, it is possible for the abnormal lymphocytes to spread into other parts of your body, such as your bone marrow, spleen, liver, skin and lungs.

Who is most at risk?

      While the cause of the initial mutation that triggers Hodgkin lymphoma is unknown, a number of factors can increase your risk of developing the condition:

• having a medical condition that weakens your immune system, such as HIV
• having medical treatment that weakens your immune system –for example, taking medication to suppress your immune system after an organ transplant
• being previously exposed to the Epstein-Barr virus (EBV), a common virus that causes glandular fever
• having previously had non-Hodgkin lymphoma, possibly because of treatment with chemotherapy or radiotherapy

        Hodgkin lymphoma isn't infectious and isn't thought to run in families. Although your risk is increased if a first-degree relative (parent, sibling or child) has had lymphoma, it is not clear if this is because of an inherited genetic fault or lifestyle factors.

         Hodgkin lymphoma can occur at any age, although most cases are diagnosed in people in their 20s or 70s. The condition is slightly more common in men than women.

Treatment for GOUT

    

     When gout is mild, infrequent, and uncomplicated, it can be treated with diet and lifestyle changes. However, studies have shown that even the most rigorous diet does not lower the serum uric acid enough to control severe gout, and therefore medications are generally necessary. When attacks are frequent, uric acid kidney stones have occurred, tophi are present, or there is evidence of joint damage from gout attacks, medications are typically used to lower the uric acid blood level.

     Medications for the treatment of gout generally fall into one of three categories: uric-acid-lowering medications, prophylactic medications (medications used in conjunction with uric-acid-lowering medications to prevent a gout flare), and rescue medications to provide immediate relief from gout pain.

Uric-acid-lowering medications are the primary treatment for gout. These medications decrease the total amount of uric acid in the body and s lower the serum uric acid level. For most patients, the goal of uric-acid-lowering medication is to achieve a serum uric acid level of less than 6 mg/dl. These medications also are effective treatments to decrease the size of tophi, with the ultimate goal of eradicating them. Uric-acid-lowering medications include allopurinol (Zyloprim, Aloprim), febuxostat (Uloric), probenecid, and pegloticase (Krystexxa).

     Prophylactic medications are used during approximately the first six months of therapy with a uric-acid-lowering medication to either prevent gout flares or decrease the number and severity of flares. This is because any medication or intervention that either increases or decreases the uric acid level in the bloodstream can trigger a gout attack. Colcrys (colchicine) and any of the NSAIDs (nonsteroidal anti-inflammatory drugs) such as indomethacin (Indocin, Indocin-SR), diclofenac (Voltaren, Cataflam, Voltaren-XR, Cambia), ibuprofen (Advil), or naproxen sodium are frequently used as prophylactic medications to prevent gout flares during uric-acid lowering. By taking one of these prophylactic or preventative medications during the first six months of treatment with allopurinol, febuxostat, or probenecid, the risk of having a gout attack during this time is decreased. Prophylactic medications are not used in combination with Krystexxa.

     The third category of medications are those used during an acute gout attack to decrease pain and inflammation. Both colchicine (Colcrys) and NSAIDs can be used during an acute gout attack to decrease inflammation and pain. Steroid medications, such as prednisone and methylprednisolone (Medrol), also can be used during an acute gouty flare. However, the total dose of steroids is generally limited due to potential side effects such as cataract formation and bone loss. Steroid medications are extremely helpful in treating gout flares in patients who are unable to take colchicine or NSAIDs.

Errors and Variations of Mitosis

        Mitosis is a part of the cell cycle process by which chromosomes in a cell nucleus are separated into two identical sets of chromosomes, each in its own nucleus. In general, mitosis (division of the nucleus) is often followed by cytokinesis, which divides the cytoplasm, organelles and cell membrane into two new cells containing roughly equal shares of these cellular components. Mitosis and cytokinesis together define the mitotic (M) phase of an animal cell cycle—the division of the mother cell into two daughter cells, genetically identical to each other and to their parent cell.

        The process of mitosis is divided into stages corresponding to the completion of one set of activities and the start of the next. These stages are prophase, prometaphase, metaphase, anaphase, and telophase. During mitosis, the chromosomes, which have already duplicated, condense and attach to fibers that pull one copy of each chromosome to opposite sides of the cell. The result is two genetically identical daughter nuclei. The cell may then divide by cytokinesis to produce two daughter cells. Producing three or more daughter cells instead of normal two is a mitotic error called tripolar mitosis or multipolar mitosis (direct cell triplication / multiplication). Other errors during mitosis can induce apoptosis (programmed cell death) or cause mutations. Certain types of cancer can arise from such mutations.

        Mitosis occurs only in eukaryotic cells and the process varies in different organisms. For example, animals undergo an "open" mitosis, where the nuclear envelope breaks down before the chromosomes separate, while fungi undergo a "closed" mitosis, where chromosomes divide within an intact cell nucleus.Furthermore, most animal cells undergo a shape change, known as mitotic cell rounding, to adopt a near spherical morphology at the start of mitosis. Prokaryotic cells, which lack a nucleus, divide by a different process called binary fission.

        Errors can occur during mitosis, especially during early embryonic development in humans. Mitotic errors can create aneuploid cells that have too few or too many of one or more chromosomes, a condition associated with cancer. Early human embryos, cancer cells, infected or intoxicated cells can also suffer from pathological division into three or more daughter cells (tripolar or multipolar mitosis), resulting in severe errors in their chromosomal complements.

        In nondisjunction, sister chromatids fail to separate during anaphase.One daughter cell receives both sister chromatids from the nondisjoining chromosome and the other cell receives none. As a result, the former cell gets three copies of the chromosome, a condition known as trisomy, and the latter will have only one copy, a condition known as monosomy. On occasion, when cells experience nondisjunction, they fail to complete cytokinesis and retain both nuclei in one cell, resulting in binucleated cells.

        Anaphase lag occurs when the movement of one chromatid is impeded during anaphase. This may be caused by a failure of the mitotic spindle to properly attach to the chromosome. The lagging chromatid is excluded from both nuclei and is lost. Therefore, one of the daughter cells will be monosomic for that chromosome.

       Endoreduplication (or endoreplication) occurs when chromosomes duplicate but the cell does not subsequently divide. This results in polyploid cells or, if the chromosomes duplicates repeatedly, polytene chromosomes. Endoreduplication is found in many species and appears to be a normal part of development. Endomitosis is a variant of endoreduplication in which cells replicate their chromosomes during S phase and enter, but prematurely terminate, mitosis. Instead of being divided into two new daughter nuclei, the replicated chromosomes are retained within the original nucleus. The cells then re-enter G1 and S phase and replicate their chromosomes again. This may occur multiple times, increasing the chromosome number with each round of replication and endomitosis. Platelet-producing megakaryocytes go through endomitosis during cell differentiation.

Pathophysiology Cancer

       Cancer is fundamentally a disease of tissue growth regulation failure. In order for a normal cell to transform into a cancer cell, the genes that regulate cell growth and differentiation must be altered.
The affected genes are divided into two broad categories. Oncogenes are genes that promote cell growth and reproduction. Tumor suppressor genes are genes that inhibit cell division and survival. Malignant transformation can occur through the formation of novel oncogenes, the inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes. Typically, changes in many genes are required to transform a normal cell into a cancer cell.
Genetic changes can occur at different levels and by different mechanisms. The gain or loss of an entire chromosome can occur through errors in mitosis. More common are mutations, which are changes in the nucleotide sequence of genomic DNA.

        Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.

      Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter region of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, leading to the expression of viral oncogenes in the affected cell and its descendants.

      Replication of the enormous amount of data contained within the DNA of living cells will probabilistically result in some errors (mutations). Complex error correction and prevention is built into the process, and safeguards the cell against cancer. If significant error occurs, the damaged cell can "self-destruct" through programmed cell death, termed apoptosis. If the error control processes fail, then the mutations will survive and be passed along to daughter cells.

      Some environments make errors more likely to arise and propagate. Such environments can include the presence of disruptive substances called carcinogens, repeated physical injury, heat, ionising radiation, or hypoxia.
The errors that cause cancer are self-amplifying and compounding, for example:

• A mutation in the error-correcting machinery of a cell might cause that cell and its children to accumulate errors more rapidly.
• A further mutation in an oncogene might cause the cell to reproduce more rapidly and more frequently than its normal counterparts.
• A further mutation may cause loss of a tumor suppressor gene, disrupting the apoptosis signalling pathway and resulting in the cell becoming immortal.
• A further mutation in signaling machinery of the cell might send error-causing signals to nearby cells.

       The transformation of normal cell into cancer is akin to a chain reaction caused by initial errors, which compound into more severe errors, each progressively allowing the cell to escape the controls that limit normal tissue growth. This rebellion-like scenario becomes an undesirable survival of the fittest, where the driving forces of evolution work against the body's design and enforcement of order. Once cancer has begun to develop, this ongoing process, termed clonal evolution, drives progression towards more invasive stages. Clonal evolution leads to intra-tumour heterogeneity that complicates designing effective treatment strategies.

       Characteristic abilities developed by cancers are divided into a number of categories. Six categories were originally proposed, in a 2000 article called "The Hallmarks of Cancer" by Douglas Hanahan and Robert Weinberg: evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained angiogenesis, limitless replicative potential, and metastasis. Based on further work, the same authors added two more categories in 2011: reprogramming of energy metabolism and evasion of immune destruction.

Epigenetics

The central role of DNA damage and epigenetic defects in DNA repair genes in carcinogenesis

      Classically, cancer has been viewed as a set of diseases that are driven by progressive genetic abnormalities that include mutations in tumor-suppressor genes and oncogenes, and chromosomal abnormalities. However, it has become apparent that cancer is also driven by epigenetic alterations.

      Epigenetic alterations refer to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such modifications are changes in DNA methylation (hypermethylation and hypomethylation) and histone modification and changes in chromosomal architecture (caused by inappropriate expression of proteins such as HMGA2 or HMGA1).Each of these epigenetic alterations serves to regulate gene expression without altering the underlying DNA sequence. These changes may remain through cell divisions, last for multiple generations, and can be considered to be epimutations (equivalent to mutations).

        Epigenetic alterations occur frequently in cancers. As an example, Schnekenburger and Diederich listed protein coding genes that were frequently altered in their methylation in association with colon cancer. These included 147 hypermethylated and 27 hypomethylated genes. Of the hypermethylated genes, 10 were hypermethylated in 100% of colon cancers, and many others were hypermethylated in more than 50% of colon cancers.

     While large numbers of epigenetic alterations are found in cancers, the epigenetic alterations in DNA repair genes, causing reduced expression of DNA repair proteins, may be of particular importance. Such alterations are thought to occur early in progression to cancer and to be a likely cause of the genetic instability characteristic of cancers.

       Reduced expression of DNA repair genes causes deficient DNA repair. This is shown in the figure at the 4th level from the top. (In the figure, red wording indicates the central role of DNA damage and defects in DNA repair in progression to cancer.) When DNA repair is deficient DNA damages remain in cells at a higher than usual level (5th level from the top in figure), and these excess damages cause increased frequencies of mutation and/or epimutation (6th level from top of figure). Mutation rates increase substantially in cells defective in DNA mismatch repair or in homologous recombinational repair (HRR). Chromosomal rearrangements and aneuploidy also increase in HRR defective cells.
       Higher levels of DNA damage not only cause increased mutation (right side of figure), but also cause increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.

        Deficient expression of DNA repair proteins due to an inherited mutation can cause an increased risk of cancer. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) have an increased risk of cancer, with some defects causing up to a 100% lifetime chance of cancer (e.g. p53 mutations). Germ line DNA repair mutations are noted in a box on the left side of the figure, with an arrow indicating their contribution to DNA repair deficiency. However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.
       In sporadic cancers, deficiencies in DNA repair are occasionally caused by a mutation in a DNA repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes. This is indicated in the figure at the 3rd level from the top. Many studies of heavy metal-induced carcinogenesis show that such heavy metals cause reduction in expression of DNA repair enzymes, some through epigenetic mechanisms. In some cases, DNA repair inhibition is proposed to be a predominant mechanism in heavy metal-induced carcinogenicity. In addition, there are frequent epigenetic alterations of the DNA sequences coding for small RNAs called microRNAs (or miRNAs). MiRNAs do not code for proteins, but can “target” protein-coding genes and reduce their expression.

     Cancers usually arise from an assemblage of mutations and epimutations that confer a selective advantage leading to clonal expansion (see Field defects in progression to cancer). Mutations, however, may not be as frequent in cancers as epigenetic alterations. An average cancer of the breast or colon can have about 60 to 70 protein-altering mutations, of which about three or four may be “driver” mutations, and the remaining ones may be “passenger” mutations.
      As pointed out above under genetic alterations, cancer is caused by failure to regulate tissue growth, when the genes that regulate cell growth and differentiation are altered. It has become clear that these alterations are caused by both DNA sequence mutation in oncogenes and tumor suppressor genes as well as by epigenetic alterations. The epigenetic deficiencies in expression of DNA repair genes, in particular, likely cause an increased frequency of mutations, some of which then occur in oncogenes and tumor suppressor genes.
 

Metastasis

       Metastasis is the spread of cancer to other locations in the body. The new tumors are called metastatic tumors, while the original is called the primary tumor. Almost all cancers can metastasize. Most cancer deaths are due to cancer that has spread from its primary site to other organs (metastasized).

      Metastasis is very common in the late stages of cancer, and it can occur via the blood or the lymphatic system or both. The typical steps in metastasis are local invasion, intravasation into the blood or lymph, circulation through the body, extravasation into the new tissue, proliferation, and angiogenesis. Different types of cancers tend to metastasize to particular organs, but overall the most common places for metastases to occur are the lungs, liver, brain, and the bones.