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PBL CR Unfamiliar Terms 1. Intramuscular hydroxocobalamin: Natural analogue of vitamin B12, it has an intense red colour. Together with folic acid, cobalamins are essential cofactors required for DNA synthesis in cells where chromosomal replication and division are occurring—most notably the bone marrow and myeloid cells. 2. Hemodialysis: Hemodialysis can be carried out in a hospital, in a separate clinic, in a self-care centre or even in your own home in some cases. Takes about fou
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  PBL CR Unfamiliar Terms 1.   Intramuscular hydroxocobalamin:  Natural analogue of vitamin B12, it has an intense red colour. Together with folic acid, cobalamins are essential cofactors required for DNA synthesis in cells where chromosomal replication and division are occurring — most notably the bone marrow and myeloid cells. 2.   Hemodialysis:  Hemodialysis can be carried out in a hospital, in a separate clinic, in a self-care centre or even in your own home in some cases. Takes about four to five hours. The patient usually lies on a couch or sits in a chair while connected to the kidney machine. First, a pair of access points are created by your doctor, usually in the forearm, usually fistulas, (these are permanent access points and the surgery to insert them can be done quite some time before the patient starts the actual treatment). Using these, blood is transferred, at a low flow rate, from your body to the kidney machine through one such point. In the machine, heparin is added to the blood to prevent clotting occurring, and the blood is passed into the dialyser where the waste products and toxins are removed. The cleaned blood is then returned to the body via the second access point. In the dialyser are thousands of fine fibre tubes that mimic the body's own glomeruli and filter the blood as it flows through them. They are semi-permeable and allow the small molecules of fluids and soluble wastes to move into the surrounding canister which is continuously flushed with dialysis fluid. This fluid is what carries away the waste products. The larger blood cells and the rest of the blood's constituents cannot move through the semi-permeable membrane and are returned to the body, having been cleansed. The dialysis solution that is used is a sterilized solution of mineral ions. Urea and other waste products, potassium, and phosphate diffuse into the dialysis solution. However, concentrations of  sodium and chloride are similar to those of normal plasma to prevent loss. Sodium bicarbonate is added in a higher concentration than plasma to correct blood acidity. A small amount of glucose is also commonly used. 3.   Atrophic glossitis:  smooth glossy tongue that is often tender and painful. The papillae (tiny, red, raised areas), which normally cover the surface of the tongue, shrink or disappear and the tongue (a muscle) wastes away -- giving the tongue a thin, shiny appearance (smooth). The tongue may also show patches of redness and inflammation. Red patches on the tongue, Sensitivity to spicy food, Bad Breath,There may be ulcers (open sores) on the tongue or mouth. Causes- 1. Diseases 1.   Streptococcus (bacteria) infection 2.   HIV (virus) infection 3.   Candidiasis -- infection caused by a fungus 4.   Herpes (Virus) infection 5.   Cancer of the tongue, trauma (burns, irritating chemicals) 2.   Nutritional deficiency: 1.   Vitamin B12 -- pernicious anemia 2.   Iron Deficiency Anemia 3.   Folic Acid -- pernicious anemia 4.   Riboflavin Deficiency 5.   Niacin Deficiency known as pellegra (fiery red) 4.   Angular stomatitis : an inflammatory lesion at corner of the mouth, and often occurs bilaterally. The condition manifests as deep cracks or splits. In severe cases, the splits can bleed when the mouth is opened and shallow ulcers or a crust may form. Studies have linked the initial onset with nutritional deficiencies, namely riboflavin (vitamin B 2 ) [2][3]  and iron deficiency anemia, [3]  which in turn may be evidence of poor diets or malnutrition (e.g. celiac disease). Zinc deficiency has also been associated with angular cheilitis.   5.   Erythropoietin therapy : Erythropoietin is available as a therapeutic agent produced by recombinant DNA technology in   mammalian cell culture. It is used in treating anaemia resulting from chronic kidney disease and myelodysplasia, from the   treatment of  cancer (chemotherapy and radiation), and from other critical illnesses (heart failure).      Epogen which is made by Amgen      Betapoietin which is made by CinnaGen and Zahravi    RELIPOIETIN which is made by Reliance Life Sciences Pvt. Ltd    Epokine which is made by Intas Biopharmaceutica Pvt. Ltd 6.   Pallor:  a pale colour most notable on the face and palms of hands, caused by reduced amount of oxyhaemoglobin in skin or mucous membranes. It can be caused by illness, emotional shock or stress, avoiding excessive exposure to sunlight, anemia or genetics. 7.   Folate:  vitamin B9. Folic acid is itself not biologically active, but its biological importance is due to tetrahydrofolate and other derivatives after its conversion to dihydrofolic acid in the liver. Vitamin B 9  (folic acid and folate inclusive) is essential to numerous bodily functions ranging from nucleotide biosynthesis to the remethylation of  homocysteine. The human body needs folate to synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in biological  PBL CR reactions involving folate. [3]  It is especially important during periods of rapid cell division and growth. Both children and adults require folic acid to produce healthy red blood cells and prevent anemia.  Leafy vegetables such as spinach, asparagus, turnip greens, romaine lettuces, dried or fresh beans and peas, fortified grain products (pasta, cereal, bread), sunflower seeds and certain other fruits (orange juice, canned pineapple juice, cantaloupe, honeydew melon, grapefruit juice, banana, raspberry, grapefruit, strawberry) and vegetables (beets, broccoli, corn, tomato juice, vegetable juice, brussels sprouts, bok choy) are rich sources of folate. [8]  Liver and liver products also contain high amounts of folate, as does baker's yeast. Some breakfast cereals (ready-to-eat and others) are fortified with 25% to 100% of the recommended dietary allowance (RDA) for folic acid.   Women Pregnant Women Men RDA 400 mcg DFE 600 mcg DFE 400 mcg DFE UL 1000 mcg DFE 1000 mcg DFE 1000 mcg DFE 8.   Vitamin B12: Vitamin B12 is a term that refers to a group of compounds called cobalamins that are available in the human body in a variety of mostly interconvertible forms. Vitamin B12 is a member of the vitamin B complex. It contains cobalt, and so is also known as cobalamin. It is exclusively synthesised by bacteria and is found primarily in meat, eggs and dairy products. Vitamin B12 is necessary for the synthesis of red blood cells, the maintenance of the nervous system, and is necessary for the rapid synthesis of DNA during cell division. Deficiency can cause anaemia. Vitamin B12 neuropathy, involving the degeneration of nerve fibres and irreversible neurological damage, can also occur. Together with folic acid, cobalamins are essential cofactors required for DNA synthesis in cells where chromosomal replication and division are occurring — most notably the bone marrow and myeloid cells. As a cofactor,  cobalamins are essential for two cellular reactions: (1) the mitochondrial methylmalonylcoenzyme A mutase conversion of  methylmalonic acid (MMA) to succinate, which links lipid and carbohydrate metabolism, and (2) activation of methionine synthase, which is the rate limiting step in the synthesis of methionine from homocysteine and tetrahydrofolate. Daily requirement is 1microg, normal diet has 10-15microg. Body stores of B12, largely in the liver, can last 2-4 years. 9.   fL:  femtolitre, metric unit of volume 10 -15  litre. 10.   MCV:   mean corpuscular volume . can be calculated (in litres) by dividing the hematocrit by the red blood cell count (no. red blood cells per litre). The result is typically reported in femtolitres. Reference range 80-100fL . High=  hemolytic anemia, pernicious, alcoholism and Vitamin B12 and/or Folic Acid deficiency . Low=  iron deficiency (due to inadequate dietary intake, gastrointestinal blood loss, or menstrual blood loss), thalassemia, or chronic disease 11.   HSN:  hypersegmented neutrophil, associated with megaloblastic anemia (anemias caused by failure of bone marrow blood-forming cells to make DNA, often caused by vitamin B-12 or folate deficiencies, or DNA-replication poisons including pernicious). There are greater than 5 lobes of the nucleus (normal= 3 or 4) One of the earliest, notable changes in the peripheral blood in megaloblastic processes 12.   Reticulocytes:  Immature red blood cells. Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells, reticulocytes do not have a cell nucleus. They are called reticulocytes because of a reticular (mesh-like) network of ribosomal RNA that becomes visible under a microscope with certain stains such as new methylene blue. 13.   Hemoglobin   Synthesis= heme (requires iron) and globin synthesis (2β and 2α).   right shift   left shift  temperature high low 2.3-DPG   high low p(CO 2 ) high low p(CO)   low high pH ( Bohr effect)     low (acidosis) high CO2= increased H+ high (alkalosis) type of haemoglobin adult haemoglobin foetal haemoglobin    PBL CR This relationship, sigmoid shape, referred to as the oxyhemoglobin dissociation curve, enables both efficient loading in the lungs at high PO2 and efficient unloading in the tissues at low PO2 levels Haldane effect- Deoxygenation of the blood increases its ability to carry carbon dioxide; this property is the Haldane effect. Conversely, oxygenated blood has a reduced capacity for carbon dioxide. Hemoglobin has an oxygen binding capacity of between 1.36 and 1.37 ml O 2  per gram of hemoglobin. The iron ion may either be in the Fe 2+  or Fe 3+  state, but ferrihemoglobin (methemoglobin) (Fe 3+ ) cannot bind oxygen, methemoglobin reductase.  Learning Objectives 1.   How is EPO stimulated? Regulation is believed to rely on a feed-back mechanism measuring blood oxygenation. Constitutively synthesized transcription factors for EPO, known as hypoxia-inducible factors (HIFs), are hydroxylated and proteosomally digested in the presence of oxygen. [5]  It binds to the erythropoietin receptor (EpoR) on the red cell surface and activates a JAK2 cascade. This receptor is also found in a large number of tissues such as bone marrow cells and peripheral/central nerve cells, many of which activate intracellular biological pathways upon binding with Epo.   Erythropoietin has its primary effect on red blood cells by promoting red blood cell survival through protecting these cells from apoptosis. It also cooperates with various growth factors involved in the development of precursor red cells. Specifically, the colony forming unit-erythroid (CFU-E) is completely dependent on erythropoietin. The burst forming unit-erythroid (BFU-E) is also responsive to erythropoietin. Under hypoxic conditions, the kidney will produce and secrete erythropoietin to increase the production of red blood cells by targeting CFU-E. Erythropoietin is produced mainly by peritubular fibroblasts of the renal cortex in adults and a small amount being produced in the liver. It is a glycoprotein hormone, a cytokine for erythrocyte precursors in the bone marrow.  Haemopoiesis is the production of blood cells, the haemopoietic system includes the bone marrow, liver, spleen, lymph nodes and thymus. Erythropoiesis is the production of red blood cells. It is stimulated by decreased O 2  delivery to the kidneys, which then secrete the hormone erythropoietin. Pluripotent stem cell   mixed myeloid progenitor cell CFU GEMM (colony forming unit granulocyte-erythrocyte-monocyte-megakaryocyte) IL-9, IL-3, GM-CSF, SCF  BFU E ( burst forming unit  erythroid ) EPO, IL-3, SCF   CFU E  colony forming unit  erythroid  (unipotent stem cell) IGF-1,EPO   pronormoblast/proerythroblast   basophilic normoblast/early normoblast   polychromatophilic normoblast/intermediate normoblast   orthochromatic normoblast/late normoblast   reticulocyte   Erythrocytes Pluripotent stem cells = self renewal and proliferation and differentiation into progenitor cells, committed to one specific cell line (lymphoid stem cell and myeloid stem cell). Blood islands form in the yolk sac in third week of gestation and produce primitive blood cells which migrate to liver and spleen. These organs are the main sites of haemopoiesis from week 6 to 7months, when the bone marrow becomes the main source; and the only source during normal childhood and adulthood. At birth haemopoiesis is present in the marrow of almost every bone. As the child grows the active red marrow is replaced by yellow marrow (fat) and haemopoiesis in the adult id confined to the central skeleton and proximal ends of long bones. Pathological processes may result in resumption of haemopoiesis in the liver and spleen, called extramedullary haemopoiesis.  PBL CR 2. Anaemia- When Hb is lower than the reference range, 11.5  –  15.5 g/dL (f) 13.5  –  17.5 (m) Decreased   red cell production or increased loss.   Macrocytic Megaloblastic Vitamin B12 deficiency MCV >98 fL Folate deficiency Other (non megaloblastic) Alcohol liver disease aplastic aneamia pregnancy myelodysplastic syndromes myeloma neonatal cytotoxic drugs reticulocytosis Normocytic Most haemolytic anaemias MCV 78-90 fL Secondary anaemias Microcytic Irin defeciency MCV <78 fL Thalassaemias other hemoglobin defects Anaemia of chronic disorders (some) e.g. rheumatoid arthritus Congenital sideroblastic anaemias (some) a)   CAUSES:      Bleeding: loss of blood through wounds or heavy menstrual periods, gastrointestinal ulcers and cancers such as of the colon may cause it.    dietary deficiency, malabsorption, systemic illness, haemolysis, bone marrow failure, inherited abnormalities of red blood cells. B12, folate or iron deficiency.    Chronic disease e.g. infection and cancer    Renal disease- In people with chronic (long-standing) kidney disease, the production of EPO is diminished, and this in turn diminishes the production of red blood cells,    Pregnancy Water weight gain during pregnancy dilutes the blood, which may be reflected as anaemia    Pernicious Immune attack on IF therefore malabsorption of vitamin B12    Sickle Cell    Thalasseamias    Alcoholism    Aplastic Occasionally some viral infections may severely affect the bone marrow and diminish production of all blood cells. Chemotherapy (cancer medications) and some other medications may pose the same problems    Hemolytic red blood cells and become dysfunctional. This could happen due to a variety of reasons; can be hereditary with constant destruction and rapid reproduction of red blood cells or in certain conditions, for example, with abnormal heart valves damaging the blood cells    Other less common causes of anemia include medication side effects, thyroid problems, cancers, liver disease, other genetic disorders, lead poisoning, AIDS, and bleeding disorders b)   PHYSIOLGICAL RESPONSE; SYMPTOMS shortness of breath of exertion, tiredness, headache or angina, more severe if anaemia is severe and rapid onset in the elderly. The amount of O2 delivered, either to the whole body or to specific organs, is the product of blood flow and arterial O2 content. In anemia, O2 carrying capacity is decreased but tissue oxygenation is preserved at [Hb] well below 100 g/L. Adaptive responses include:    a shift in the oxyhemoglobin dissociation curve,  The shift to the right of the oxyhemoglobin dissociation curve in anemia is primarily the result of increased synthesis of 2,3-diphosphoglycerate (2,3-DPG) in RBCs.This enables more O2 to be released to the tissues at a given PO2, offsetting the effect of the reduced O2 carrying capacity of the blood. This shift also occurs in vitro with decreases in temperature and pH.    hemodynamic alterations, increased heart rate. The most important determinant of cardiovascular response is the patient’s volume  status or more specifically, left ventricular preload. The combined effect of hypovolemia and anemia often occur as a result of blood loss. Thus, acute anemia may cause tissue hypoxia or anoxia through both diminished CO resulting in stagnant hypoxia and decreased O2 carrying capacity (anemic hypoxia). The body attempts to preserve
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