If DNA cannot be repaired, it triggers cellular apoptosis instead of necrosis.

Genetic Conditions and Their Association with Surgical Diseases

Li-Fraumeni Syndrome is an autosomal dominant genetic condition caused by mutations in the p53 tumour suppressor gene. Individuals with this syndrome have a high incidence of malignancies, particularly sarcomas and leukaemias. The diagnosis is made when an individual develops sarcoma under the age of 45 or when a first-degree relative is diagnosed with any cancer below the age of 45 and another family member develops malignancy under the age of 45 or sarcoma at any age.

BRCA 1 and 2 are genetic conditions carried on chromosome 17 and chromosome 13, respectively. These conditions are linked to developing breast cancer with a 60% risk and an associated risk of developing ovarian cancer with a 55% risk for BRCA 1 and 25% risk for BRCA 2. BRCA2 mutation is also associated with prostate cancer in men.

Lynch Syndrome is another autosomal dominant genetic condition that causes individuals to develop colonic cancer and endometrial cancer at a young age. 80% of affected individuals will get colonic and/or endometrial cancer. High-risk individuals may be identified using the Amsterdam criteria, which include three or more family members with a confirmed diagnosis of colorectal cancer, two successive affected generations, and one or more colon cancers diagnosed under the age of 50 years.

Gardners syndrome is an autosomal dominant familial colorectal polyposis that causes multiple colonic polyps. Extra colonic diseases include skull osteoma, thyroid cancer, and epidermoid cysts. Desmoid tumours are seen in 15% of individuals with this syndrome. Due to colonic polyps, most patients will undergo colectomy to reduce the risk of colorectal cancer. It is now considered a variant of familial adenomatous polyposis coli.

Overall, these genetic conditions have a significant association with surgical diseases, and early identification and management can help reduce the risk of malignancies and other associated conditions.

Lead poisoning can cause the accumulation of lead in the metaphysis of bones, which can be seen as bands of increased density on x-rays. In this case, the child’s recent deterioration in academic and physical performance, along with the history of moving to an old house, suggests the possibility of lead-based paint exposure. The presence of a lead line on the gums further supports this suspicion. While normocytic anemia can have many causes, the addition of radiodense lines in the metaphysis of long bones increases the likelihood of lead poisoning. Cretinism, caused by maternal hypothyroidism, typically presents earlier and has different symptoms. Osteomyelitis, an infection of the bone, has different x-ray findings. Sickle cell anemia and iron deficiency are not associated with the symptoms and x-ray findings in this case.

Lead poisoning is a condition that should be considered when a patient presents with abdominal pain and neurological symptoms, along with acute intermittent porphyria. This condition is caused by defective ferrochelatase and ALA dehydratase function. Symptoms of lead poisoning include abdominal pain, peripheral neuropathy (mainly motor), neuropsychiatric features, fatigue, constipation, and blue lines on the gum margin (which is rare in children and only present in 20% of adult patients).

To diagnose lead poisoning, doctors typically measure the patient’s blood lead level, with levels greater than 10 mcg/dl considered significant. A full blood count may also be performed, which can reveal microcytic anemia and red cell abnormalities such as basophilic stippling and clover-leaf morphology. Additionally, raised serum and urine levels of delta aminolaevulinic acid may be seen, which can sometimes make it difficult to differentiate from acute intermittent porphyria. Urinary coproporphyrin is also increased, while urinary porphobilinogen and uroporphyrin levels are normal to slightly increased. In children, lead can accumulate in the metaphysis of the bones, although x-rays are not typically part of the standard work-up.

Various chelating agents are currently used to manage lead poisoning, including dimercaptosuccinic acid (DMSA), D-penicillamine, EDTA, and dimercaprol. These agents work to remove the lead from the body and can help alleviate symptoms.

The ovarian vessels directly branch from the aorta to supply ovarian tumours. Meanwhile, the internal and external iliac nodes are responsible for draining the cervix.

Para-aortic Lymphadenopathy and its Association with Metastasis

Para-aortic lymphadenopathy is a condition where the lymph nodes located near the aorta become enlarged due to the spread of cancer cells. This condition is commonly associated with the metastasis of cancer cells from various organs, including the testis, ovary, and uterine fundus. In these cases, the cancer cells spread to the para-aortic lymph nodes at an early stage of the disease.

However, it is important to note that para-aortic nodal disease may also occur as a result of cancer cells spreading from other organs. In these cases, the para-aortic nodal disease represents a much later stage of the disease, as other nodal stations are involved earlier.

Overall, para-aortic lymphadenopathy is a significant concern for individuals with cancer, as it can indicate the spread of cancer cells to other parts of the body. Early detection and treatment of para-aortic nodal disease can improve the chances of successful treatment and recovery.

Hodgkin’s disease is characterized by the presence of Reed Sternberg cells, while sarcoid is associated with the presence of all other cell types.

Chronic inflammation can occur as a result of acute inflammation or as a primary process. There are three main processes that can lead to chronic inflammation: persisting infection with certain organisms, prolonged exposure to non-biodegradable substances, and autoimmune conditions involving antibodies formed against host antigens. Acute inflammation involves changes to existing vascular structure and increased permeability of endothelial cells, as well as infiltration of neutrophils. In contrast, chronic inflammation is characterized by angiogenesis and the predominance of macrophages, plasma cells, and lymphocytes. The process may resolve with suppuration, complete resolution, abscess formation, or progression to chronic inflammation. Healing by fibrosis is the main result of chronic inflammation. Granulomas, which consist of a microscopic aggregation of macrophages, are pathognomonic of chronic inflammation and can be found in conditions such as colonic Crohn’s disease. Growth factors released by activated macrophages, such as interferon and fibroblast growth factor, may have systemic features resulting in systemic symptoms and signs in individuals with long-standing chronic inflammation.

The Development of Haematopoiesis in the Foetus

The development of haematopoiesis in the foetus is a complex process that involves several organs. Initially, the yolk sac is the primary site of haematopoiesis until around two months gestation when the liver takes over. The liver remains the most important site of haematopoiesis until about month seven when the bone marrow becomes the predominant site throughout life.

After the age of 20, haematopoiesis occurs mainly in the proximal bones, with production in the distal lone bones decreasing. However, in certain disease states such as β-thalassaemia, haematopoiesis can occur outside of the bone marrow, known as extra-medullary haematopoiesis. the development of haematopoiesis in the foetus is important for identifying potential abnormalities and diseases that may arise during this process.

The internal iliac lymph nodes are responsible for draining the lower part of the rectum, as well as the pelvic viscera and the anal canal above the pectinate line. The ileocolic nodes primarily drain the ileum and proximal ascending colon, while the inferior mesenteric nodes drain the hindgut structures from the transverse colon down to the superior portion of the rectum. The para-aortic nodes do not directly drain the lower part of the rectum, but they do receive drainage from the testes and ovaries.

Lymphatic drainage is the process by which lymphatic vessels carry lymph, a clear fluid containing white blood cells, away from tissues and organs and towards lymph nodes. The lymphatic vessels that drain the skin and follow venous drainage are called superficial lymphatic vessels, while those that drain internal organs and structures follow the arteries and are called deep lymphatic vessels. These vessels eventually lead to lymph nodes, which filter and remove harmful substances from the lymph before it is returned to the bloodstream.

The lymphatic system is divided into two main ducts: the right lymphatic duct and the thoracic duct. The right lymphatic duct drains the right side of the head and right arm, while the thoracic duct drains everything else. Both ducts eventually drain into the venous system.

Different areas of the body have specific primary lymph node drainage sites. For example, the superficial inguinal lymph nodes drain the anal canal below the pectinate line, perineum, skin of the thigh, penis, scrotum, and vagina. The deep inguinal lymph nodes drain the glans penis, while the para-aortic lymph nodes drain the testes, ovaries, kidney, and adrenal gland. The axillary lymph nodes drain the lateral breast and upper limb, while the internal iliac lymph nodes drain the anal canal above the pectinate line, lower part of the rectum, and pelvic structures including the cervix and inferior part of the uterus. The superior mesenteric lymph nodes drain the duodenum and jejunum, while the inferior mesenteric lymph nodes drain the descending colon, sigmoid colon, and upper part of the rectum. Finally, the coeliac lymph nodes drain the stomach.

The aPTT time is the most effective way to evaluate the intrinsic pathway of the clotting cascade. If the aPTT time is prolonged, it may indicate haemophilia or the use of heparin.

To assess the extrinsic pathway, the prothrombin time (PT) is the preferred measurement.

The thrombin time is a test that evaluates the formation of fibrin from fibrinogen in plasma. It can be prolonged by heparin, fibrin degradation products, and fibrinogen deficiency.

A 50:50 mixing study is utilized to determine whether a prolonged PT or aPTT is caused by a factor deficiency or a factor inhibitor.

The Coagulation Cascade: Two Pathways to Fibrin Formation

The coagulation cascade is a complex process that leads to the formation of a blood clot. There are two pathways that can lead to fibrin formation: the intrinsic pathway and the extrinsic pathway. The intrinsic pathway involves components that are already present in the blood and has a minor role in clotting. It is initiated by subendothelial damage, such as collagen, which leads to the formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein, and Factor 12. This complex activates Factor 11, which in turn activates Factor 9. Factor 9, along with its co-factor Factor 8a, forms the tenase complex, which activates Factor 10.

The extrinsic pathway, on the other hand, requires tissue factor released by damaged tissue. This pathway is initiated by tissue damage, which leads to the binding of Factor 7 to tissue factor. This complex activates Factor 9, which works with Factor 8 to activate Factor 10. Both pathways converge at the common pathway, where activated Factor 10 causes the conversion of prothrombin to thrombin. Thrombin hydrolyses fibrinogen peptide bonds to form fibrin and also activates factor 8 to form links between fibrin molecules.

Finally, fibrinolysis occurs, which is the process of clot resorption. Plasminogen is converted to plasmin to facilitate this process. It is important to note that certain factors are involved in both pathways, such as Factor 10, and that some factors are vitamin K dependent, such as Factors 2, 7, 9, and 10. The intrinsic pathway can be assessed by measuring the activated partial thromboplastin time (APTT), while the extrinsic pathway can be assessed by measuring the prothrombin time (PT).

The chemotherapy regime R-CHOP, which is likely being used to manage the patient’s non-Hodgkin’s lymphoma, includes cyclophosphamide, a drug that functions as an alkylating agent and promotes cross-linking of DNA. This can lead to haemorrhagic cystitis, which is likely the cause of the patient’s haematuria. Other drugs in the regime have different mechanisms of action, such as inhibition of microtubule formation with vincristine, inhibition of topoisomerase II and DNA/RNA synthesis with doxorubicin, and monoclonal antibody targeting of CD20 with rituximab. Pyrimidine analogues like 5-fluorouracil, which block thymidylate synthase and induce cell cycle arrest and apoptosis, are not commonly used in the management of non-Hodgkin’s lymphoma.

Cytotoxic agents are drugs that are used to kill cancer cells. There are several types of cytotoxic agents, each with their own mechanism of action and potential adverse effects. Alkylating agents, such as cyclophosphamide, work by causing cross-linking in DNA. However, they can also cause haemorrhagic cystitis, myelosuppression, and transitional cell carcinoma. Cytotoxic antibiotics, like bleomycin and anthracyclines, degrade preformed DNA and stabilize DNA-topoisomerase II complex, respectively. However, they can also cause lung fibrosis and cardiomyopathy. Antimetabolites, such as methotrexate and fluorouracil, inhibit dihydrofolate reductase and thymidylate synthesis, respectively. However, they can also cause myelosuppression, mucositis, and liver or lung fibrosis. Drugs that act on microtubules, like vincristine and docetaxel, inhibit the formation of microtubules and prevent microtubule depolymerisation & disassembly, respectively. However, they can also cause peripheral neuropathy, myelosuppression, and paralytic ileus. Topoisomerase inhibitors, like irinotecan, inhibit topoisomerase I, which prevents relaxation of supercoiled DNA. However, they can also cause myelosuppression. Other cytotoxic drugs, such as cisplatin and hydroxyurea, cause cross-linking in DNA and inhibit ribonucleotide reductase, respectively. However, they can also cause ototoxicity, peripheral neuropathy, hypomagnesaemia, and myelosuppression.

The patient is displaying typical signs and symptoms of cervical carcinoma, with a constant dull pelvic pain indicating possible invasion of pelvic structures and nerves. The strongest risk factor for this patient is having had multiple sexual partners at a young age, which increases the likelihood of being infected with the human papillomavirus.

1: Multiple sexual partners are the strongest risk factor for cervical carcinoma due to the increased chance of contracting the human papillomavirus, specifically the 16 and 18 viral strains that inhibit the tumor suppressor genes p53 and RB, triggering carcinogenesis.
2: While cigarette smoking can have an oncogenic effect, it is not the primary risk factor in this case.
3: HIV is a risk factor for cervical carcinoma, but it is less common than the human papillomavirus.
4: The human papillomavirus is the primary risk factor, but it does not activate oncogenes. Instead, it inhibits tumor suppressor genes.
5: Age alone is not a risk factor for cervical carcinoma. However, an older person who has been exposed to the human papillomavirus may have a higher risk due to the longer exposure time for the virus to induce carcinogenesis via the inhibition of tumor suppressor genes.

HPV Infection and Cervical Cancer

Human papillomavirus (HPV) infection is the primary risk factor for cervical cancer, with subtypes 16, 18, and 33 being the most carcinogenic. Other common subtypes, such as 6 and 11, are associated with genital warts but are not carcinogenic. When endocervical cells become infected with HPV, they may undergo changes that lead to the development of koilocytes. These cells have distinct characteristics, including an enlarged nucleus, irregular nuclear membrane contour, hyperchromasia (darker staining of the nucleus), and a perinuclear halo. These changes are important diagnostic markers for cervical cancer and can be detected through Pap smears or other screening methods. Early detection and treatment of HPV infection and cervical cancer can greatly improve outcomes and reduce the risk of complications.

Understanding Mantle Cell Lymphoma

Mantle cell lymphoma is a type of B-cell lymphoma that is characterized by the over-expression of the cyclin D1 (BCL-1) gene due to a translocation (11;14). This cancer is identified by the presence of CD5+, CD19+, CD22+, and CD23- markers. Unfortunately, mantle cell lymphoma has a poor prognosis and is often associated with widespread lymphadenopathy.

In summary, mantle cell lymphoma is a type of cancer that affects B-cells and is caused by a specific genetic translocation. It is identified by certain markers and is known for its poor prognosis and widespread lymphadenopathy. Understanding the basics of this disease can help with early detection and treatment.

Lead poisoning is a condition that should be considered when a patient presents with abdominal pain and neurological symptoms, along with acute intermittent porphyria. This condition is caused by defective ferrochelatase and ALA dehydratase function. Symptoms of lead poisoning include abdominal pain, peripheral neuropathy (mainly motor), neuropsychiatric features, fatigue, constipation, and blue lines on the gum margin (which is rare in children and only present in 20% of adult patients).

To diagnose lead poisoning, doctors typically measure the patient’s blood lead level, with levels greater than 10 mcg/dl considered significant. A full blood count may also be performed, which can reveal microcytic anemia and red cell abnormalities such as basophilic stippling and clover-leaf morphology. Additionally, raised serum and urine levels of delta aminolaevulinic acid may be seen, which can sometimes make it difficult to differentiate from acute intermittent porphyria. Urinary coproporphyrin is also increased, while urinary porphobilinogen and uroporphyrin levels are normal to slightly increased. In children, lead can accumulate in the metaphysis of the bones, although x-rays are not typically part of the standard work-up.

Various chelating agents are currently used to manage lead poisoning, including dimercaptosuccinic acid (DMSA), D-penicillamine, EDTA, and dimercaprol. These agents work to remove the lead from the body and can help alleviate symptoms.

The clotting cascade is an example of a positive feedback mechanism, where the presence of clotting factors attracts further clotting factors until a functioning clot is formed. On the other hand, blood sugar, blood pressure, and cortisol are controlled via negative feedback mechanisms. When blood sugar rises, insulin is released to transport glucose into cells, lowering blood sugar. When BP is low, the RAAS is activated to increase BP through vasoconstriction and retention of salt and water. Cortisol is released in response to ACTH, which is inhibited by high levels of cortisol through negative feedback on the hypothalamus and anterior pituitary.

The Coagulation Cascade: Two Pathways to Fibrin Formation

The coagulation cascade is a complex process that leads to the formation of a blood clot. There are two pathways that can lead to fibrin formation: the intrinsic pathway and the extrinsic pathway. The intrinsic pathway involves components that are already present in the blood and has a minor role in clotting. It is initiated by subendothelial damage, such as collagen, which leads to the formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein, and Factor 12. This complex activates Factor 11, which in turn activates Factor 9. Factor 9, along with its co-factor Factor 8a, forms the tenase complex, which activates Factor 10.

The extrinsic pathway, on the other hand, requires tissue factor released by damaged tissue. This pathway is initiated by tissue damage, which leads to the binding of Factor 7 to tissue factor. This complex activates Factor 9, which works with Factor 8 to activate Factor 10. Both pathways converge at the common pathway, where activated Factor 10 causes the conversion of prothrombin to thrombin. Thrombin hydrolyses fibrinogen peptide bonds to form fibrin and also activates factor 8 to form links between fibrin molecules.

Finally, fibrinolysis occurs, which is the process of clot resorption. Plasminogen is converted to plasmin to facilitate this process. It is important to note that certain factors are involved in both pathways, such as Factor 10, and that some factors are vitamin K dependent, such as Factors 2, 7, 9, and 10. The intrinsic pathway can be assessed by measuring the activated partial thromboplastin time (APTT), while the extrinsic pathway can be assessed by measuring the prothrombin time (PT).

In the case of uterine body tumours, the initial spread is likely to occur in the iliac nodes. This becomes clinically significant when nodal clearance is carried out during a Wertheims type hysterectomy, as the tumour may cross different nodal margins.

Lymphatic Drainage of Female Reproductive Organs

The lymphatic drainage of the female reproductive organs is a complex system that involves multiple nodal stations. The ovaries drain to the para-aortic lymphatics via the gonadal vessels. The uterine fundus has a lymphatic drainage that runs with the ovarian vessels and may thus drain to the para-aortic nodes. Some drainage may also pass along the round ligament to the inguinal nodes. The body of the uterus drains through lymphatics contained within the broad ligament to the iliac lymph nodes. The cervix drains into three potential nodal stations; laterally through the broad ligament to the external iliac nodes, along the lymphatics of the uterosacral fold to the presacral nodes and posterolaterally along lymphatics lying alongside the uterine vessels to the internal iliac nodes. Understanding the lymphatic drainage of the female reproductive organs is important for the diagnosis and treatment of gynecological cancers.

Platelets, also known as thrombocytes, are derived from myeloid stem cells, similar to red blood cells. The process involves the development of a megakaryocyte from a common myeloid progenitor cell. Megakaryocytes are large cells with multilobulated nuclei that grow to become massive before breaking up to form platelets.

The primary signal responsible for megakaryocyte and platelet production is thrombopoietin.

Erythropoietin initiates the signal for red blood cell production, while granulocyte-colony stimulating factor stimulates the bone marrow to produce granulocytes. Interleukin-5 is a cytokine that stimulates the proliferation and activation of eosinophils.

Haematopoiesis: The Generation of Immune Cells

Haematopoiesis is the process by which immune cells are produced from haematopoietic stem cells in the bone marrow. These stem cells give rise to two main types of progenitor cells: myeloid and lymphoid progenitor cells. All immune cells are derived from these progenitor cells.

The myeloid progenitor cells generate cells such as macrophages/monocytes, dendritic cells, neutrophils, eosinophils, basophils, and mast cells. On the other hand, lymphoid progenitor cells give rise to T cells, NK cells, B cells, and dendritic cells.

This process is essential for the proper functioning of the immune system. Without haematopoiesis, the body would not be able to produce the necessary immune cells to fight off infections and diseases. Understanding haematopoiesis is crucial in developing treatments for diseases that affect the immune system.

Understanding Antithrombin III Deficiency

Antithrombin III deficiency is a genetic condition that affects approximately 1 in 3,000 people. It is inherited in an autosomal dominant manner. This condition occurs when the body does not produce enough antithrombin III, a protein that helps to prevent blood clots by inhibiting certain clotting factors. Some patients with this deficiency have a shortage of normal antithrombin III, while others produce abnormal antithrombin III.

People with antithrombin III deficiency are at an increased risk of developing recurrent venous thromboses, which are blood clots that form in the veins. While arterial thromboses can also occur, they are less common. To manage this condition, patients may need to take warfarin for the rest of their lives to prevent thromboembolic events. During pregnancy, heparin may be used instead. Antithrombin III concentrates may also be used during surgery or childbirth.

It is important to note that patients with antithrombin III deficiency have a degree of resistance to heparin, so anti-Xa levels should be monitored carefully to ensure adequate anticoagulation. Compared to other inherited thrombophilias, antithrombin III deficiency is less common but has a higher relative risk of venous thromboembolism. Understanding this condition and its management is crucial for those affected and their healthcare providers.

The correct answer is T lymphocytes, as the thymus plays a role in their maturation. DiGeorge syndrome is caused by a microdeletion on chromosome 22, resulting in the failure of development of the third and fourth pharyngeal arches. The syndrome is characterized by cardiac abnormalities, abnormal facies, thymus aplasia, cleft palate, and hypoparathyroidism, which can be remembered with the acronym CATCH.

The Thymus Gland: Development, Structure, and Function

The thymus gland is an encapsulated organ that develops from the third and fourth pharyngeal pouches. It descends to the anterior superior mediastinum and is subdivided into lobules, each consisting of a cortex and a medulla. The cortex is made up of tightly packed lymphocytes, while the medulla is mostly composed of epithelial cells. Hassall’s corpuscles, which are concentrically arranged medullary epithelial cells that may surround a keratinized center, are also present.

The inferior parathyroid glands, which also develop from the third pharyngeal pouch, may be located with the thymus gland. The thymus gland’s arterial supply comes from the internal mammary artery or pericardiophrenic arteries, while its venous drainage is to the left brachiocephalic vein. The thymus gland plays a crucial role in the development and maturation of T-cells, which are essential for the immune system’s proper functioning.

Platelets in the UK are obtained through either pooling the platelet component from four units of whole donated blood, known as random donor platelets, or by plasmapheresis from a single donor. These platelets are suspended in 200-300 ml of plasma and can be stored for up to 4 days in the transfusion laboratory, where they are kept agitated at 22oC to maintain their function. One adult platelet pool can increase the normal platelet count (150 – 450 platelets x 109/litre) by 510 platelets x 109/litre. While ABO identical or compatible platelets are preferred for adults, rhesus compatibility is necessary for recipients who are children or women of childbearing age to prevent haemolytic disease of the newborn.

Blood Products and Cell Saver Devices

Blood products are essential in various medical procedures, especially in cases where patients require transfusions due to anaemia or bleeding. Packed red cells, platelet-rich plasma, platelet concentrate, fresh frozen plasma, and cryoprecipitate are some of the commonly used whole blood fractions. Fresh frozen plasma is usually administered to patients with clotting deficiencies, while cryoprecipitate is a rich source of Factor VIII and fibrinogen. Cross-matching is necessary for all blood products, and cell saver devices are used to collect and re-infuse a patient’s own blood lost during surgery.

Cell saver devices come in two types, those that wash the blood cells before re-infusion and those that do not. The former is more expensive and complicated to operate but reduces the risk of re-infusing contaminated blood. The latter avoids the use of donor blood and may be acceptable to Jehovah’s witnesses. However, it is contraindicated in malignant diseases due to the risk of facilitating disease dissemination.

In some surgical patients, the use of warfarin can pose specific problems and may require the use of specialised blood products. Warfarin reversal can be achieved through the administration of vitamin K, fresh frozen plasma, or human prothrombin complex. Fresh frozen plasma is used less commonly now as a first-line warfarin reversal, and human prothrombin complex is preferred due to its rapid action. However, it should be given with vitamin K as factor 6 has a short half-life.

Acute Lymphoblastic Leukaemia

Acute lymphoblastic leukaemia (ALL) is a type of cancer that commonly affects children over the age of one. It occurs when a lymphocyte precursor, known as a ‘blast cell’, grows abnormally in the bone marrow, leading to a failure of normal blood cell production. This results in peripheral cytopenias, which can cause symptoms such as anaemia, recurrent infections, and purpura. While a raised peripheral white cell count may occur in severe or late-stage disease, it is not common.

Compared to other types of leukaemia and lymphoma, ALL is more likely to present with bone marrow failure symptoms. Acute myeloid leukaemia, for example, is more common in the elderly and presents with a raised peripheral white cell count. Burkitt lymphoma, on the other hand, is a high-grade non-Hodgkin lymphoma that typically presents with lymphadenopathy. Chronic lymphocytic leukaemia is also more common in the elderly and presents with a peripheral lymphocytosis. Langerhans histiocytosis, a condition that affects antigen-presenting cells, is more common in young children and often affects the skin or bones. While it can cause marrow failure, it is a rare occurrence.

In summary, ALL is a type of cancer that affects children and is caused by abnormal growth of blast cells in the bone marrow. It can cause symptoms of bone marrow failure, such as anaemia, recurrent infections, and purpura. While other types of leukaemia and lymphoma may present with different symptoms, ALL is more likely to present with bone marrow failure symptoms.

To divide the breast into four quadrants, one can visualize a vertical and horizontal line passing through the nipple. The superior lateral quadrant is where breast malignancies are most frequently detected. During a breast examination, it is crucial to palpate all quadrants and the axillary tail (which is part of the superior lateral quadrant). The quadrants also play a significant role in lymphatic drainage, as the medial quadrants can drain to the opposite side.

Breast Cancer Pathology: Understanding the Histological Features

Breast cancer pathology involves examining the histological features of the cancer cells to determine the underlying diagnosis. The invasive component of breast cancer is typically made up of ductal cells, although invasive lobular cancer may also occur. In situ lesions, such as DCIS, may also be present.

When examining breast cancer pathology, several typical changes are seen in conjunction with invasive breast cancer. These include nuclear pleomorphism, coarse chromatin, angiogenesis, invasion of the basement membrane, dystrophic calcification (which may be seen on mammography), abnormal mitoses, vascular invasion, and lymph node metastasis.

To grade the primary tumor, a scale of 1-3 is used, with 1 being the most benign lesion and 3 being the most poorly differentiated. Immunohistochemistry for estrogen receptor and herceptin status is routinely performed to further understand the cancer’s characteristics.

The grade, lymph node stage, and size are combined to provide the Nottingham prognostic index, which helps predict the patient’s prognosis and guide treatment decisions. Understanding the histological features of breast cancer is crucial in determining the best course of treatment for patients.

Haptoglobin is a liver-produced protein that binds to free haemoglobin in blood plasma, allowing the reticuloendothelial system to remove it. This consumption of haptoglobin reduces its detectable levels in the blood, making it a useful indicator of haemolysis.

If an individual has a functioning liver, conjugated bilirubin levels will increase in haemolysis. This is because the liver generates conjugated bilirubin from unconjugated bilirubin, which is produced from the porphyrin rings of haemoglobin. Conjugated bilirubin is more soluble in water and can be secreted through the kidneys.

Lactate dehydrogenase is an intracellular enzyme that is leaked from cells, including erythrocytes, which are broken down. Its levels increase due to cell breakdown, not only in haemolysis but also in cardiomyocyte damage due to infarction and lymphocyte turnover due to leukaemia.

Potassium is an intracellular ion that can increase in levels due to haemolysis and cell breakdown. This can lead to cardiac arrhythmias such as ventricular tachycardia and fibrillation.

Low platelets and a purpuric rash suggest that the likely form of intravascular haemolysis is a microangiopathic haemolytic anaemia (MAHA) such as thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemic syndrome (HUS). These rare conditions result in the accumulation of intravascular thrombosis, leading to platelet and clotting factor consumption.

Understanding Haemolytic Anaemias by Site

Haemolytic anaemias can be classified by the site of haemolysis, either intravascular or extravascular. In intravascular haemolysis, free haemoglobin is released and binds to haptoglobin. As haptoglobin becomes saturated, haemoglobin binds to albumin forming methaemalbumin, which can be detected by Schumm’s test. Free haemoglobin is then excreted in the urine as haemoglobinuria and haemosiderinuria. Causes of intravascular haemolysis include mismatched blood transfusion, red cell fragmentation due to heart valves, TTP, DIC, HUS, paroxysmal nocturnal haemoglobinuria, and cold autoimmune haemolytic anaemia.

On the other hand, extravascular haemolysis occurs when red blood cells are destroyed by macrophages in the spleen or liver. This type of haemolysis is commonly seen in haemoglobinopathies such as sickle cell anaemia and thalassaemia, hereditary spherocytosis, haemolytic disease of the newborn, and warm autoimmune haemolytic anaemia.

It is important to understand the site of haemolysis in order to properly diagnose and treat haemolytic anaemias. While both intravascular and extravascular haemolysis can lead to anaemia, the underlying causes and treatment approaches may differ.

The origin of eosinophils is from common myeloid progenitor cells. A patient with neutrophilia and low haemoglobin is likely to have chronic myeloid leukaemia (CML). CML is characterized by increased levels of all cells derived from the myeloid lineage, including basophils, monocytes, and eosinophils. The bone marrow biopsy is diagnostic for CML and typically shows the t(9;22) chromosomal translocation, also known as the Philadelphia chromosome. Imatinib, an inhibitor of the BCR-ABL fusion protein created with this translocation, is a common treatment for CML. Cells derived from common lymphoid progenitor cells are not affected in CML.

Haematopoiesis: The Generation of Immune Cells

Haematopoiesis is the process by which immune cells are produced from haematopoietic stem cells in the bone marrow. These stem cells give rise to two main types of progenitor cells: myeloid and lymphoid progenitor cells. All immune cells are derived from these progenitor cells.

The myeloid progenitor cells generate cells such as macrophages/monocytes, dendritic cells, neutrophils, eosinophils, basophils, and mast cells. On the other hand, lymphoid progenitor cells give rise to T cells, NK cells, B cells, and dendritic cells.

This process is essential for the proper functioning of the immune system. Without haematopoiesis, the body would not be able to produce the necessary immune cells to fight off infections and diseases. Understanding haematopoiesis is crucial in developing treatments for diseases that affect the immune system.

Understanding Sickle-Cell Anaemia

Sickle-cell anaemia is a genetic disorder that occurs when an abnormal haemoglobin chain, known as HbS, is synthesized due to an autosomal recessive condition. This condition is more common in people of African descent, as the heterozygous condition offers some protection against malaria. In the UK, around 10% of Afro-Caribbean individuals are carriers of HbS. Symptoms in homozygotes typically do not develop until 4-6 months when the abnormal HbSS molecules take over from fetal haemoglobin.

The pathophysiology of sickle-cell anaemia involves the substitution of the polar amino acid glutamate with the non-polar valine in each of the two beta chains (codon 6) of haemoglobin. This substitution decreases the water solubility of deoxy-Hb, causing HbS molecules to polymerize and sickle in the deoxygenated state. HbAS patients sickle at p02 2.5 – 4 kPa, while HbSS patients sickle at p02 5 – 6 kPa. Sickle cells are fragile and can cause haemolysis, block small blood vessels, and lead to infarction.

To diagnose sickle-cell anaemia, haemoglobin electrophoresis is the definitive test. It is essential to understand the pathophysiology and symptoms of sickle-cell anaemia to provide appropriate care and management for affected individuals.

Blood that has been stored has a decreased level of 2,3 DPG, resulting in a greater attraction to oxygen and a reduced capacity to release it at tissues that are undergoing metabolism.

Oxygen Transport and Factors Affecting Haemoglobin Saturation

Oxygen transport in the body is mainly carried out by erythrocytes, with only 1% of oxygen being transported as a solution due to its limited solubility. The amount of oxygen transported depends on the concentration of haemoglobin and its degree of saturation. Haemoglobin is a globular protein composed of four subunits, with two alpha and two beta subunits forming globin. Haem, which surrounds an iron atom in its ferrous state, can form two additional bonds with oxygen and a polypeptide chain. The oxygenation of haemoglobin is a reversible reaction, and the molecular shape of haemoglobin facilitates the binding of subsequent oxygen molecules.

The oxygen dissociation curve describes the relationship between the percentage of saturated haemoglobin and partial pressure of oxygen in the blood, and it is not affected by haemoglobin concentration. The curve can be shifted to the right or left by various factors. Chronic anaemia, for example, causes an increase in 2,3 DPG levels, which shifts the curve to the right, resulting in lower oxygen delivery. The Haldane effect causes a shift to the left, resulting in decreased oxygen delivery to tissues, while the Bohr effect causes a shift to the right, resulting in enhanced oxygen delivery to tissues. Factors that shift the curve to the left include low levels of H+, pCO2, 2,3-DPG, and temperature, as well as the presence of HbF, methaemoglobin, and carboxyhaemoglobin. Factors that shift the curve to the right include raised levels of H+, pCO2, and 2,3-DPG, as well as increased temperature.

Plasma cells would be visible in a bone marrow aspirate to diagnose multiple myeloma, which is characterized by osteolytic lesions, decreased renal function, bony pain, and the presence of Bence-Jones proteins. This condition is a type of B-cell neoplasm affecting plasma cells.

Understanding Multiple Myeloma: Features and Investigations

Multiple myeloma is a type of cancer that affects the plasma cells in the bone marrow. It is most commonly found in patients aged 60-70 years. The disease is characterized by a range of symptoms, which can be remembered using the mnemonic CRABBI. These include hypercalcemia, renal damage, anemia, bleeding, bone lesions, and increased susceptibility to infection. Other features of multiple myeloma include amyloidosis, carpal tunnel syndrome, neuropathy, and hyperviscosity.

To diagnose multiple myeloma, a range of investigations are required. Blood tests can reveal anemia, renal failure, and hypercalcemia. Protein electrophoresis can detect raised levels of monoclonal IgA/IgG proteins in the serum, while bone marrow aspiration can confirm the diagnosis if the number of plasma cells is significantly raised. Imaging studies, such as whole-body MRI or X-rays, can be used to detect osteolytic lesions.

The diagnostic criteria for multiple myeloma require one major and one minor criteria or three minor criteria in an individual who has signs or symptoms of the disease. Major criteria include the presence of plasmacytoma, 30% plasma cells in a bone marrow sample, or elevated levels of M protein in the blood or urine. Minor criteria include 10% to 30% plasma cells in a bone marrow sample, minor elevations in the level of M protein in the blood or urine, osteolytic lesions, or low levels of antibodies in the blood. Understanding the features and investigations of multiple myeloma is crucial for early detection and effective treatment.

Macrophages are still the most frequent cell type that can generate giant cells, despite the possibility of other cell types doing so.

Giant cells are masses that result from the fusion of various types of cells. Typically, these masses are composed of macrophages. It is important to note that giant cells are not the same as granulomas, although the agents that cause them may be similar. In fact, giant cells are often a reaction to foreign materials, such as suture material, and can be seen in histological sections stained with haematoxylin and eosin. Overall, giant cells are a unique phenomenon in cellular biology that can provide insight into the body’s response to foreign substances.

Understanding Burkitt’s Lymphoma

Burkitt’s lymphoma is a type of high-grade B-cell neoplasm that can occur in two major forms. The endemic or African form typically affects the maxilla or mandible, while the sporadic form is commonly found in the abdomen, particularly in patients with HIV. The development of Burkitt’s lymphoma is strongly associated with the c-myc gene translocation, usually t(8:14), and the Epstein-Barr virus (EBV) is also implicated in its development.

Microscopy findings of Burkitt’s lymphoma show a starry sky appearance, characterized by lymphocyte sheets interspersed with macrophages containing dead apoptotic tumor cells. Management of this condition involves chemotherapy, which can produce a rapid response but may also cause tumor lysis syndrome. To reduce the risk of this occurring, rasburicase, a recombinant version of urate oxidase, is often given before chemotherapy. Complications of tumor lysis syndrome include hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, and acute renal failure.

In summary, Burkitt’s lymphoma is a serious condition that can occur in two major forms and is associated with c-myc gene translocation and the Epstein-Barr virus. Microscopy findings show a characteristic appearance, and management involves chemotherapy with the use of rasburicase to reduce the risk of complications.

The para-aortic nodes receive lymphatic drainage from the ovary through the gonadal vessels.

Lymphatic Drainage of Female Reproductive Organs

The lymphatic drainage of the female reproductive organs is a complex system that involves multiple nodal stations. The ovaries drain to the para-aortic lymphatics via the gonadal vessels. The uterine fundus has a lymphatic drainage that runs with the ovarian vessels and may thus drain to the para-aortic nodes. Some drainage may also pass along the round ligament to the inguinal nodes. The body of the uterus drains through lymphatics contained within the broad ligament to the iliac lymph nodes. The cervix drains into three potential nodal stations; laterally through the broad ligament to the external iliac nodes, along the lymphatics of the uterosacral fold to the presacral nodes and posterolaterally along lymphatics lying alongside the uterine vessels to the internal iliac nodes. Understanding the lymphatic drainage of the female reproductive organs is important for the diagnosis and treatment of gynecological cancers.

Mast cells originate from common myeloid progenitor cells.

Haematopoiesis: The Generation of Immune Cells

Haematopoiesis is the process by which immune cells are produced from haematopoietic stem cells in the bone marrow. These stem cells give rise to two main types of progenitor cells: myeloid and lymphoid progenitor cells. All immune cells are derived from these progenitor cells.

The myeloid progenitor cells generate cells such as macrophages/monocytes, dendritic cells, neutrophils, eosinophils, basophils, and mast cells. On the other hand, lymphoid progenitor cells give rise to T cells, NK cells, B cells, and dendritic cells.

This process is essential for the proper functioning of the immune system. Without haematopoiesis, the body would not be able to produce the necessary immune cells to fight off infections and diseases. Understanding haematopoiesis is crucial in developing treatments for diseases that affect the immune system.