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In contrast to benign cartilaginous tumours, majority of chondrosarcomas are found more often in the central skeleton. Radiologic appearance is of hugely expansile and osteolytic growth with foci of calcification. G/A Chondrosarcoma may vary in size from a few centimeters to extremely large and lobulated masses of firm consistency. Cut section of the tumour shows translucent, bluish-white, gelatinous or myxoid appearance with foci of ossification. M/E the two hallmarks of chondrosarcoma are: invasive character and formation of lobules of anaplastic cartilage cells. These tumour cells show cellular features of malignancy such as hyperchromatism, pleomorphism, two or more cells in the lacunae and tumour giant cells. Most common sites of involvement are lower end of femur and upper end of tibia. Giant cell tumour occurs in patients between 20 and 40 years of age with no sex predilection. G/A Giant cell tumour is eccentrically located in the epiphyseal end of a long bone which is expanded. The tumour is well-circumscribed, dark-tan and covered by a thin shell of subperiosteal bone. Cut surface of the tumour is characteristically haemorrhagic, necrotic, and honey-combed due to focal areas of cystic degeneration. M/E the hallmark features of giant cell tumour are the presence of large number of multinucleate osteoclast-like giant cells regularly scattered throughout the stromal mononuclear cells: 1. Giant cells often contain as many as 100 benign nuclei and have many similarities to normal osteoclasts. Stromal cells are mononuclear cells and are the real tumour cells and their histologic appearance determines the biologic behaviour of the tumour. Typically, they are uniform, plump, spindle-shaped or round to oval cells with numerous mitotic figures. Other features of the stroma include its scanty collagen content, rich vascularity, areas of haemorrhages and presence of macrophages. Giant cell tumour of the bone has certain peculiarities which deserve further elaboration. These benign giant cell lesions are: chondroblastoma, brown tumour of hyperparathyroidism, reparative giant cell granuloma, aneurysmal bone cyst, simple bone cyst and metaphyseal fibrous defect (non-ossifying fibroma). The three are linked together by a common neuroectodermal origin and by a common cytogenetic translocation abnormality t(11; 22) (q24; q12). The common sites are shafts and metaphysis of long bones, particularly femur, tibia, humerus and fibula. Pattern the tumour is divided by fibrous septa into irregular lobules of closely-packed tumour cells. These tumour cells are characteristically arranged around capillaries forming pseudorosettes. Based on these cytological features the tumour is also called round cell tumour or small blue cell tumour. Other features the tumour is richly vascularised and lacks the intercellular network of reticulin fibres. Currently, use of combined regimen consisting of radiotherapy and systemic chemotherapy has improved the outcome greatly (5-year survival rate 40-80%). Notochord is the primitive axial skeleton which subsequently develops into the spine. Chordomas thus occur in the axial skeleton, particularly sacrum and coccyx (50%), spheno-occipital region (35%), and less often in the spine (15%). Chordoma is usually found in patients over the age of 40 years with no sex predilection.

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Syndromes have considerable clinical overlap, and it is often difficult to distinguish them (see Table 9. The most common of the myeloproliferative disorders, it shows no clear age predominance. Symptoms are related to higher blood viscosity and expanded blood volume and include dizziness, headache, tinnitus, blurred vision, and plethora. Erythromelalgia is frequently associated with polycythemia vera and is characterized by erythema, warmth, and pain in the distal extremities. Diagnostic criteria from the Polycythemia Vera Study Group are outlined in Table 9. Helpful medications include the following: Hydroxyurea or anagrelide to keep platelet count < 400,000; both medications have been shown to prevent thromboses. The current standard is to recommend low-dose aspirin in patients with erythromelalgia or other microvascular manifestations. B4: Characteristic bone marrow colony growth (almost never used) or low serum erythropoietin. Bone marrow biopsy is not necessary for diagnosis but is often done to determine the prognosis. The disease has three phases based on the percentage of blasts in peripheral blood: Chronic phase: Bone marrow and circulating blasts < 10%. Note the large number of immature myeloid forms in the peripheral blood, including metamyelocytes, myelocytes, and promyelocytes, as well as a large number of eosinophils and basophils. Major remissions can virtually always be achieved with imatinib mesylate (Gleevec). The durability of these responses remains uncertain, but after five years > 80% of patients remain in cytogenetic remission. Myelofibrosis (Agnogenic Myeloid Metaplasia) Fibrosis of bone marrow leading to extramedullary hematopoiesis (marked splenomegaly, bizarre peripheral blood smear). Note the large number of teardrop cells suggestive of bone marrow infiltrative disease. Splenectomy or splenic irradiation is appropriate if the spleen is painful or if transfusion requirements are unacceptably high. Essential Thrombocythemia A clonal disorder with elevated platelet counts and a tendency toward thrombosis and bleeding. Occasionally presents with erythromelalgia, pruritus, and thrombosis (at risk for both arterial and venous clots). Diagnosed by a persistent platelet count > 600,000 with no other cause of thrombocytosis. Not part of diagnostic criteria, but can be useful in distinguishing essential thrombocythemia from other causes of thrombocytosis. Consider platelet pheresis for elevated platelets with severe bleeding or clotting. Paraprotein: Depression of normal immunoglobulins leads to infections; excess protein may cause renal tubular disease, amyloidosis, or narrowed anion gap (due to positively charged paraproteins). Myeloma is characterized by purely osteolytic lesions, so bone scan is and alkaline phosphatase is normal. Autologous stem cell transplantation is sometimes done and appears to prolong survival. Amyloidosis A rare disorder characterized by the deposition of amyloid material throughout the body. Radiation therapy and/or orthopedic surgery for impending pathologic fractures in weight-bearing bones. Soft tissues: Macroglossia, carpal tunnel syndrome, "shoulder pad sign," "raccoon eyes.

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Osteogenesis imperfecta (brittle bone disease) this is a group of disorders of collagen metabolism causing bone fragility, with bowing and frequent fractures. In the most common form (type I), which is auto somaldominant,therearefracturesduringchildhood. Marfan syndrome Thisisanautosomaldominantdisorderofconnective tissue associated with tall stature, long thin digits (arachnodactyly),hyperextensiblejoints,ahigharched palate, dislocation (usually upwards) of the lenses of the eyes and severe myopia. British Society for Paediatric and Adolescent Rheumatology: Information about clinical guidelines and protocols. There is a genetic predisposi tion,withfirstandseconddegreerelativesoftenalso affected. Secondary headaches Raised intracranial pressure and space-occupying lesions Headachesoftenraisethefearofbraintumours;itmay well be the reason for parents to consult a doctor. Management Themainstayofmanagementisathoroughhistoryand examination with detailed explanation and advice. There is nothing medicine can do to cure this problembutthereismuchitcanoffertomakethebad spellsmorebearable. Summary History Premonitory symptoms, aura, character, position, radiation, frequency, duration, triggers, relieving and exacerbating factors? Seizures Aseizureisaclinicaleventinwhichthereisasudden disturbance of neurological function caused by an abnormal or excessive neuronal discharge. Febrile seizures Afebrileseizureisaseizureaccompaniedbyafeverin the absence of intracranial infection due to bacterial meningitis or viral encephalitis. Thisis morelikelytheyoungerthechild,theshorterthedura tion of illness before the seizure, the lower the tem peratureatthetimeofseizureandifthereisapositive familyhistory. Examination should focus on the cause of thefever,whichisusuallyaviralillness,butabacterial infection including meningitis should always be con sidered. Ifthere is a history of prolonged seizures (>5min), rescue therapywithrectaldiazepamorbuccalmidazolamcan besupplied. Commonest triggers are pain or discomfort, particularly from minor head trauma, cold food (such as ice-cream or cold drinks), fright or fever. Children may faint if in a hot and stuffy environment, on standing for long periods, or from fear. May sometimes lead to paroxysmal headache involving unsteadiness or light-headedness as well as the more common visual or gastrointestinal disturbance. In focal seizures, the level of consciousness may be retained,consciousnessmaybelost,ortheseizuremay befollowedbygeneralisedtonicclonicseizure. Inthe newclassification,theterms,simpleorcomplexordis cognitive are no longer used and the impairment of consciousnessisnotclassifiedbutdescribed. Epilepsy is a chronic neurological disorder character ised by recurrent unprovoked seizures, consisting of transient signs and/or symptoms associated with abnormal, excessive or synchronous neuronal activity in the brain. Aspecialistepilepsy nurse may assist families by providing education and continuing advice on lifestyle issues. Genetic studies will become increas ingly helpful as certain epilepsy syndromes are now knowntobeduetogeneticdeletionscausingabnor malitiesofsodiumandotherionchannels.

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High fat diet results in rise in the level of bile acids and their intermediate metabolites produced by intestinal bacteria which act as carcinogens. The low fibre diet, on the other hand, does not provide 146 Section I General Pathology adequate protection to the mucosa and reduces the stool bulk and thus increases the time the stools remain in the colon. These substances in normal amounts in the body act as antioxidants and protect the cells against free radical injury. Fatty change in liver only In starvation, first nutrient to be depleted in the body is: A. Maintenance of structure and function of epithelia Most active form of vitamin D is: A. The branch of science dealing with the study of developmental anomalies is called teratology. Certain chemicals, drugs, physical and biologic agents are known to induce such birth defects and are called teratogens. The morphologic abnormality or defect in an organ or anatomic region of the body so produced is called malformation. Aplasia is the absence of development of an organ with presence of rudiment or anlage. Hypoplasia is incomplete development of an organ not reaching the normal adult size. Developmental dysplasia is defective development of cells and tissues resulting in abnormal or primitive histogenetic structures. Anencephaly-spinabifidacomplex this is the group of anomalies resulting from failure to fuse (dystraphy). Thalidomide malformations Thalidomide is the best known example of teratogenic drug which was used as a sedative by pregnant women and resulted in high incidence of limb-reduction anomalies (phocomelia) in the 149 newborns. Foetal hydantoin syndrome Babies born to mothers on anti-epileptic treatment with hydantoin have characteristic facial features and congenital heart defects. Consumptionofalcoholbypregnantmotherinfirsttrimesterincreasesthe risk of miscarriages, stillbirths, growth retardation and mental retardation in the newborn. An inactive X chromosome in the somatic cells in females lies condensed in the nucleus and is called as sex chromatin seen specifically in the somatic cells in females. Nuclear sexing can be done for genetic female testing by preparing and staining the smears of squamous cells scraped from oral cavity, or by identifying the Barr body in the circulating neutrophils as drumstick appendage attached to one of the nuclear lobes. A minimum of 30% cells positive for sex chromatin is indicative of genetically female composition. Banding techniques include: i) G-banding (Giemsa stain); ii) Q-banding(quinacrinefluorescencestain); iii) R-banding (reverse Giemsa staining); and iv) C-banding (constitutive heterochromatin demonstration). Polyploidy is the term used for the number of chromosomes which is a multiple of haploid number. Aneuploidy is the number of chromosomes which is not an exact multiple of haploid number. Nondisjunction is the failure of chromosomes to separate normally during celldivisionduringfirstorsecondstageofmeiosis,orinmitosis. There are two main types of translocations: reciprocal in about two-third and Robertsonian in one-third cases: Reciprocal translocation Reciprocal translocation may be balanced (without any loss of genetic material during the exchange) or unbalanced (with some loss of genetic material). This translocation is termed Philadelphia chromosome seen in most cases of chronic myeloid leukaemia. Robertsonian translocation In this, there is fusion of two acrocentric chromosomes (having very short arms) at the centromere (centric fusion) with loss of short arms. With mapping of human genome consisting of about 30,000 genes, it is possible to perform molecular profilingofdiseasesatgeneticlevel. Mutations affecting germ cells are transmitted to the next progeny producing inherited diseases, while the mutations affecting somatic cells give rise to various cancers and congenital malformations. Presently, following types of mutations have been described: i) Point mutation is the result of substitution of a single nucleotide base by a different base. However, when both alleles of a gene pair are expressed in heterozygous state, it is called codominant inheritance.

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Clinical evaluation of circulating blood volume in critically ill patients-contribution of a clinical scoring system. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock, 2016. Which of the following is most correct regarding the use of colloid solutions for volume resuscitation in the critically ill? Colloid solutions help maintain lower intracranial pressure in patients with traumatic brain injury b. The total volume of colloids administered to achieve hemodynamic goals is less than that required for resuscitation with crystalloid solutions 2. A 63-year old male with a history of dyschezia (painful defecation) who is admitted with severe left flank pain. A 70-year old female who complained of hemoptysis status post right total knee replacement. When measured or observed correctly, which physical exam finding is most indicative of a depleted extracellular fluid volume (hypovolemia) due to severe diarrhea in a 40-year old woman? Ultrafiltration is a process by which water moves across a semipermeable membrane due to a trans-membrane pressure gradient. His postoperative course is complicated by acute kidney injury, respiratory failure, and hypotension. After 1 week, there is improvement in his hemodynamics and he is transitioned to conventional intermittent hemodialysis. Solute exchange across the semipermeable membrane occurs by either diffusion or convection. Diffusion is the movement of solutes from an area of high concentration to low concentration. Convection refers to the movement of solutes across a semipermeable membrane driven by the movement of a solvent across the membrane. Low-flux (cellulose-based) membranes have low water permeability and limit the size of solutes to less than 500 Daltons (small proteins and electrolytes). High-flux (synthetic-based) membranes have high water permeability and allow larger molecules (5,000-50,000 Daltons) to cross. Current guidelines suggest using the overall clinical picture as opposed to lab values. Hemodialysis utilizes the concept of diffusion to rid the blood of unwanted solutes. During hemodialysis, blood is pumped through an extracorporeal membrane where it is physically separated from a crystalloid solution (dialysate) by a semipermeable membrane. For example, bicarbonate moves from the dialysate to the blood (higher concentration in the dialysate) while urea and potassium move from the blood to the dialysate (lower concentration in the dialysate). The dialysate travels in a countercurrent direction to the blood; this maintains the solute concentration gradients and maximizes the efficiency of solute exchange. Hemodialysis typically employs low-flux membranes that have lower water permeability and allow small molecules and electrolytes to cross. With hemofiltration, blood is pumped through an extracorporeal system incorporating a semipermeable membrane. During this process, molecules small enough to pass through the membrane are dragged across the membrane along with the water molecules (convection). This is replaced by replacement fluid, which is adjustable in volume and composition, but usually consists of glucose, electrolytes, and a buffer (bicarbonate, citrate, lactate, etc). These membranes are more permeable to water and have larger pores allowing large molecules (5,000-50,000 Daltons) to cross. Hemodiafiltration exploits concepts common to both hemofiltration and hemodialysis with benefits of each; however, to a lesser extent than when the individual techniques are used alone. In hemodiafiltration, blood is pumped through a extracorporeal system where it is separated from a dialysate solution by a semipermeable membrane. Hydrostatic pressure is applied to the blood-side of the membrane, forcing water into the dialysate/ultrafiltrate as in hemofiltration. During ultrafiltration, hydrostatic pressure is applied to the blood-side of the membrane (or negative pressure is applied to the opposite side of the membrane) and water transverses the membrane. Rapid solute removal from the intravascular space can result in cerebral edema limiting this modality for patients with head trauma or hepatic encephalopathy.

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There are small capillary angiectases throughout the gastrointestinal tract, including the buccal mucosa and tongue. There is systemic activation of coagulation pathways that leads to formation of fibrin clots, which may cause organ failure, together with consumption of platelets and coagulation factors, which may result in bleeding. Transfusions of platelet, plasma or factor concentrates may be used to prevent or stop bleeding. Chronic myeloid leukaemia this usually presents in middle age, often insidiously with anaemia, weight loss and fever. White cell count is markedly raised with myeloid precursors in the marrow and peripheral blood. In over 90% of patients leucocytes contain the Philadelphia chromosome, a translocation of the breakpoint cluster region (bcr) gene on the long arm of chromosome 22 to a position adjacent to the c-abl gene on chromosome 9. Leukaemia this refers to malignant proliferation of bloodforming cells and is broadly classified according to. Symptoms, if present, include lethargy, anorexia, weight loss, fever, night sweats and pruritus. Infiltration of bone marrow with lymphoblastic cells causes anaemia, bruising (thrombocytopenia) and infections (neutropenia). Lymphoblasts are usually present in the peripheral blood and always in the marrow. Chronic lymphatic leukaemia this occurs in the elderly with a generalised lymphadenopathy and a raised white cell count with lymphocytosis. It usually follows a benign course and treatment is only indicated if symptoms develop. Treatment is with chemotherapy, radiotherapy or a combination of the two depending on clinical, radiological and histological staging. Myeloma There is malignant proliferation of a specific clone of plasma cells resulting in the production of a monoclonal immunoglobulin known as a paraprotein. Bone destruction from the expanding plasma cell clone causes pain, fractures and hypercalcaemia. Normochromic anaemia, thrombocytopenia and leukopenia (infections are common) occur as the normal bone marrow is replaced. Renal failure may result from hypercalcaemia or the presence of light chains, which may be nephrotoxic or become precipitated in tubules. Radiological involvement of bone is rare, but anaemia and a bleeding tendency occur. Management of haematological malignancies Management of haematological malignancies is under continuous review, and many patients are entered into multicentre trials. Patients should be treated in units with specialist experience of the drug regimens and supportive treatment, including transfusions and antibiotics. Cytotoxics (to destroy rapidly dividing cells) are used alone or in combination with radiotherapy. In some cases induction of remission by intensive chemotherapy is followed by bone marrow transplantation. They reduce fertility in males (consider sperm storage) and may be associated with premature menopause in females. They are teratogenic, but there does not appear to be an increase in fetal abnormalities in patients who are fertile after treatment. Bone marrow depression is common and prolonged use is associated with an increased incidence of acute non-lymphocytic leukaemia. The monoclonal antibody is detected as a discrete M band on plasma protein electrophoresis. Free immunoglobulin light chains may be detectable in the urine (Bence Jones proteins are urinary light chains that precipitate on heating to 56 C and redissolve on boiling).

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Used for meningococcal prophylaxis and chemoprophylaxis in contacts of children with Haemophilus influenzae type B. Minor hepatotoxicity and drug interactions (cytochrome P-450); orange body fluids (nonhazardous side effect). Pyrazinamide is a prodrug that is converted to the active compound pyrazinoic acid. Multidrug-resistant P aeruginosa, multidrug-resistant Acinetobacter baumannii: polymyxins B and E (colistin). Cryptococcus (amphotericin B with/without flucytosine for cryptococcal meningitis), Blastomyces, Coccidioides, Histoplasma, Candida, Mucor. Systemic fungal infections (especially meningitis caused by Cryptococcus) in combination with amphotericin B. Inhibit fungal sterol (ergosterol) synthesis by inhibiting the cytochrome P-450 enzyme that converts lanosterol to ergosterol. Testosterone synthesis inhibition (gynecomastia, especially with ketoconazole), liver dysfunction (inhibits cytochrome P-450). Dermatophytoses (especially onychomycosis-fungal infection of finger or toe nails). Oral treatment of superficial infections; inhibits growth of dermatophytes (tinea, ringworm). Teratogenic, carcinogenic, confusion, headaches, disulfiram-like reaction, cytochrome P-450 and warfarin metabolism. Treatment of plasmodial species other than P falciparum (frequency of resistance in P falciparum is too high). Beginning therapy within 48 hours of symptom onset may shorten duration of illness. Obstructive crystalline nephropathy and acute renal failure if not adequately hydrated. Bone marrow suppression (leukopenia, neutropenia, thrombocytopenia), renal toxicity. Nephrotoxicity, electrolyte abnormalities (hypo- or hypercalcemia, hypo- or hyperphosphatemia, hypokalemia, hypomagnesemia) can lead to seizures. Disinfection and sterilization Autoclave Alcohols Chlorhexidine Hydrogen peroxide Iodine and iodophors Goals include the reduction of pathogenic organism counts to safe levels (disinfection) and the inactivation of self-propagating biological entities (sterilization). Major topics such as inflammation and neoplasia appear frequently in questions across different organ systems, and such topics are definitely high yield. For example, the concepts of cell injury and inflammation are key to understanding the inflammatory response that follows myocardial infarction, a very common subject of board questions. Similarly, a familiarity with the early cellular changes that culminate in the development of neoplasias-for example, esophageal or colon cancer-is critical. Finally, make sure you recognize the major tumor-associated genes and are comfortable with key cancer concepts such as tumor staging and metastasis. Intrinsic and extrinsic pathways; both pathways activate caspases (cytosolic proteases) cellular breakdown including cell shrinkage, chromatin condensation, membrane blebbing, and formation of apoptotic bodies, which are then phagocytosed. Characterized by deeply eosinophilic cytoplasm and basophilic nucleus, pyknosis (nuclear shrinkage), and karyorrhexis (fragmentation caused by endonuclease-mediated cleavage). Cell membrane typically remains intact without significant inflammation (unlike necrosis). Bcl-2 keeps the mitochondrial outer membrane impermeable and therefore prevents cytochrome c release from the inner mitochondrial matrix. Bcl-2 overexpression (eg, follicular lymphoma t[14;18]) caspase activation tumorigenesis. Mutations in Fas numbers of circulating self-reacting lymphocytes due to failure of clonal deletion. Pale infarct B Pale (anemic) infarcts B occur in solid organs with a single (end-arterial) blood supply, such as heart, kidney, and spleen. Inflammation Vascular component Cellular component Acute Characterized by rubor (redness), dolor (pain), calor (heat), tumor (swelling), and functio laesa (loss of function). Neutrophils extravasate from circulation to injured tissue to participate in inflammation through phagocytosis, degranulation, and inflammatory mediator release. Neutrophil, eosinophil, antibody (pre-existing), mast cell, and basophil mediated. Acute inflammation is rapid onset (seconds to minutes) and of short duration (minutes to days).

References:

  • https://www.niaid.nih.gov/sites/default/files/Trans-NIH-Hep-B-Strategic-Plan-2019.pdf
  • https://acgmeetings.gi.org/wp-content/uploads/2019/10/ACG2019_Final-Program.pdf
  • https://www.researchsquare.com/article/rs-1912/v1.pdf
  • https://slpemad.files.wordpress.com/2015/04/essentials-of-adhd-assessment-for-children-and-adolescents-sparrow-elizabeth-p-erhardt-drew.pdf
  • http://unmhospitalist.pbworks.com/f/Rhabdomyolysis.pdf
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