By I. Merdarion. Westmont College.
B symptoms may be present (fever >38C super cialis 80mg without prescription erectile dysfunction due to old age, drenching night sweats buy discount super cialis 80 mg on line erectile dysfunction doctors near me, weight loss of Prognosis more than 10% within 6 months). The staging of Hodgkin s s disease is accord- ing to the Ann Arbor system, which is sufxed by B if Chronic myelogenous Leukaemia Bsymptoms are present and A if they are absent (see See Myeloproliferative disorders page 482. Microscopy Non-Hodgkin s lymphoma Classical Reed-Sternberg cells are large cells with a pale cytoplasm and two nuclei with prominent nucleoli said Denition to resemble owl eyes. Incidence r Mixedcellularity disease which mainly affects older 20 per 100,000 per year. Tumours arise due therapy or a combination depending on the stage of to multiple genetic lesions affecting proto-oncogenes Table12. Clinical features r Indolent: Most patients present with painless slowly Prognosis progressive lymphadenopathy. Lymph nodes may re- Indolent lymphomas have a predicted median survival duce in size spontaneously making it difcult to dis- time of 5 10 years. B symp- sponsive to chemotherapy but have a predicted median toms (fever >38 C, drenching night sweats, weight survival 2 5 years. On Paraproteinaemias examination there is lymphadenopathy and hep- atosplenomegaly. The cells are trophic to the skin particularly the hands and feet, and result Age in plaques and lumps of associated with generalised Most commonly diagnosed 60 65 years. Gas- trointestinallymphomaisparticularlycommoninthe Pathophysiology MiddleEastandisalsoseeninassociationwithcoeliac There is expansion of a single clone of plasma cells that disease. Cleavage of these immunoglobulins tribution according to the Ann Arbor system, which result in the production of Fab and Fc fragments; the Fab is sufxed by B if B symptoms are present (see fragment is termed the Bence-Jones protein and is found Table 12. Investigations There is also production of osteoclast stimulation fac- Thediagnosisismadebylymphnodebiopsy,cytogenetic tor causing lytic bone lesions, bone pain and hypercal- studies of lymphoma cells may give prognostic informa- caemia. Spinal cord compression occurs in approx- imately 10 20% of patients at some time during Pathophysiology the course of disease. Hypercalcaemia causes thirst, The abnormal proliferation of lymphoplasmacytoid polyuria, constipation and abdominal pain. Investigations The diagnosis of myeloma is made if there are: Clinical features r Bone marrow aspirate has at least 10 15% plasma Hyperviscosity presents as weakness, tiredness, confu- cells. Patients also often have peripheral lymphadenopa- Other investigations include: thy. Chemotherapy with single alkylating agents improves r Protein electrophoresis shows an IgM parapro- prognosis. Recently, thalidomide has been demonstrated to produce a signicant response Management in 30% of patients whose disease progressed following Chemotherapy produces a variable response. Supportive care includes blood transfu- pheresis is used for symptomatic hyperviscosity. Investigations Sex Electropheresis of serum protein demonstrates a raised X linked; males only affected. Aetiology Mutations on the X chromosome including deletions, Management frame shifts and insertions. One third of cases are new Aproportionofpatients will go on to develop multi- mutations. Clinical features Type 1 and 2 causes mild disease with bleeding following Investigations injury, menorrhagia and epistaxis. Type 3 causes spon- r Activated partial thromboplastin time is raised, but taneous bleeding from early life. Clinical features Investigations Similar to haemophilia A with mild deciency causing r Coagulation studies reveal prolonged clotting times only bleeding post surgery and trauma. Activated partial thromboplastin time is raised, but correctablewith50%normalserum(i. Patients re- quire supportive care and normally are managed in in- Management tensive care units. Denition Deciency of vitamin K, a fat-soluble vitamin, leads to a Disseminated intravascular bleeding tendency. Deciency occurs in obstructive jaundice and cer- widespread generation of brin within blood vessels and tain malabsorption syndromes. Vitamin K is also involved in Pathophysiology producing proteins required for bone calcication. Widespread activation of intrinsic, extrinsic pathways and platelet aggregation causes consumption of platelets Clinical features and clotting factors (a consumptive coagulopathy) re- Patients present with bruising, mucosal bleeding and sulting in a severe bleeding risk. Red cells are fragmented during Investigations passage through occluded vessels causing a micro angio- The prothrombin time and the partial thromboplastin pathic haemolytic picture. If given orally in malabsorption syndromes it must be performed to exclude leukaemia. Pre- vious response to intravenous immunoglobulin is sug- Acute immune thrombocytopenia gestive of a favourable outcome of splenectomy. Chronic idiopathic thrombocytopenia purpura Age Denition More common in childhood, peak onset 2 10 years. The cause is largely not understood but it may arise 1 4 weeks after a viral infection. Clinical problems only ders such as systemic lupus erythematosus and thyroid become apparent when the platelet count falls below disease. Clinical features Clinical features Children present with petechiae and supercial bruis- Patients present with easy bruising, purpura, epistaxis ing, however in severe cases mucosal bleeds occur such and menorrhagia.
Autoimmune diseases arise when such distinctions are lost and the immune system attacks self antigens generic 80 mg super cialis mastercard erectile dysfunction rates, a phenomenon originally described by Paul Erlich as horror autotoxicus cheap 80mg super cialis otc impotence at 35. Well-known examples include rheumatoid arthritis, psoriasis, systemic lupus erythematosus, and some forms of diabetes. Antigens can be divided into three general types immunogens, haptens, and tolerogens depending on the way in which they stimulate and interact with the immune system (2,3 and 4). An immunogen can, by itself, both stimulate an immune response and subsequently serve as a target of that response. The terms immunogen and antigen are often, but inappropriately, used interchangeably. However, if a hapten is attached to a larger immunogenic molecule (a carrier ), responses can be stimulated against both the carrier and the hapten, and the hapten itself can subsequently serve as the target of a response so invoked. A tolerogen is a substance that, after an initial exposure to the immune system, inhibits future responses against itself. Because of the genetic diversity among individuals, a substance that is an immunogen for one person may be a tolerogen for another and may be ignored completely by the immune system of still others. Antigens are usually protein or carbohydrate in nature and may be found as free single molecules or as parts of larger structures (e. Although some antigens are very small and simple, others are large and complex, containing many different sites that can be individually identified by lymphocyte receptors or free immunoglobulins. Each such individual part of an antigen that can be distinctly identified by the immune system is called an epitope or determinant (i. In general, the more complex the molecule and the greater the number of epitopes it displays, the more potent it is as an immunogen. Adjuvants are substances that, when administered together with an immunogen (or a hapten coupled to an immunogen), enhance the response against it ( 5). All immunoglobulins produced by a single B cell, or by a clonally derived set of B cells, have the same specificity and are able to recognize and bind only a single antigen or epitope ( 2,3 and 4). Immunoglobulin exists either as a surface membrane-bound molecule or in a secreted form by B cells that have been appropriately stimulated and matured. The immunoglobulin molecule is a glycoprotein composed of two identical light chains and two identical heavy chains ( Fig. Papain produces two antigen-binding fragments (Fab) and one crystallizable fragment (Fc). Together, the variable regions of the light and heavy chains contribute to the antigen-binding sites (Fab) of the immunoglobulin molecule. The constant regions of the heavy chain (particularly in the Fc portion) determine what subsequent interactions may occur between the bound immunoglobulin and other cells or molecules of the immune system. When the antigen-binding sites are filled, a signal is transmitted through the immunoglobulin molecule, which results in conformational changes in the Fc portion of the heavy chain. These conformational changes permit the Fc portion to then interact with other molecules and cells. The conformationally altered Fc may be recognized by receptors (Fc receptors [FcR]) on macrophages and other cells, which allow them to distinguish bound from unbound immunoglobulin molecules ( 7,8), increasing their efficiency of phagocytosis. Other conformational changes in the Fc portion of bound immunoglobulin permit the binding of complement component C1q to initiate the classic pathway of complement activation. Within a single immunoglobulin molecule, both light chains are identical and of the same type (both k or both l), and the two heavy chains are likewise identical and of the same isotype. IgD, IgG, and IgE exist only as monomeric basic immunoglobulin units (two heavy chains and two light chains), but serum IgM exists as a pentamer of five basic units united by a J (joining) chain. In passing through specialized epithelial cells to external fluids, it also adds a secretory piece, which increases its resistance to degradation by external enzymes ( 10). Immunoglobulin isotypes In addition to antigen-binding specificity, variability among immunoglobulin molecules derives from three further sources: allotypes, isotypes, and idiotypes. Allotypes are dictated by minor amino acid sequence differences in the constant regions of heavy or light chains, which result from slight polymorphisms in the genes encoding these molecules. Allotypic differences typically do not affect the function of the molecule and segregate within families like typical mendelian traits. Isotypes, as already discussed, are determined by more substantial differences in the heavy chain constant regions affecting the functional properties of the immunoglobulins ( 11) (Table 1. These differences within the antigen-binding domains of immunoglobulins that bind the same antigenic determinants are termed idiotypes. Generation of Antigen Binding Diversity among Immunoglobulins Each immunoglobulin chain, light and heavy, is encoded not by a single gene but by a series of genes occurring in clusters along the chromosome ( 11). In humans, the series of genes encoding k light chains, the series encoding l light chains, and the series encoding heavy chains are all located on separate chromosomes. All of the genes are present in embryonic and germ cells and in cells other than B lymphocytes. Each differentiating B cell chooses either the k series or the l series (but not both). In addition, although both the maternally and paternally derived chromosomes carry these sets of genes, each B cell uses only one of them ( either paternal or maternal) to produce a functional chain, a phenomenon termed allelic exclusion. In addition, each V gene is preceded by a leader sequence encoding a portion of the polypeptide that is important during the synthetic process but is removed when the molecule becomes functional. As with the light chain genes, each V gene is preceded by a leader sequence (L) that plays a role during synthesis but is subsequently lost. Thus, the surface immunoglobulin of nave unstimulated B cells includes only the IgM and IgD isotypes. As a result of the isotype switch, B-cell subclones are generated that produce an array of immunoglobulins that have identical antigen-binding specificity but different isotypes.
Deciency of niacin causes pel- Pyridoxine is important in the metabolism of amino lagra purchase super cialis 80 mg with amex erectile dysfunction drugs in kenya. In some rare metabolic disorders cheap 80mg super cialis fast delivery erectile dysfunction milkshake, pyridoxine deciency is as- Aetiology sociated with infantile convulsions and sideroblastic Niacin is found in plants, meat and sh. Deciency causes men- and Hartnup disease, an autosomal recessive congenital tal confusion, glossitis, dry skin lesions and peripheral disorder with reduced absorption of tryptophan from neuropathy. Management Pathophysiology Oral replacement; however, high doses may cause Nicotinic acid is involved in energy utilisation. Vitamin B12 deciency It is also used in maintaining skin, especially in sun- exposed areas. Vitamin C deciency Clinical features Pellagra is due to lack of nicotinic acid, it often occurs Denition as part of a more general nutritional deciency. Pellagra Vitamin C deciency causes scurvy, which was rst de- presents with dermatitis, diarrhoea and dementia. Genetic factors Occurs in the poor, pregnant or those on a peculiar may be involved in predisposing to the development of diet. Vitamin C brillogenesis and amyloidosis: (ascorbic acid) is found in citrus fruits, potatoes, green r Geneticmutationsresultinginproteinswithincreased vegetables and fortied fruit drinks. The precursor protein, the tissue distribution and the amount of amyloid deposited affect the clinical presen- Management tation. Deposition in the coronary arteries can lead Vitamin K deciency to ischaemic heart disease. This form of deposition is particularly seen many of which circulate as constituents of plasma. At least 21 different protein precursors of amyloid brils are now known (see Table 13. Investigations Besides systemic amyloid deposition, organ specic Where possible biopsy and histology is used to con- amyloid may occur in the skin or heart and most no- rm clinical suspicion. Familial amyloidosis Various Autosomal dominant inherited, including familial transthyretin-associated amyloidosis. Denition Management Theporphyriasaregeneticoracquireddecienciesinthe Therapy is aimed at the underlying cause where possi- activity of enzymes in the heme biosynthetic pathway. Differing manifestations such as renal failure require Aetiology/pathophysiology support. Inthehereditaryamyloidoseswheretheprecur- Heme is synthesised from succinyl Co A and glycine (see sor protein is produced by the liver, liver transplantation Fig 13. Enzyme deciencies result in increases in metabolic ing folic acid as a co-factor. It presents in adult life with muscle cell proliferation, activation of clotting factors abdominal pain, vomiting and constipation, polyneu- and a pro-aggregatory effect on platelets. Acuteepisodes also be a pro-inammatory effect by upregulating neu- areprecipitatedbyalcoholanddrugs. Urinary levels of Clinical features uroporphyrinogen (the substrate for the decient en- 1 Homocystinuria presents in childhood with devel- zyme)areraised. Other features include a Marfan s r Congenital erythropoietic porphyria is inherited in likesyndrome,ocularabnormalities,thromboembolic an autosomal recessive fashion. The photosensitivity that ischaemicheartdiseaseandstroke,althoughtheeffects results can be controlled with -carotene by an un- are less strong than those of, e. It is more strongly asso- ciated with an increased risk of pulmonary embolism and deep vein thrombosis. Hyperhomocysteinaemia Investigations Denition Homocysteine levels can be measured (normal be- Raised levels of homocysteine (an amino acid formed ing 5 15 mol/L, moderate 15 30 mol/L and severe by the conversion of methionine to cysteine) have been >100 mol/L). A methionine challenge can be given to associated with premature atherosclerotic disease. Increased folic acid intake reduces homocysteine lev- 2 Moderate homocysteinaemia occurs in approximately els. Causes include the following: B6 and vitamin B12 is advocated by some for those with r Genetic defects in enzymes involved in homocys- premature cardiovascular disease and recurrent venous teine metabolism. There is as yet no clear evidence that monly (approximately 10% of the population) is supplements should be given to all those with ischaemic avariant of methylene tetrahydrofolate reductase, heart disease, although several trials are in progress. G enetic syndrom es 1 Patterns of inheritance, 516 Incidence Patterns of inheritance Rises with increasing maternal age (1 in 3000 when mother is less than 30 years to 1 in 300 when mother Autosomal dominant:Mendelian pattern of inheritance is 35 40 years and 1 in 30 in women above 45 years). Be- where the presence of a single abnormal allele is able cause of the high birth rate in mothers below 35, half to produce the disease. There may be reduced expres- of all Down syndrome children are born to mothers sion of the condition if the condition does not have full below 35. Autosomal recessive: Mendelian pattern in which Age both genes must be defective to produce the clinical phe- Congenital. M = F There is no male-to-male transmission, daughters of an affected male will be obligate carriers. In X linked domi- Geography nant conditions, females may also demonstrate the clin- All ethnic communities. The additional chromosome 21 is usually follow normal Mendelian patterns of inheritance. In this (94% of cases) the result of non-disjunction of chromo- set of conditions males and females may be affected, but some 21 during the formation of the maternal ovum. In about 3% of cases there is mosaicism with some cells demonstrating a normal Down syndrome karyotype. Denition Pathophysiology Down syndrome is the clinical condition usually result- The Alzheimer s disease seen with Down syndrome is ing from a trisomy of chromosome 21 rst described by thought to be due to the presence of three copies of the Langdon Down in 1865. Chronic granulomatous Recessive Cytochrome Neutrophils can phagocytose material, but are unable disease b245 to generate respiratory burst and hence kill bacteria. Duchenne muscular dystrophy Recessive Dystrophin Progressive proximal muscle weakness with calf psuedohypertrophy.