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Thalassemia Thalassemias are inherited disorders caused by mutations in globin genes that decrease the synthesis of α- or β-globin. Decreased synthesis of one globin results not only in a deficiency of Hb but also in red cell damage that is caused by precipitates formed from excess unpaired "normal" globin chains. The mutations that cause thalassemia are particularly common in Mediterranean, African, and Asian regions in which malaria is endemic. As with HbS, it is hypothesized that globin mutations associated with thalassemia protect against falciparum malaria. Pathogenesis A diverse collection of α-globin and β-globin mutations underlies the thalassemias, which are autosomal codominant conditions. Adult hemoglobin (HbA) is composed of two α chains and two β chains. α chains are encoded by two α-globin genes on chromosome 16. β chains are encoded by a single β-globin gene on chromosome 11. Clinical features vary widely depending on the combination of mutated alleles inherite...

Hereditary Spherocytosis This disorder stems from inherited (intrinsic) defects in the red cell membrane. Leads to formation of spherocytes — non-deformable cells that are highly vulnerable to sequestration and destruction in the spleen. Usually transmitted as an autosomal dominant trait . A more severe autosomal recessive form affects a small minority of patients. Pathogenesis Caused by inherited defects in the membrane skeleton , a network of proteins stabilizing the lipid bilayer of red cells. Major membrane skeleton protein: spectrin — a long, flexible heterodimer that: Self-associates at one end. Binds short actin filaments at the other. These interactions form a two-dimensional meshwork , connected to transmembrane proteins ( band 3 and glycophorin ) via linker proteins : ankyrin band 4.2 band 4.1 Most common mutations involve: ankyrin band 3 spectrin Pathogenic mutations: Weaken vertical interactions between the m...

Sickle Cell Anemia Hemoglobinopathies are a group of hereditary disorders caused by inherited mutations that lead to structural abnormalities in hemoglobin. Sickle cell anemia, the prototypic hemoglobinopathy, is caused by a mutation in B-globin that creates hemoglobin (HLS) . Numerous other hemoglobinopathies have been described, but these are infrequent and beyond the scope of this discussion. Sickle cell anemia is the most common familial hemolytic anemia. In parts of Africa where malaria is endemic, the gene frequency approaches 30% as a result of a protective effect against Plasmodium falciparum malaria. In the United States, approximately 8% of blacks are heterozygous HbS carriers, and about 1 in 600 have sickle cell anemia. Pathogenesis Sickle cell anemia is caused by a single amino acid substitution in β-globin that results in a tendency for deoxygenated HbS to self-associate into polymers. Normal hemoglobins are tetramers composed of two pairs of similar chains. On average, th...

Mechanisms of Viral Injury 1. Viral Tropism (Tissue and Cell Specificity) Host receptors for viruses Viruses are coated with surface proteins that bind with high specificity to particular host cell surface proteins. Entry of many viruses into cells commences with binding to normal host cell receptors. For example, HIV glycoprotein gp120 binds to CD4 and CXCR4 and CCR5 on T cells and macrophages. Host proteases may be needed to enable binding of the virus to host cells; for instance, a host protease cleaves and activates the influenza virus hemagglutinin. Specificity of transcription factors The ability of the virus to replicate inside particular cell types depends on the presence of lineage-specific transcription factors that recognize viral enhancer and promoter elements. For example, the JC virus, which causes leukoencephalopathy, replicates only in oligodendroglia in the CNS because the promoter and enhancer DNA sequences regulating viral gene expression are active in glial c...

 Von Willebrand disease Von Willebrand disease (VWD) is the most common inherited bleeding disorder. It occurs due to a deficiency or dysfunction of von Willebrand factor (vWF) — a protein that plays a critical role in blood clotting. Causes of Von Willebrand Disease Von Willebrand disease is primarily a genetic disorder , meaning it is usually inherited from one or both parents. The condition occurs when there is a deficiency or abnormal function of von Willebrand factor (vWF) , a protein that helps blood clot properly. This protein plays a key role in the initial stages of blood clotting by helping platelets stick to the walls of damaged blood vessels and stabilizing factor VIII, another important clotting protein. The most common form of the disease, Type 1 , is caused by a partial deficiency of vWF and is typically inherited in an autosomal dominant pattern , which means only one copy of the altered gene is enough to cause the disorder. Type 2 results from structural or func...

 Granulomatosis With Polyangiitis Previously called Wegener granulomatosis, granulomatosis with polyangiitis (GPA) is a necrotizing vasculitis charac-terized by a triad of the following: Necrotizing granulomas of the upper-respiratory tract (ear, nose, sinuses, throat) or the lower-respiratory tract (lung) or both Necrotizing or granulomatous vasculitis affecting small-to medium-sized vessels (e.g., capillaries, venules, arteri-oles, and arteries), most prominently the lungs and upper airways but other sites as well Focal necrotizing , often crescentic, glomerulonephritis.   "Limited" forms of disease can be restricted to the respi ratory tract. Conversely, when widespread the disease may affect the eyes, skin, and other organs, most notably the heart; clinically, widespread GPA resembles PAN with the additional feature of respiratory involvement. GPA is likely initiated as a cell-mediated hypersensitivity response to inhaled infectious or envirorimental antigens. PR3-ANCA...

 Polyarteritis Nodosa Polyarteritis nodosa (PAN) is a systemic vasculitis of small- or medium-sized muscular arteries; it typically involves the renal and visceral vessels and spares the pulmonary circulation. There is no association with ANCAS , but one-third of patients have chronic hepatitis B infection, which leads to the formation of immune complexes containing hepatitis B antigens that deposit in affected vessels. The cause is unknown in the remaining cases. Pathogenesis of PAN Immune complex–mediated vasculitis , often linked to Hepatitis B . Immune complexes deposit in medium-sized arteries. Activate the complement  system → recruit neutrophils . Causes fibrinoid necrosis and inflammation of the vessel wall. Leads to thrombosis , aneurysms , and organ ischemia . Not associated with ANCA . Morphology of PAN Classic PAN is a segmental transmural necrotizing inflammation of small- to medium-sized arteries, often with superimposed thrombosis. Kidne...

 Microscopic Polyangiitis Microscopic polyangiitis is a necrotizing vasculitis that generally affects capillaries, as well as small arterioles and venules. It also is called hypersensitivity vasculitis or leukocytoclastic vasculitis. Unlike in PAN (polyarteritis nodosa) , all lesions of microscopic polyangiitis tend to be of the same age in any given patient. The skin, mucous membranes, lungs, brain, heart, gastrointestinal tract, kidneys, and muscle all can be involved; necrotizing glomerulonephritis (seen in 90% of patients) and pulmonary capillaritis are particularly common Microscopic angiitis can be a feature of a number of immune disorders, such as Henoch-Schönlein purpura, essential mixed cryoglobulinemia, or the vasculitis associated with connective tissue disorders. In some cases, antibody responses to antigens such as drugs (e.g., penicillin), microorganisms (e.g., streptococci) , heterologous proteins, or tumor proteins have been implicated. These reactions can eithe...

 Kawasaki Disease Kawasaki disease is an acute, febrile, usually self-limited illness of infancy and childhood associated with an arteritis of mainly large- to medium-sized vessels. Approximately 80% of patients are younger than 4 years of age. Its clinical significance stems from the involvement of coronary arteries. Coronary arteritis can result in aneurysms that rupture or thrombose, causing myocardial infarction. Originally described in Japan, the disease is now recognized in the United States and elsewhere. In genetically susceptible individuals, a variety of infectious agents (mostly viral) have been posited to trigger the disease. The vasculitis may result from a delayed-type hypersensitivity response directed against cross-reactive or newly uncovered vascular antigen(s). Subsequent cytokine production and polyclonal B cell activation result in auto-antibodies to ECs and SMCs that precipitate the vasculitis. Morphology of Kawasaki disease Affects medium-sized arteries , es...

CLINICAL EXAMINATION OF SENSORY SYSTEM During examination of the sensory system, test various types of sensations.  Peripheral nervous system functions (PNSF) 1. Tactile sensibility 2 Pain 3. Temperature 4. Sense of position 5 Vibrations 6. Presence of any abnormal sensation Cortical sensory functions: 1. Point localization 2. Two point discrimination 3. Recognition of size, weight, shapes and form of objects (Sterorignotis) 4 Graph aesthesia 5. Extinction phenomenon Before starting the examination, introduce yourself and explain the nature of the test to be performed to the patient to get his full cooperation. The eyes should then be closed, and the test should elicit different forms of sensations. Always compare corresponding points on both sides of the body It routinely involves assessing the sensation of the hands, lower arms, abdomen, feet, and lower legs. Facial sensation is tested during the evaluation of cranial nerves PRINCIPLES OF SENSORY ASSESSMENT: The sensations are ev...

Pathogenesis of Polymyositis The pathogenesis of polymyositis involves a complex interplay of immune system dysfunction , autoimmunity , and muscle fiber damage . It is primarily considered a T-cell-mediated autoimmune disorder that targets muscle fibers , leading to chronic inflammation and muscle weakness. 1. Immune System Dysregulation Polymyositis is thought to be initiated by an abnormal immune response , where the body fails to recognize its own muscle tissues and begins attacking them. This response is primarily cell-mediated rather than antibody-mediated. 2. Role of CD8+ T-Cells Cytotoxic CD8+ T lymphocytes are the main effector cells. These T cells  recognize antigens presented on muscle fibers via MHC class I molecules , which are abnormally upregulated on the surface of muscle cells in polymyositis. The T cells then directly invade muscle fibers and release perforin and granzymes, leading to muscle cell necrosis (cell death). 3. Muscle Fiber Inju...

What is Polymyositis? Polymyositis is a rare, chronic inflammatory muscle disease that causes muscle weakness , particularly in the muscles closest to the trunk of the body , such as the shoulders, hips, and thighs. It is classified as an idiopathic inflammatory myopathy (IIM) , meaning its exact cause is unknown and it involves immune system-related muscle inflammation. Key Features of Polymyositis Symmetrical muscle weakness : Both sides of the body are affected equally. Progressive condition : Symptoms develop slowly over time. Primarily affects adults : Most common between ages 30 and 60. More common in women than in men. Causes and Risk Factors The exact cause of polymyositis is unknown, but it is considered an autoimmune disorder , where the body's immune system mistakenly attacks healthy muscle tissue. Possible triggers include: Viral infections Genetic predisposition Autoimmune reactions Other connective tissue diseases (e.g., lupus, rheuma...

  Clinical Features of Crohn’s Disease Crohn’s disease is a chronic inflammatory condition of the gastrointestinal (GI) tract, and its clinical features vary depending on the site , severity , and extent of the disease. The presentation may be gradual or acute, with both intestinal and extraintestinal symptoms. 1. Gastrointestinal (Intestinal) Symptoms Symptom Description Chronic diarrhea Often watery, may contain mucus or blood (especially if the colon is involved) Abdominal pain Usually crampy and localized in the right lower quadrant (ileum area) Weight loss Due to malabsorption and reduced intake Fever Especially during flare-ups Fatigue From chronic inflammation and anemia Nausea and vomiting If the upper GI tract or small bowel is involved Tenesmus Feeling of incomplete bowel evacuation (common with rectal involvement) Rectal bleeding Less common than in ulcerative colitis but may occur Fistulas Abnormal connections between b...

  Morphology of Crohn’s Disease The morphology of Crohn’s disease refers to the structural and microscopic changes observed in the gastrointestinal (GI) tract during the disease. These changes can be seen through gross examination (macroscopy) and microscopic (histological) analysis. Crohn’s disease shows distinct morphological features that help differentiate it from other types of inflammatory bowel diseases, especially ulcerative colitis .  1. Gross Morphology (Macroscopic Features) Key Macroscopic Features of Crohn’s Disease : Feature Description Segmental involvement ("skip lesions") Diseased segments are interspersed with normal bowel segments Transmural inflammation Inflammation involves the entire thickness of the bowel wall Thickened bowel wall Due to inflammation, edema, fibrosis, and muscular hypertrophy Cobblestone appearance Mucosal ulcerations with raised areas of edematous tissue give a cobblestone-like look Fissures and ulcer...

What is Crohn’s Disease? Crohn’s disease is a type of Inflammatory Bowel Disease (IBD) that causes chronic inflammation of the gastrointestinal (GI) tract. It can affect any part of the digestive tract , from the mouth to the anus , but most commonly involves the end of the small intestine (ileum) and the beginning of the colon . Unlike ulcerative colitis (another form of IBD), Crohn’s disease affects all layers of the intestinal wall and can occur in patches , leaving normal tissue between inflamed areas. This is called a "skip lesion" pattern.  Key Features of Crohn’s Disease Type : Chronic autoimmune condition Location : Can affect any part of the GI tract (commonly ileum and colon) Pattern : Patchy (skip lesions) Depth of Inflammation : Transmural (affects all layers of the bowel wall)  Causes and Risk Factors The exact cause is unknown, but several factors contribute: Genetic predisposition (e.g., NOD2 gene mutations) Immune system dysfunct...

  Pathogenesis of Inflammatory Bowel Disease (IBD) The pathogenesis of Inflammatory Bowel Disease (IBD) —which includes Crohn’s disease and ulcerative colitis —is complex and multifactorial. It involves a combination of genetic predisposition, environmental triggers, dysregulation of the immune system, and alterations in the gut microbiome. Here's a detailed breakdown of the key mechanisms involved:  1. Genetic Susceptibility IBD tends to run in families, indicating a strong genetic component. Over 200 genetic loci have been associated with IBD, especially: NOD2 gene mutations (strongly linked with Crohn’s disease) IL23R , ATG16L1 , and other genes affecting immune response and autophagy These mutations impair the immune system’s ability to handle intestinal bacteria properly.  2. Immune System Dysregulation In IBD, the immune system overreacts to harmless gut microbes or self-antigens. This results in chronic inflammation of the intestin...