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Urinary Porphyrins the urine for porphyrin examination must be alkalinized because porphyrins readily precipitate in acid urine pain treatment with antidepressants generic 5 mg rizact with mastercard. Place 5ml urine in a 250-ml separatory funnel and add 5ml acetate buffer (four parts glacial acetic acid: 1 part saturated sodium acetate) and adjust pH to 4 florida pain treatment center miami fl buy 10 mg rizact visa. Most of the porphyrins in urine are in the form of their nonfluorescent precursors pain treatment lupus purchase rizact 5 mg visa. Storage of the urine for 24 h in a refrigerator will enhance their conversion to the fluorescent pigments pain treatment west plains mo rizact 5 mg amex. Summary In summary advanced pain treatment center union sc rizact 10 mg sale, the synthesis of porphyrins acute pain treatment guidelines order 10 mg rizact overnight delivery, heme, and globin can only occur in those respiring cells with full complements of mitochondrial and cytosolic enzymes. Therefore, the reticulocyte with its residual complement of enzymes can synthesize hemoglobin, but the mature erythrocyte, which is devoid of mitochondrial enzymes, cannot. The color of the fluorescence cannot be used to distinguish between the uroporphyrins and the coproporphyrins, and, therefore, these must be separated before examination for fluorescence. The separation procedures are based on the solubility differences of the porphyrins in various organic solvents. Therefore, fluorescence in the aqueous urinary phase indicates the presence of uroporphyrins. Fecal Porphyrins the screening test as described for urine can also be used with fecal samples after prior extraction with strong acid. The mixture is next diluted to 200ml with water, filtered, and the filtrate examined for porphyrins as described for urine. Blood Porphyrins Almost all porphyrins in blood are present in the erythrocytes, and only trace amounts are in plasma. Therefore, it is important to use whole blood in the test and to understand that the test is a measure of the porphyrin content of the erythrocytes. Mix 2ml heparinized whole blood and 6ml ethyl acetate:glacial acetic acid (4:1) in a glass centrifuge tube. Stir thoroughly, centrifuge, and pour off the supernate into a second centrifuge tube. Normally, there will only be a trace of fluorescence so that more than a trace indicates an abnormal concentration. Depending on the fundamental biochemical defect, the porphyrias can be broadly classified on the basis of their tissue of origin, the erythropoietic system, or the liver. The term porphyrinuria is used to define those acquired conditions in which the principal, if not the sole, porphyrins being excreted are the coproporphyrins. Excess coproporphyrin excretion is observed in a wide variety of conditions including infections, hemolytic anemias, liver disease, and lead poisoning. The screening test for coproporphyrinuria has been especially useful for detecting exposure to lead. Many systems for classifying porphyrias have been devised, and most are based on the defect in the tissue of origin, the erythropoietic system, or the liver. There is general agreement on the classification of the erythropoietic forms, but there is still some uncertainty as to the classification of the hepatic forms. These have been classified on the basis of their clinical manifestations, heredity, porphyrins excreted, and their enzymatic defects (Elder and Sheppard, 1982; Hindmarsh, 1986; Sassa, 2006; Sassa and Kappas, 2000). Each of the enzymatic defects has now been described on a molecular level in humans, and they have been summarized by Sassa and Kappas (2000). The genes have been cloned, and it is now known that there is a great deal of genetic heterogeneity, which presumably accounts for the wide variety of disease manifestations in each of the porphyrias. Methods are also available for the experimental production of the two major types of porphyria. Porphobilinogen the Watson and Schwartz test for porphobilinogen is reliable for screening (Watson and Schwartz, 1941). Next, 5ml chloroform are added, shaken vigorously in a separatory flask, and allowed to separate. The porphobilinogen aldehyde formed in the test is insoluble in chloroform and will remain in the lower aqueous phase. If the pink color is due to urobilinogen, it will be extracted into the chloroform phase. Porphobilinogen is found characteristically in the urine of patients with hepatic forms of porphyria, forms that have not been reported in animals. Classification By convention, the term porphyria is used to define those disease states that have a hereditary basis and increased Inheritance: A abbreviations. A hepatic form can be produced with sedormid (allylisopropylacetylcarbamide) (Schmid and Schwartz, 1952), dihydrocollidine (Granick and Urata, 1963), or hexachlorobenzene. Discolorations of this type have been observed in cattle at slaughter since the turn of the century, and these cattle are presumed to have had the disease. The first living cases were encountered in South Africa in a herd of grade Shorthorn cattle. The disease has been seen primarily in Holsteins with a few cases in Shorthorns and Jamaican cattle. The simple Mendelian autosomal recessive heredity of the disease was established by the study of the genealogy of the affected cattle and by breeding experiments. The affected homozygotes are characterized by discoloration of the teeth and urine, photosensitivity of the light areas of the skin, and generalized lack of condition and weakness. The condition is present at birth, and severely affected calves must be protected from sunlight if a state of health is to be maintained. The predominant symptoms of teeth and urine discoloration and the photosensitization of the severely affected animal are readily apparent, and a tentative diagnosis can be confirmed by the orange-red fluorescence of the teeth and urine when examined with near ultraviolet light or a Woods lamp. The symptomatology of affected animals, however, may vary from minimal to severe and with age and season. The discoloration of the teeth may vary in the same breed, being more pronounced in the young and less apparent in the older animals. Porphyrin deposits are heavily concentrated in the dentine so the occlusal surfaces should also be examined. If porphyrins are present, the discoloration and the fluorescence of the dentine will be readily detected. The degree of photosensitization will vary with the amount of porphyrin deposition in the dermis, coat color, density of the coat, and extent of exposure to sunlight. At times, loss of condition may be the only outward symptom for which the veterinarian is called. These may range from minimal to thousands of micrograms in the same animal so that the urine color may vary widely. The variations observed in this disease indicate the dynamic state of flux of porphyrin metabolism in the living animal, and the porphyrin deposits constitute a part of this dynamic state. Distribution of Porphyrins Some normal values for the porphyrins in animals are given in Table 8-4. These values are to be considered as best approximations obtained from a relatively few animals. The figures, however, indicate the very low concentrations of the free porphyrins normally found in the body. Thus, the finding of porphyrins in greater than trace amounts is always significant. Porphyrin concentrations in porphyric cows and calves are given in Table 8-5 (Kaneko and Mills, 1970). Bile and Feces Bovine fecal porphyrins may be derived from two sources: the bile and from chlorophyll of the food. The porphyrins derived from chlorophyll are excluded by the usual analytical method. Plasma and Erythrocytes Only traces of free porphyrins are normally present in the plasma and in the erythrocytes. The deposition of porphyrins throughout the bones and soft tissues is readily apparent at postmortem of severe cases by the generalized discoloration. A reddish brown discoloration is most apparent in the teeth, bones, and bone marrow. Discoloration of skin, muscle, heart, liver, and kidney is also observed but only a part is due to porphyrins. The discoloration is likely due to other porphyrin derivatives and to hemoglobin staining. Hematology the hematological picture of the majority of reported cases is one of a responsive hemolytic anemia. In general, the degree of response is correlated with the severity of the hemolytic anemia. A consistent monocytosis has been observed (Kaneko, 1963; Rhode and Cornelius, 1958), but this remains unexplained. There is a markedly decreased M:E ratio in the presence of the anemia, indicating a marked bone marrow hyperplasia. The presence of porphyrins in the nucleated erythrocytes is clearly evident by examination of unfixed and unstained bone marrow smears with a fluorescent microscope. They also reported that the fluorescence was seen only in morphologically abnormal nucleated erythrocytes that contained abnormal nuclear inclusions. The presence of two populations of erythrocytes was reported in humans, but this was attributed to the intermittent hemolytic crises that occurred (Gray et al. Nucleated erythrocyte counts during the first 24 h of life ranged from 5000 to 63,500l. The persistent reticulocytosis is thought to be due to a delay in maturation of the reticulocytes (Rudolph and Kaneko, 1971; Smith and Kaneko, 1966). This delay in maturation of the reticulocyte, which is proportional to the degree of anemia, is now a well-established phenomenon during the reticulocyte response to a blood loss or hemolytic anemia. In essence, this delay represents the increase in survival time of the reticulocyte beyond its normal 1-day survival time. There is general agreement that this shortening of life span is associated with the hemolytic process, but the mechanism of the hemolysis remains obscure. The shortest erythrocyte survival time of 27 days (normal 150 days) was associated with the highest erythrocyte coproporphyrin concentration. The porphyrins through their lipid solubility are presumed to damage the erythrocyte membrane leading to the hemolysis. In vivo 59Fe metabolic studies were completely compatible with a hemolytic type of anemia, and ineffective erythropoiesis. Plasma iron turnover and transfer rates, erythrocyte iron uptake, and organ uptakes were increased as expected in a hemolytic process. The mechanism of cell damage has also been studied in reticulocytes and in nucleated erythrocytes. The T1/2 for the maturation of the reticulocyte was 50 h compared to a normal of 3 to 10 h. This delay in reticulocyte maturation is thought to be the direct result of the defect in heme synthesis, because the rate of heme synthesis controls the rate of maturation of the reticulocyte (Schulman, 1968). This means that there is an increase in the reticulocyte survival time inversely proportional to the degree of anemia. Therefore, the more mature erythrocytic cells are the cells most affected by the high porphyrin content. This is not surprising because heme and hemoglobin synthesis are most active in the later stages of erythrocytic cell development. Ultimately, the accumulation of porphyrins in these cells, whether in bone marrow or in blood, induces hemolysis. Upon exposure of surface capillaries to sunlight, photohemolysis of the type observed in erythropoietic protoporphyria (Harber et al. This hemolytic mechanism might also explain the striking erythrogenic response seen in the neonatal porphyric calf. Because most of the porphyrins are within the fetal erythrocytes and these would not normally cross the placenta, the porphyrin containing erythrocytes would accumulate in the fetus and a profound hemolysis would occur in utero. This hemolysis in turn would induce a marked erythrogenic response in the fetus, and this is observed at birth. This is comparable to the rate of clearance of 14C-porphyrin into urine, which fell to 0. Furthermore, 3 weeks is also the time at which the erythrogenic response is stabilized at a steady state level in the neonatal calf (Kaneko and Mills, 1970). In summary, as a result of the heme synthetic defect in erythropoietic porphyria, there is excess porphyrin accumulation in the mature and developing erythrocytes, which induces their hemolysis in the circulation or in the bone marrow. There is a corresponding shortening of erythrocyte 252 Chapter 8 Porphyrins and the Porphyrias life span. In addition, the decrease in heme synthesis induces an increase in the survival time of the reticulocyte by inhibiting the maturation of the developing erythrocytes, which further aggravates the anemia. This biochemical defect in heme synthesis is morphologically expressed in the fluorocytes and in the evidence of erythrogenic response in the blood and bone marrow, the degree of which is directly related to the severity of the enzymatic defect of the porphyria. Previously, carrier animals were detectable only by the occurrence of the disease in their progeny. There is a compartmentation of the enzymes of heme biosynthesis between the mitochondria and the cytosol. Mitochondria are present only in the immature nucleated erythropoietic cells and in the reticulocytes. The most active heme and hemoglobin synthesis occurs in the metarubricyte and secondly in the reticulocyte. Thus, the relative activities of these enzymes govern the extent as to which of these pathways is traversed. In addition, the porphyrins are released into the circulation and are widely distributed throughout the body in all body fluids and are readily excreted in the feces and urine. When exposed to ultraviolet light, the porphyrins in the skin are excited by absorption of the ultraviolet light energy into an unstable higher-level energy state. The excitation energy is then emitted when the excited molecule returns to its ground state.
Fibrinogen synthesis is elevated in fasting cancer patients with an acute phase response back pain treatment options discount rizact 10 mg otc. Albumin turnover: experimental approach and its application in health and renal diseases home treatment for uti pain buy rizact 10 mg overnight delivery. Serum protein electrophoresis as a prognostic marker of chronic liver disease in dogs treatment for uti back pain purchase rizact 10 mg online. Development of an elisa based test for bovine haptoglobin using the monoclonalantibody hap1 pain treatment for rheumatoid arthritis generic rizact 10 mg otc. Cardiac troponin I: evaluation of a biomarker for the diagnosis of heart disease in the dog pain medication for dogs with kidney disease cheap rizact 5 mg visa. Development and validation of an enzyme-linked immunosorbent assay for feline trypsin-like immunoreactivity sacroiliac pain treatment options order rizact 5 mg fast delivery. Overestimation of canine albumin concentration with the bromcresol green method in heparinized plasma samples. Measurement of serum amyloid A in the neonatal foal using a latex agglutination immunoturbidimetric assay: determination of the normal range, variation with age and response to disease. Isolation, characterization and quantitative measurement of serum a1-acid glycoprotein in cattle. Preliminary studies of serum acute-phase protein concentrations in hematologic and neoplastic diseases of the dog. The physiological structure of human C-reactive protein and its complex with phosphocholine. Polyacrylamide-gel electrophoretic patterns of chicken serum in acute-inflammation induced by intramuscular injection of turpentine. Implication of clinical pathology in assessment of animal health and in animal production and meat inspection. Serum protein electrophoresis: guidelines for diagnosis evaluation in the dog, cat, and horse. Evaluation of a whole blood glutaraldehyde coagulation test for the detection of failure of passive transfer in calves. Widespread expression of serum amyloid A in histologically normal human tissues: predominant localization to the epithelium. Concentrations of serum amyloid A and lipopolysaccharide-binding protein in horses with colic. Growth of foals, body mass of mares and serum protein concentration of mares during the anovulatory, transitional and pregnant periods. Acutephase protein profile during gestation and diestrous: proposal for an early pregnancy test in bitches. Lipopolysaccharide binding protein and serum amyloid A secretion by human intestinal epithlial cells during the acute phase response. Strategies for proteomics with incompletely characterized genomes: the proteome of Bos taurus serum. Serum amyloid A in the serum and milk of ewes with mastitis induced experimentally with Staphylococcus epidermidis. Changes in serum orvotransferrin levels in chickens with experimentally induced inflammation and diseases. Cell-type-specific and inflammatory-induced expression of haptoglobin gene in lung. Canine parvovirus vaccine elicits protection from the inflammatory and clinical consequences of the disease. Gershwin Department of Pathology, Microbiology, and Immunology School of Veterinary Medicine University of California, Davis Davis, California I. Yet it is still involved with evaluation of the immune system of patients and the ability of the immune system to respond to antigenic stimuli. Assays developed to target specific parts of the immune system enable the clinician not only to determine if a patient has normal immune responsiveness but also to target those parts of the immune system that are suspect of inadequate function. Serology has historically been used to determine retrospectively if a patient were infected with a particular disease agent; antibody titers continue to have importance in diagnostics. Current technologies have created expanded opportunities to diagnose infectious, autoimmune, and allergic diseases with new tools. Yet growing concern that veterinarians may be overvaccinating their patients has provided a new incentive for the development of sensitive and specific immunoassays to measure the immune response to vaccine antigens. Another increasing trend since the previous edition of this book is the use of diagnostic flow cytometry. This technique can evaluate multiple parameters on cells using multicolor analysis. The current availability of antibodies to many cytokines makes it now possible to determine not only cell phenotype but also the intracellular cytokines being made. Production of monoclonal antibodies specific to some leukocyte antigens expressed on leukemic cells has allowed diagnosis of these conditions to be achieved through flow cytometry. Flow cytometry is currently being used for detection of autoantibodies to platelets and erythrocytes. Clinical Biochemistry of Domestic Animals, 6th Edition 157 158 Chapter 6 Clinical Veterinary Immunology test is often supplemented with more specific assays for evaluation of the presence of autoantibodies in animal patients. Diagnosis of allergic conditions is now commonplace because of the development of reagents and assays to measure IgE in dogs, horses, and cats. This chapter reviews some basic principles of immunology and presents current methodologies used in the clinical immunology laboratory. This division is based on the need for the host to have previously been exposed to the antigen/ pathogen in order to rapidly mount a protective response. Innate immunity does not require previous exposure to a pathogen for it to be effective. Innate immunity is a broad category that includes protective barriers such as skin and mucosa. Reflexes are included, such as the cough coupled with the anatomical/physiological function of the mucociliary apparatus, which moves inhaled material out of the respiratory system. Dogs with inherited ciliary dyskinesis have nonfunctional cilia and suffer from repeated respiratory infections because of their inability to remove inhaled particles (such as bacteria) from the lung. The initial responder to infection is usually the polymorphonuclear leukocyte or neutrophil. Dogs with inherited cyclic neutropenia develop cyclic bouts of bacterial disease that coincide with the episodes during which the bone marrow shuts down its production of these essential phagocytes. These animals develop even more critical disease because their defect is not cyclic, but constant. These calves generally succumb to overwhelming bacterial disease within the first 6 months of life. These experiments in nature demonstrate the importance of the innate defense provided by the neutrophil. This cell plays a role not only as a phagocyte, generally entering an area of inflammation after the neutrophil, but also as a vital link to the acquired immune response. As such they engulf a pathogen, digest it within a vacuole, and then display peptides generated from the engulfed organism on their cell surface. However, there is another cell type, the dendritic cell, that performs the antigen presentation function more efficiently than the macrophage. These cells are pivotal to induction of the acquired immune response and serve as an effecter for innate immunity. The need for acquired immunity is demonstrated by certain bacterial species that are able to live and divide after being ingested by a macrophage. These organisms, called facultative intracellular bacteria, are able to overcome the macrophage and prevent their own digestion in the phagosome. To overcome the infection, the macrophages infected with these bacteria require signals from cytokines that are secreted by T cells stimulated in an acquired immune response. Infection of cattle with Mycobacterium bovis subspecies paratuberculosis causes a chronic wasting disease because of the ability of the bacteria to overcome the killing function of the macrophages. The acquired immune response required for killing these organisms is discussed with cellular immunity. There is a population of lymphocytes that are neither T nor B cells; they lack the receptors for antigen recognition. Thus, once a host has encountered an antigen and initiated an immune response, the next time the antigen is encountered by that host, the response is more rapid and more robust. Acquired Immunity 159 be a protein (as in an injected biological or an ingested or inhaled protein). Initially an antigen is taken up by a dendritic cell and is carried in the lymph to a local lymph node. When the T cell with the appropriate receptor recognizes the antigenic peptide on the surface of the antigen-presenting cell, it binds and begins a process of activation. Ultimately the activated T cell secretes cytokines that enhance the development of the T cell response and others that stimulate the growth and differentiation of B lymphocytes. There are multiple signals involved in antigen stimulation of T and B lymphocytes; these are receptor binding, cytokine binding, and binding of co-stimulatory molecules. Once this has been accomplished, a B cell can differentiate into a plasma cell to make antibody with the same specificity as that which stimulated the original B cell. This latter group has the capacity to kill target cells that are infected with antigens, such as viruses. The Th1 cells assist in cellular immune responses, such as activation of the macrophages infected with facultative intracellular bacteria. The Th2 cells provide "help" to B cells by provision of cytokines and co-stimulatory molecules (as described earlier). This T cell help initiates clonal expansion into mature B cells and ultimately into memory B cells and plasma cells. The plasma cells are the end cell that makes the immunoglobulin (antibody) that is so important in humoral immunity. These Th1 and Th2 cells are primarily identified by the cytokines that they produce. The former activates T cells to divide and proliferate, and the latter activates macrophages to become more efficient killers. The T helper cell subsets were originally described in the inbred mouse, where the division between the two is distinct. However, in many of out bred species, such as humans and cattle, the distinction is less clear, with a T helper 1 or 2 skew more commonly identified than a complete polarization of the immune response. Humoral Immunity Electrophoretic separation of serum proteins separates the proteins into four broad categories: albumin, alpha globulins, beta globulins, and gamma globulins. The antibody activity is present in the gamma globulin fraction, with a slight amount in the beta fraction. These immunoglobulins are heterogeneous, having different molecular weights and functional properties. There are five classes (isotypes) of immunoglobulins: IgG, IgM, IgA, IgD, and IgE. They share a basic structure, which consists of four polypeptide chains bound together by disulfide bonds. Two of these chains are called light chains, because with a molecular weight of about 22K each they are lighter than the other two heavy chains (approximately 55K each). At the nitrogen terminal of the polypeptide chains on all four chains is a portion of variable amino acid sequences. The hinge region of the immunoglobulin provides for flexibility of the molecule for binding to antigenic epitopes. In the serum, IgG is the antibody class with the greatest concentration, approximately 1 to 2 g/100 ml, with some species differences (Tizard, 2008). IgG has a four polypeptidechain structure with a total molecular weight of 180,000 daltons. Immunoglobulin G is important in host defense because it can exit the vascular system and distribute throughout the extravascular tissue fluid where it has many protective functions. For example, IgG can agglutinate bacteria, causing them to clump; it can opsonize bacteria, by binding to the bacteria by the Fab fragment and to the phagocyte by receptors for the Fc fragment, thereby facilitating engulfment of the bacteria by the phagocyte. The complement system (a series of serum proteins to be discussed later in this chapter) can be activated by two IgG molecules bound near each other on a cell membrane and target cells can be lysed by this mechanism. This mechanism allows destruction of virus-infected cells by lymphocytes that lack specific antigen receptors. The ability of IgG to neutralize toxins, such as those produced by Clostridium tetani, is an important protective mechanism for bacterial diseases. Immunoglobulin M (IgM) is the first antibody to be synthesized in response to an immunogenic stimulus and is the first antibody seen in ontogeny. In serum, IgM is present in the second greatest concentration, generally between 100 and 400mg/100ml (species dependent). The structure of IgM consists of five of the basic four polypeptide units held together by a J chain. The large size of IgM (900,000 daltons) keeps it confined to the intravascular space. Even though in reality, because of steric hindrance, only five to seven of the antigen-binding sites are functionally active, this large capacity to bind antigens makes IgM an efficient antibody at agglutination, precipitation, opsonization, complement fixation, and virus neutralization. Immunoglobulin A exists primarily in two forms, as a monomer (160,000 daltons) in the blood-vascular compartment and in a dimeric secretory form (390,000 daltons). The dimeric form consists of two monomers, each containing a heavy chain (alpha) and a light chain. These are held together by J chain and include an additional component called secretory piece. The secretory piece is produced by mucosal epithelial cells and functions to assist in transport of IgA dimers from the lamina propria of the intestine through into the lumen where it then protects the IgA dimer from proteolysis by intestinal enzymes.
Viral enteritis damages the intestinal lining pain medication for dogs at home generic rizact 5 mg on-line, causing malabsorption and osmotic diarrhea chronic back pain treatment guidelines purchase rizact 5 mg visa. The associated inflammation results in release of mediators that cause excessive secretion pacific pain treatment center san francisco order 5 mg rizact with visa. The history should include the onset of diarrhea pain treatment a historical overview discount rizact 5 mg mastercard, number and character of stools pain medication for dogs dose discount rizact 5 mg online, estimates of stool volume pain treatment center of greater washington justin wasserman buy discount rizact 5 mg on-line, and presence of other symptoms, such as blood in the stool, fever, and weight loss. Recent travel and exposures should be documented, dietary factors should be investigated, and a list of medications recently used should be obtained. Physical examination should be thorough, evaluating for abdominal distention, tenderness, quality of bowel sounds, presence of blood in the stool or a large fecal mass on rectal examination, and anal sphincter tone. Laboratory testing should include stool culture and complete blood count if bacterial enteritis is suspected. If diarrhea occurs after a course of antibiotics, a Clostridium difficile toxin assay should be ordered; if stools are reported to be oily or fatty, fecal fat content or fecal elastase to test for pancreatic Differential Diagnosis the differential diagnosis is listed in Table 126-10. Functional constipation commonly occurs during toilet training, when the child is unwilling to defecate on the toilet. Retained stool becomes harder and larger over time, leading to painful defecation. This aggravates voluntary withholding of stool, with perpetuation of the constipation. Hirschsprung disease is characterized by delayed meconium passage in newborns, abdominal distention, vomiting, occasional fever, and foul-smelling stools. This condition is caused by failure of ganglion cells to migrate into the distal bowel, resulting in spasm and functional obstruction of the aganglionic segment. Only about 6% of infants with Hirschsprung disease pass meconium in the first 24 hours of life, compared with 95% of normal infants. Most affected babies rapidly become ill with symptoms of enterocolitis or obstruction. Affected older children do not pass large-caliber stools because of rectal spasm, and they do not have encopresis. Other causes of constipation include spinal cord abnormalities, hypothyroidism, drugs, cystic fibrosis, and anorectal malformations (see Table 126-10). A variety of systemic disorders affecting metabolism or muscle function can result in constipation. Children with developmental disabilities have a great propensity for constipation because of diminished capacity to cooperate with toileting, reduced effort or control of pelvic floor muscles during defecation, and diminished perception of the need to pass stool. Distinguishing Features Table 126-10 includes typical characteristics of the common causes of constipation. Not associated with large-caliber stools or encopresis Examination: Snug anal sphincter, empty, contracted rectum. Functional constipation is overwhelmingly the most common diagnosis in older patients. Constipation in older children often begins after starting school, when free and private access to toilets may be restricted. Use of some drugs, especially opiates and some psychotropic medications, also is associated with constipation. For a few specific causes of constipation, directed diagnostic testing can make the diagnosis. A narrowed, aganglionic distal bowel and dilated proximal bowel on barium enema suggests Hirschsprung disease. Rectal suction biopsy confirms the absence of ganglion cells in the rectal submucosal plexus, with hypertrophy of nerve fibers. Most children with constipation have functional constipation and do not have any laboratory abnormality. Examination reveals normal or reduced anal sphincter tone (owing to stretching by passage of large stools). Fecal impaction is usually present, but a large-caliber, empty rectum may be found if a stool has just been passed. In these patients, no testing other than a good physical examination is necessary. Young children with painful defecation must have a prolonged course of stool softener therapy to alleviate fear of defecation. The child should be asked to sit on the toilet for a few minutes on awakening in the morning and immediately after meals, when the colon is most active and it is easiest to pass a stool. Use of a positive reinforcement system for taking medication and sitting on the toilet is helpful for younger children. Distinguishing Features Red substances in foods, beverages, or medications (such as cefdinir) occasionally can be mistaken for blood. A history of cough and examination of the mouth, nostrils, and lungs is needed to exclude these as a source of hematemesis. Blood in the toilet or diaper may be coming from the urinary tract, vagina, or even a severe diaper rash. When dark clots or melena are seen mixed with stool, a higher location is suspected, whereas bright red blood on the surface of stool probably is coming from lower in the colon. The location and hemodynamic significance of the bleeding can also be assessed by history and examination. Assessment of the vital signs including orthostatic changes when bleeding volume is large, pulses, capillary refill and assessment of pallor of the mucous membranes provides valuable information. Laboratory assessment and imaging studies should be ordered as indicated (Table 126-12). Oxygen should be administered and the airway protected with an endotracheal tube if massive hematemesis is present. Frequent reassessment should continue to ensure maintenance of physiological stability. Drugs with anticholinergic properties diminish saliva production and increase the risk of dental caries and parotitis. Excessive fluoride in vitamin preparations or in drinking water can result in mottled teeth. Gingival hypertrophy may be caused by cyclosporine, phenytoin, and calcium channel blockers. Neonatal hyperbilirubinemia can result in bluish discoloration of the deciduous teeth. Congenital syphilis causes marked abnormalities in the shape of teeth, especially incisors and molars. Abnormal pigmentation of the lips and buccal mucosa is seen with Peutz-Jeghers syndrome and Addison disease. Leukemic infiltrates result in gum hyperplasia and bleeding; treatment of neoplastic conditions can cause severe mucositis. Some tumors, including lymphoma, may present as mass lesions of the buccal cavity. Disorders resulting in facial dysmorphism can have a profound effect on dental occlusion and mandibular function. Examples include mandibulofacial dysostosis, Crouzon syndrome, conditions associated with dwarfism, and others. The sequence of replacement is similar to that of the appearance of deciduous teeth. Bacteria (Streptococcus mutans) that can adhere to and colonize the teeth, survive at low pH, and produce acids during fermentation of carbohydrates cause dental caries. This condition results when infants are allowed to have a bottle in the mouth for prolonged periods, especially during sleep, and with sweet beverages or milk in the bottle. Bacteria then have continuous substrate for acid production and can destroy multiple teeth, especially the upper incisors. Natal teeth are present at birth, are usually supernumerary, and may be poorly attached. Usually, no treatment is necessary, but removal by a dentist may be needed if they are causing difficulties with feeding or injuries to the tongue. The lower central incisors are typically the first to erupt, followed by the upper central incisors, lateral incisors, first molars, and bicuspids. Delayed eruption may occur in association with hypopituitarism, hypothyroidism, osteopetrosis, Gaucher disease, Down syndrome, cleidocranial dysplasia, and rickets. Deciduous teeth begin to be replaced by the permanent teeth at around age 6 Risk of caries is associated with lack of dental care and poor socioeconomic status and, predictably, is greatest in developing countries. If the damage is severe, a protective crown may be required; extraction of the tooth may be necessary when not salvageable. If not properly treated, dental decay results in inflammation and infection of the dental pulp and surrounding alveolar bone, which can lead to abscess and facial space infections. Prevention Avoiding inappropriate use of bottles and excessive sweets is a commonsense remedy for baby bottle caries. Oral hygiene 430 Section 17 u the Digestive System offers some protection, but young children (<8 years old) do not have the ability to brush their own teeth adequately; brushing should be done by the parents. Fluoride supplementation of community water supplies to a concentration of 1 ppm is highly effective in reducing dental caries. Home water supplies, such as from a well, should have the fluoride content tested before supplements are prescribed. If the child spends part of the day at another location, the total fluoride concentration from all sources must be considered before prescribing any oral supplements. Excessive fluoride supplementation causes fluorosis, a largely cosmetic defect of chalky white marks and brown staining of the teeth. Thrush in healthy older patients can occur, but should suggest the possibility of an immunodeficiency, broad-spectrum antibiotic use, or diabetes. Clefting occurs with two possible patterns: isolated soft tissue cleft palate or cleft lip with or without associated clefts of the hard palate. Isolated cleft palate is associated with a higher risk of other congenital malformations. Thrush is easily visible as white plaques, often with a "fuzzy" appearance, on oral mucous membranes. When scraped with a tongue depressor, the plaques are difficult to remove, and the underlying mucosa is inflamed and friable. Clinical diagnosis is usually adequate, but may be confirmed by fungal culture or potassium hydroxide smear. Oropharyngeal candidiasis is sometimes painful (especially if associated with esophagitis) and can interfere with feeding. Treatment Etiology Cleft lip is due to hypoplasia of the mesenchymal tissues with subsequent failure of fusion. There is a strong genetic component; the risk is highest in children with affected first-degree relatives. Monozygotic twins are affected with only 60% concordance, suggesting other nongenomic factors. Environmental factors during gestation also increase risk, including drugs (phenytoin, valproic acid, thalidomide), maternal alcohol and tobacco use, dioxins and other herbicides, and possibly high altitude. Chromosomal and nonchromosomal syndromes are associated with clefting, as are specific genes in some families. Thrush is treated with topical nystatin or an azole antifungal agent such as fluconazole. Because thrush is commonly self-limited in newborns, withholding therapy in asymptomatic infants and treating only persistent or severe cases is a reasonable approach. When present, palatal defects allow direct communication between the nasal and oral cavities, creating problems with speech and feeding. Management includes squeeze-bottle feedings, special nipples, nipples with attached shields to seal the palate, and gastrostomy in severe cases. Surgical treatment is effective, but sometimes does not restore palatal function completely. Speech therapy or, occasionally, the use of a speech-assisting appliance may help. Frequent episodes of otitis media are common, as are defects of teeth and the alveolar ridge. Chapter 128 nutrition and have no signs of respiratory complications or esophagitis. As infants grow, they spend more time upright, eat more solid foods, develop a longer and larger diameter esophagus, have a larger and more compliant stomach, and experience lower caloric needs per unit of body weight. Data typically are gathered for 24 hours and analyzed for the number and temporal pattern of acid reflux events. Esophageal impedance monitoring records the migration of electrolyte-rich gastric fluid in the esophagus. Endoscopy is useful to evaluate for esophagitis, esophageal stricture, and anatomic abnormalities. In severe cases of esophagitis, there may be laboratory evidence of anemia and hypoalbuminemia secondary to esophageal bleeding and inflammation. When severe symptoms persist despite medication, or if life-threatening aspiration is present, surgical intervention may be required. In children with a severe neurologic defect who cannot tolerate oral or gastric tube feedings, placement of a feeding jejunostomy may be considered as an alternative to fundoplication. In older children, lifestyle changes should be discussed, including cessation of smoking, weight loss, not eating before bed or exercise, and limiting intake of caffeine, carbonation, and high-fat foods. However, proton pump inhibitor therapy is more effective in reducing symptoms and healing.
The lumen of the neural tube forms the ventricles of the brain and the central canal of the spinal cord pediatric pain treatment guidelines generic rizact 5 mg on line. Most brain malformations are produced by a variety of injuries occurring during a vulnerable period of gestation opioid treatment guidelines journal of pain order 10 mg rizact. Precipitating factors include chromosomal pain wrist treatment buy rizact 5 mg free shipping, genetic joint pain treatment in urdu order rizact 10 mg, and metabolic abnormalities; infections (toxoplasmosis lower back pain treatment videos rizact 5 mg mastercard, rubella best treatment for pain from shingles generic 10 mg rizact amex, cytomegalovirus, herpes); and exposure to irradiation, certain drugs, and maternal illness during pregnancy. In a meningocele, the spinal canal and cystic meninges are exposed on the back, but the underlying spinal cord is anatomically and functionally intact. In spina bifida occulta, the skin of the back is apparently intact, but defects of the underlying bone or spinal canal are present. Meningoceles and spina bifida occulta may be associated with a lipoma, dermoid cyst, or tethering of the cord to a thick filum terminale. Patients may also have an associated dermoid sinus, an epithelial tract extending from the skin surface to the meninges; this increases the risk of meningitis. Patients with spina bifida occulta or meningocele may have weakness and numbness in the feet that can result in recurrent ulcerations, or difficulties controlling bowel or bladder function that may result in recurrent urinary tract infections, reflux nephropathy, and renal insufficiency. In diastematomyelia, a bone spicule or fibrous band divides the spinal cord into two longitudinal sections. An associated lipoma that infiltrates the cord and tethers it to the vertebrae may be present. After birth, screening ultrasound may be used with magnetic resonance imaging to confirm less dramatic underlying spinal abnormalities. Toddlers and children with lower spinal cord dysfunction require physical therapy, bracing of the lower extremities, and intermittent bladder catheterization. In the absence of associated brain anomalies, most survivors have normal intelligence, but learning problems and epilepsy are more common than in the general population. Spina bifida can be prevented in many cases by folate administration to the pregnant mother. Because the defect occurs so early in gestation, all women of childbearing age are advised to take oral folic acid daily. Treatment and Prevention Defective closure of the caudal neural tube at the end of week 4 of gestation results in anomalies of the lumbar and sacral vertebrae or spinal cord called spina bifida. The latter severe defect, called a myelomeningocele, results Defective closure of the rostral neural tube produces anencephaly or encephaloceles. Neonates with anencephaly have a rudimentary brainstem or midbrain, but no cortex or cranium. Patients with encephalocele usually have a skull defect and exposure of meninges alone or meninges and brain. Within a family, an anencephalic birth may be followed by the birth of a child affected with a lumbosacral myelomeningocele. Agenesis of the corpus callosum may be partial or complete and may occur in an isolated fashion or in association with other anomalies of cellular migration. Dandy-Walker malformation is diagnosed on the basis of the classic triad: complete or partial agenesis of the cerebellar vermis, cystic dilation of the fourth ventricle, and enlarged posterior fossa. There may be associated hydrocephalus, absence of the corpus callosum, and neuronal migration abnormalities. Intelligence may be normal or impaired, depending on the degree of associated cerebral dysgenesis. Holoprosencephaly represents varying degrees of failure of the forebrain (prosencephalon) to divide into two distinct cerebral hemispheres. Holoprosencephaly is often associated with midline facial defects (hypotelorism, cleft lip, cleft palate). This anomaly may be isolated or associated with a chromosomal or genetic disorder. The prognosis for infants with severe (alobar) holoprosencephaly is uniformly poor, but those with milder forms (semilobar, or lobar) may have less severe neurological outcomes. Children with trisomy 13 and trisomy 18 characteristically have varying degrees of holoprosencephaly. Hydranencephaly is a condition in which the brain presumably develops normally, but then is destroyed by an intrauterine, probably vascular, insult. Children may have a normal external appearance at the time of birth, but do not achieve developmental milestones. Macrocrania (increased skull thickness) Achondroplasia Hypochondroplasia Fragile X syndrome Osteopetrosis Chronic, severe anemia Hydrocephalus (enlargement of the ventricles; see Chapter 184) Masses Cysts Arteriovenous malformations Subdural fluid collections/hematoma Neoplasm Megalencephaly (enlargement of the brain) Embryologic disorder causing abnormal proliferation of brain tissue Neurofibromatosis Tuberous sclerosis Sturge-Weber syndrome Sotos syndrome Riley-Smith syndrome Hemi-megalencephaly Accumulation of abnormal metabolic substances Alexander disease Canavan disease Gangliosidoses Mucopolysaccharidoses Benign causes Benign extracerebral collections of infancy Familial macrocephaly Macrocephaly and Microcephaly Macrocephaly represents a head circumference above the 97th percentile and may be the result of macrocrania (increased skull thickness), hydrocephalus (enlargement of the ventricles; see Chapter 184), or megalencephaly (enlargement of the brain). Megalencephaly may be the result of a significant disorder of brain development or an accumulation of abnormal metabolic substances (Table 1871). Most often, however, macrocephaly is a familial trait of no clinical significance. Myriad syndromes and metabolic disorders are associated with microcephaly, some of which are hereditary (Table 187-2). Brain growth is rapid during the perinatal period, and any insult (infectious, metabolic, toxic, vascular) sustained during this period or during early infancy is likely to impair brain growth and result in microcephaly. Rarely, a small head is the result of premature closure of one or more skull sutures, called craniosynostosis. As a rule, macrocephaly and microcephaly raise a concern about cognitive ability, but head circumference alone should never be used to establish a prognosis for intellectual development. Disorders of Neuronal Migration Many malformations result from the failure of normal migration of neurons from the periventricular germinal matrix zone to the cortical surface at 1 to 5 months of gestation. Neurologic development with these anomalies varies and depends on the type and extent of the malformation. Schizencephaly is characterized by clefts within the cerebral hemispheres that extend from the cortical surface to the ventricular cavity. Unilateral clefts can cause isolated congenital hemiparesis, whereas bilateral schizencephaly causes spastic quadriparesis and associated intellectual disability. A severe defect in cortical migration, lissencephaly results in a smooth brain without sulcation (agyria). Affected children have difficult-to-control seizures and profound developmental retardation. Sometimes pachygyria and polymicrogyria affect an entire hemisphere, producing enlargement of that hemisphere and a clinical syndrome of severe, medically intractable seizures that begin in early infancy. Gray matter heterotopias are abnormal islands within the central white matter of neurons that have never completed the migratory process. James Dowling for his generous help in preparing Chapter 182 on weakness and hypotonia. The most common cutaneous diseases encountered in community settings are dermatophytosis, acne vulgaris, seborrheic dermatitis, atopic dermatitis (eczema), verrucae (warts), tumors, psoriasis, vitiligo, and infections such as herpes simplex and impetigo. In children attending pediatric dermatology clinics, atopic dermatitis, impetigo, tinea capitis, acne vulgaris, verrucae vulgaris, and seborrheic dermatitis are the most common diagnoses. A descriptive nomenclature of skin lesions helps with generating a differential diagnosis and also with communication between health care providers. Determination of the primary lesion and secondary change is the cornerstone of dermatologic diagnosis. A primary lesion is defined as the basic lesion that arises de novo and is most characteristic of the disease process (Table 188-1 and. Obtaining an accurate description of the original lesion improves diagnostic accuracy. Patients often do not consider a topical antibiotic or anti-itch medication as treatment. Other important information includes a history of allergies, environmental exposure, travel history, previous treatment, affected contacts, and family history. Mucous membranes, hair, nails, and teeth, all of ectodermal origin, also may be involved in cutaneous disorders and should be assessed. A search for the primary lesion often proves worthwhile and focuses the differential diagnosis to a category of lesion that is specific for the underlying diagnosis. In most cases, secondary lesions are the residue, or result, of the effects of the primary lesion. They may be created by scratching or secondary infection and may be seen in the absence of a primary lesion (Table 188-2). The color, texture, configuration, location, and distribution of the lesion should be recorded. A localized or grouped eruption may suggest a cutaneous infection, whereas widespread, symmetrical involvement of extensor surfaces may suggest a primary skin disorder, such as psoriasis. Lesions on mucous membranes are usually short-lived, and lesions in thick-skinned areas, such as the palms and soles, may be particularly difficult to characterize. The biopsy specimen can be accomplished by either shave or punch biopsy, and both are simple, in-office procedures. Acne is caused by chronic inflammation of the pilosebaceous unit (hair follicle with an associated sebaceous gland). The primary event in all acne lesions is the development of the micro-comedo, which results from the obstruction of the hair follicle with keratin, increased sebum production from sebaceous glands, and overgrowth of normal skin flora, leading to pilosebaceous occlusion and enlargement. The subsequent inflammatory component and pustule formation results from proliferation of Propionibacterium acnes, a commensal organism of the skin. The pathogenesis of acne thus involves three components: increased sebum production, hyperkeratosis, and bacterial proliferation. The incidence is similar in both sexes, although boys often are more severely affected. Superficial plugging of the pilosebaceous unit results in noninflammatory small (1- to 2-mm) open (blackhead) and closed (whitehead) comedones. Larger, skin-colored or red cysts and nodules represent deeper plugging and cystic acne. Increased and persistent inflammation, especially with rupture of a deep cyst, increases the risk of scarring. The diagnosis of acne is usually not difficult because of the characteristic and chronic lesions. Laboratory studies and imaging studies are usually not necessary to diagnose acne. Screening tests may be necessary if there are signs of hyperandrogenism due to polycystic ovarian syndrome (irregular menses, hirsutism, insulin resistance) or an underlying androgen-secreting tumor (irregular menses, hirsutism, deepening voice, clitoromegaly). The mainstays of treatment of acne are topical keratolytic agents and topical antibiotics. Gels and solutions are commonly used because acne skin is generally greasier and these agents tend to be drying, but they have the tendency to be irritating and may not be as well tolerated. The keratolytic agents (salicylic acid, azelaic acid, tretinoin, adapalene, tazarotene) produce superficial desquamation and, subsequently, relieve follicular obstruction. The topical retinoids (tretinoin, adapalene, tazarotene) are based on the vitamin A molecule. They decrease keratin and sebum production and have some anti-inflammatory and antibacterial activity; thus they can be the most effective when used as monotherapy. Topical antimicrobials (benzoyl peroxide, dapsone, sulfur-sulfacetamide) and topical antibiotics (erythromycin, clindamycin) are anti-inflammatory and inhibit P. Combination therapy of a topical keratolytic agent and a topical antimicrobial is more effective than either agent alone for inflammatory acne. Oral antibiotics (tetracycline, doxycycline, minocycline) are typically used for deeper cystic lesions but should always be used in combination with a topical regimen. Tetracyclines are the most effective antibiotics because of their significant anti-inflammatory activity. As with topical erythromycin, oral erythromycin is rarely used because of bacterial resistance. For recalcitrant or severe nodulocystic acne, oral isotretinoin may be instituted. Because of the high incidence of adverse effects, it should be used only by physicians familiar with this medication. Isotretinoin therapy requires careful patient selection, pretreatment counseling, and monthly laboratory monitoring. Acne lesions often heal with temporary postinflammatory erythema and hyperpigmentation. Depending on the severity, chronicity, and depth of involvement, pitted, atrophic, or hypertrophic scars may develop. Cystic acne has the highest incidence of Chapter 190 scarring because rupture of a deep cyst induces the greatest inflammation, though scarring may be caused by milder pustular or even comedonal acne. There are no effective means for preventing acne, and there is little evidence that diet is associated with acne. Repetitive cleansing with soap and water or use of astringents or abrasives removes only surface lipids. Their use makes the skin appear less oily but does not prevent formation of microcomedones and may paradoxically worsen acne. It is associated with significant psychosocial morbidity and decreased health-related quality of life. For many affected individuals, atopic dermatitis is the skin manifestation of atopy accompanied by asthma and allergic rhinitis. Atopic dermatitis manifests with a defective skin barrier, reduced innate immune responses, and exaggerated immune responses to allergens and microbes. Both genetic predisposition and environmental factors play a role in the development of atopic dermatitis. Genes associated with skin barrier dysfunction and inflammation have been linked with atopic dermatitis. Langerhans cells, IgE, and eosinophils play a prominent role, as well as many other inflammatory mediators. Environmental and contact allergens, infections, irritants, extremes of temperature, sweat, and lack of humidity can exacerbate the condition, as can scratching or rubbing.
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