Deborah K Armstrong, M.D.

• Director, Breast and Ovarian Surveillance Service
• Professor of Oncology

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0000590/deborah-armstrong

Increased Hb A2 levels are associated with increasing -globin gene deletions; the Hb F levels are not consistently affected antibiotics guidelines discount keftab online mastercard. Clinically infection from miscarriage cheap keftab 500mg fast delivery, the impact of -globin gene deletions on sickle cell is not as consistent as that of high Hb F treatment for dogs eye discharge order generic keftab line. There is a decreased incidence of leg ulcers but an increased incidence of osteonecrosis antibiotic sinus infection discount keftab online american express. The frequency of retinal vessel closure is higher but not the incidence of retinopathy antibiotic colitis buy keftab in india. Lorey F antimicrobial herbs and phytochemicals cheap keftab online american express, Cunningham G, Shafer F, et al: Universal screening for hemoglobinopathies using high-performance liquid chromatography: clinical results of 2. Consensus Conference: Newborn screening for sickle cell disease and other hemoglobinopathies. Saraf S, Farooqui M, Infusino G, et al: Standard clinical practice underestimates the role and significance of erythropoietin deficiency in sickle cell disease. Hord J, Byrd R, Stowe L, et al: Streptococcus pneumoniae sepsis and meningitis during the penicillin prophylaxis era in children with sickle cell disease. Ferster A, Tahriri P, Vermylen C, et al: Five years of experience with hydroxyurea in children and young adults with sickle cell disease. Locatelli F, Rocha V, Reed W, et al: Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Bouchair N, Manigne P, Kanfer A, et al: Prevention of sickle cell crises with multiple phlebotomies. Niederau C, Fischer R, Purschel A, et al: Long-term survival in patients with hereditary hemochromatosis. Pakbaz Z, Fischer R, Fung E, et al: Serum ferritin underestimates liver iron concentration in transfusion independent thalassemia patients as compared to regularly transfused thalassemia and sickle cell patients. Gulbis B, Haberman D, Dufour D, et al: Hydroxyurea for sickle cell disease in children and for prevention of cerebrovascular events: the Belgian experience. Weinfeld A, Swolin B, Westin J: Acute leukaemia after hydroxyurea therapy in polycythaemia vera and allied disorders: prospective study of efficacy and leukaemogenicity with therapeutic implications. Triadou P, Maier-Redelsperger M, Krishnamoorty R, et al: Fetal haemoglobin variations following hydroxyurea treatment in patients with cyanotic congenital heart disease. Dhar M, Bellevue R, Carmel R: Pernicious anemia with neuropsychiatric dysfunction in a patient with sickle cell anemia treated with folate supplementation. Amer J, Ghoti H, Rachmilewitz E, et al: Red blood cells, platelets and polymorphonuclear neutrophils of patients with sickle cell disease exhibit oxidative stress that can be ameliorated by antioxidants. Vichinsky E, Kleman K, Embury S, et al: the diagnosis of iron deficiency anemia in sickle cell disease. Maggio A: Light and shadows in the iron chelation treatment of haematological diseases. Vichinsky E, Onyekwere O, Porter J, et al: A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Greenberg J, Ohene-Frempong K, Halus J, et al: Trial of low doses of aspirin as prophylaxis in sickle cell disease. Godeau B, Schaeffer A, Bachir D, et al: Bronchoalveolar lavage in adult sickle cell patients with acute chest syndrome: value for diagnostic assessment of fat embolism. Zakaria N, Knisely A, Portmann B, et al: Acute sickle cell hepatopathy represents a potential contraindication for percutaneous liver biopsy. Powars D, Wilson B, Imbus C, et al: the natural history of stroke in sickle cell disease. Koshy M, Thomas C, Goodwin J: Vascular lesions in the central nervous system in sickle cell disease (neuropathology). Hoppe C, Klitz W, Cheng S, et al: Gene interactions and stroke risk in children with sickle cell anemia. Foucan L, Bourhis V, Bangou J, et al: A randomized trial of captopril for microalbuminuria in normotensive adults with sickle cell anemia. Clare A, FitzHenley M, Harris J, et al: Chronic leg ulceration in homozygous sickle cell disease: the role of venous incompetence. Koshy M, Entsuah R, Koranda A, et al: Leg ulcers in patients with sickle cell disease. Schleucher R, Gaessler M, Knobloch J: Rapid healing of a late diagnosed sickle cell leg ulcer using a new combination of treatment methods. Kumar S, Powars D, Allen J, et al: Anxiety, self-concept, and personal and social adjustments in children with sickle cell anemia. Hyposthenuria, hematuria, sudden death, rhabdomyolysis, and acute tubular necrosis. Christakis J, Vavatsi N, Hassapopoulou H, et al: A comparison of sickle cell syndromes in northern Greece. Friedman S, Schwartz E, Ahern E, et al: Variations in globin chain synthesis in hereditary persistence of fetal hemoglobin. Ebert Hemoglobinopathies are inherited diseases caused primarily by mutations affecting the globin genes. Nearly 1000 mutations are known to alter the structure, expression, or developmental regulation of individual globin genes and the hemoglobins that they encode. Many are highly instructive for students, of gene structure, function, and regulation, but further consideration of most is not warranted in a clinically oriented textbook. The gene mutations that cause sickle cell anemia and the thalassemia syndromes are by far the most important mutations that cause clinical morbidity, in terms of both the complexity of the clinical syndromes they cause and the number of patients affected. These conditions are considered in detail in other chapters (see Chapters 40, 41 and 42). This article reviews other abnormalities of the hemoglobin molecule that produce clinical syndromes. Even though each variant is uncommon, these hemoglobinopathies represent, in the aggregate, important problems for hematologists, because they must be considered as possible causes for conditions about which hematologists are often consulted: hemolytic anemia, cyanosis, polycythemia, jaundice, rubor, splenomegaly, and reticulocytosis. In some patients, secondary hematologic complications such as hypercoagulable states are also encountered. The major inherited hemoglobinopathies producing clinical symptoms (other than sickle cell anemia and thalassemias) can be classified as those hemoglobins exhibiting altered solubility (unstable hemoglobins), hemoglobins with increased oxygen affinity, hemoglobins with decreased oxygen affinity, and methemoglobins (Table 43. A few acquired conditions in which toxic modifications of the hemoglobin molecule are important. The sections that follow emphasize hemoglobinopathies that produce the most severe or dramatic alterations in clinical phenotype and those in which a single clinical abnormality. It is important to emphasize at the outset, however, that although more than 100 mutations affect solubility or affinity, only a few are clinically important. The abnormal functional properties of most mutant hemoglobins can be readily detected in sophisticated research laboratories, but only a few mutant hemoglobins produce laboratory or clinical abnormalities relevant to clinical practice. Moreover, many mutations are pleiotropic, affecting several functional properties of the hemoglobin molecule. Thus a single mutation can increase oxygen affinity and reduce solubility, or produce methemoglobinemia and reduce solubility. This table serves as a point of reference for the remaining sections of the chapter. This probably reflects the potential for -globin variants to exert pathologic effects in utero. Clinical symptoms of unstable hemoglobins also depend, in part, on the quantitative proportion of the abnormal hemoglobin. Because the -globin genes are duplicated, mutations in an individual locus generally produce only 25% to 35% abnormal globin. By contrast, a simple heterozygote at the single -globin locus usually produces approximately 50% of the abnormal variant. The common pathway to reduced solubility invariably involves weakening of the binding of heme to globin. Actual loss of heme groups can occur, for example, in Hb Gun Hill, in which five amino acids, including the F8 histidine, are deleted. In other cases, mutations that introduce prolines into helical segments disrupt the helices and interfere with normal folding of the polypeptide around the heme group. Another feature of these mutations is disruption of the integrity of the tetrameric structure of globin chains. Only the intact hemoglobin tetramer can remain dissolved at the high concentrations that must be achieved within the circulating red blood cell (see Chapters 30 and 40). The fundamental step in pathogenesis appears to be derangement of the normal linkages between heme and globin. Loss of appropriate globin chain folding and interaction may ultimately destabilize the hemeglobin linkage or lead to partial proteolysis of the chain, thereby releasing heme from that linkage. Once freed from its cleft, heme probably binds nonspecifically to other regions of the globin molecule, forming precipitated hemichromes, which leads to further denaturation and aggregation of the globin subunits. These form a precipitate containing - and -globin chains, globin fragments, and heme, called the Heinz body. Heinz bodies interact with delicate red blood cell membrane components (see Chapters 43 and 45), thereby reducing red blood cell deformability. These rigid cells tend to be detained in the splenic microcirculation and "pitted," reflecting attempts by the splenic macrophages to remove the Heinz bodies. Red blood cell damage can be aggravated by the release of free heme into the red blood cell. Several biochemical perturbations correlate with the presence of free heme, such as generation of reactive oxidants. AbnormalSolubility 6 GluVal 6 121 121 GluLys GluGln GluLys IncreasedOxygenAffinity 92 ArgGln J-Capetown 141 89 99 ArgHis SerAsn AspAsn Suresnes Creteil Kempsey DecreasedOxygenAffinity 94 AspAsn Titusville 102 102 AsnThr AsnSer Kansas Beth Israel Methemoglobin 58 HisTyr 87 28 63 67 92 HisTyr LeuGln HisTyr ValGlu HisTyr M-Boston, M-Osaka M-Iwate St Louis M-Saskatoon M-Milwaukee-I M-Hyde Park premature destruction of the red blood cell, producing hemolytic anemia. Individual unstable hemoglobins vary in their propensity to generate Heinz bodies and hemolysis. Hemolysis is minimal in nonstressed patients with this variant and becomes clinically apparent only in the presence of additional oxidant stresses, such as infection, fever, or the ingestion of oxidant agents. However, the rate of spontaneous mutation appears to be high, so the absence of affected parents or siblings does not rule out the presence of an unstable hemoglobin in an individual family. Nonetheless, the presence of a positive family history can be a useful adjunct to diagnosis and should provoke consideration of an unstable hemoglobin as the cause of the familial hemolytic diathesis. The clinical syndrome associated with unstable hemoglobin disorders is often called congenital Heinz body hemolytic anemia. This term derives from the fact that only the most severe cases were detected before the widespread availability of sophisticated methods Partial list includes some of the most widely studied hemoglobin structural mutations. Clinical manifestations are highly variable, ranging from a virtually asymptomatic state in the absence of environmental stressors, to severe hemolytic anemia manifesting at birth. Most of those that have been described occur on the -chain at invariant residue sites, near critical intermolecular contacts, or in proximity to the prosthetic heme-binding site. For hemoglobin variants with a given degree of reduced solubility, the degree of anemia may fluctuate because some of these variants also exhibit altered oxygen affinity. By contrast, Hb Hammersmith exhibits decreased oxygen affinity, improving oxygen delivery and allowing patients to function at a lower hematocrit level. Hb Zurich possesses, for complex molecular reasons, a higherthan-normal affinity for carbon monoxide. A high hemoglobin carbon monoxide level develops in patients with Hb Zurich who also smoke. Binding of carbon monoxide protects Hb Zurich from denaturation, thus reducing hemolysis, so these people tend to exhibit lesser degrees of hemolytic anemia than do nonsmoking relatives. Diagnosis the presence of an unstable hemoglobin should be suspected in patients with one or more stigmata of accelerated red blood cell destruction: chronic or intermittent hemolytic anemia or jaundice, premature development of bilirubin gallstones or biliary tract disease (as a result of accelerated red blood cell turnover), unexplained reticulocytosis, or bouts of intermittent symptoms that can be related to exposure to oxidant drugs or infections. Laboratory diagnosis depends on identification of a mutant hemoglobin that precipitates more easily than normal hemoglobin. Hemoglobin electrophoresis should be performed but should not be relied on as the major diagnostic criterion for ruling in or ruling out a hemoglobinopathy. Many amino acid substitutions that have a profound effect on solubility do not change the overall charge on the hemoglobin molecule. This mutation is electrically neutral; it does not alter electrophoretic mobility. A normal electrophoretogram, however, should never be regarded as strong evidence against the presence of a mutant hemoglobin, especially if the clinical picture or family history otherwise supports the diagnosis. Mass spectrometry analysis of hemoglobin and direct globin gene sequencing are supplanting electrophoresis as diagnostic strategies. Additional sophisticated analyses of hemoglobin can be obtained from reference laboratories if detailed characterization seems warranted. For example, abnormal hemoglobin or globin bands migrating to novel positions on an isoelectric focusing gel can result from hemoglobin or globin moieties lacking heme in groups. When heme is added to the sample and the proteins are reanalyzed, these bands disappear. Detection of unstable hemoglobins is occasionally compromised by the selective precipitation of the unstable variant into Heinz bodies. Because most patients are heterozygotes, this phenomenon greatly reduces the apparent percentage of the variant in soluble form. Thus even a variant possessing altered electrophoretic mobility may be very difficult to detect. Indeed, some unstable hemoglobins, such as Hb Geneva or Hb Terre Haute, are so unstable that no mutant gene product can be detected in the steady state. They are detectable only by isotope labeling studies or direct analysis of the globin genes.

At their distal ends bacteria jobs purchase keftab 750 mg with amex, SpD bind to the junctional complexes of oligomeric actin (band 5 [5]) and protein 4 antibiotic resistance of e.coli buy keftab no prescription. Additional proteins found in the junctional complex treatment for gardnerella uti cheap 750mg keftab amex, such as adducin and tropomyosin antibiotic natural alternatives order 750 mg keftab with mastercard, are shown in the lower enlarged area antibiotic resistance human microbiome purchase keftab amex. The membrane skeleton is attached to transmembrane proteins by interactions of -spectrin with ankyrin (protein 2 infection years after hip replacement purchase keftab 500 mg mastercard. These defects are detected by ultrastructural examination of the membrane skeleton, which reveals disruption of a normally uniform hexagonal lattice. Consequently, membrane skeletons are mechanically unstable, as are whole cell membranes and the cells. It is possible that elliptocytes and poikilocytes are permanently stabilized in their abnormal shape because the weakened spectrin heterodimer contacts facilitate skeletal reorganization, which follows axial deformation of cells resulting from application of a prolonged or excessive shear stress. This reorganization is likely to involve breakage of the unidirectionally stretched protein connections followed by the formation of new protein contacts that preclude the recovery of a normal biconcave shape. This process has been shown to account for permanent deformation of irreversibly sickled cells. They contain a mutant spectrin that characteristically disrupts spectrin heterodimer self-association, and they are also partially deficient in spectrin, as evidenced by a decreased spectrin/band 3 ratio. Such synthetic defect of -spectrin is fully asymptomatic in the heterozygous carrier, because under normal conditions, the synthesis of -spectrin is approximately three to four times greater than that of -spectrin. When present in conjunction with an elliptocytogenic mutation of -spectrin, such a synthetic defect augments the expression of the mutant spectrin. Because the elliptocytogenic -spectrin mutants are often unstable, the combination of the two defects leads to spectrin deficiency in the cells. In such cases, the spectrin deficiency may be a consequence of spectrin instability that reduces the amount of spectrin available for membrane assembly. Consequently, only approximately one-half of spectrin heterodimers succeed in attaching to the ankyrin-binding sites. Instead, the mechanical instability appears to be related to a concomitant partial deficiency of protein 4. The clinical severity is highly variable among different kindred (reflecting heterogeneous molecular lesions) and, to a lesser extent, within a given kindred, presumably because of other genetic or acquired defects that modify disease expression. In one kindred with a submicroscopic chromosome X deletion, inheritance was X-linked. These individuals were found to be either homozygotes or compound (double) heterozygotes for one or two - or -spectrin mutations. Hereditary Elliptocytosis With Sporadic Hemolysis Worsening of hemolysis together with the appearance of poikilocytes on the peripheral blood film has been reported in patients with hypersplenism, infections, or vitamin B12 deficiency, as well as in those with microangiopathic hemolysis such as disseminated intravascular coagulation or thrombotic thrombocytopenic purpura. The two principal determinants of severity of hemolysis are the spectrin content of the cells and the percentage of dimeric spectrin in the crude spectrin extract. The fraction of dimeric spectrin in such extracts in turn depends on several factors. Typically, mutations that are either within or near the combined triple-helical repetitive segment representing the spectrin heterodimer self-association site produce a more severe clinical phenotype and a more severe defect of spectrin function than those seen with point mutations in the more distant triple-helical repeats. Second, the percentage of the dimeric spectrin depends on the fraction of the mutant spectrin in the cells, which in turn is determined by the gene dose. The severity of the molecular defect, in terms of the percentage of spectrin dimers and the amount of mutant spectrin in the cells, is the same in the neonatal period as it is later in life. These abnormalities are located within the site at which spectrin monomers assemble into heterodimers (the spectrin heterodimer nucleation site). In vitro studies suggest that the inability of -spectrin chains to assemble into the mature membrane skeleton is because of a combination of decreased dimer-binding affinity and increased proteolytic cleavage of the mutant -spectrin chains. Conversely, coexistence of the -spectrin mutation in cis and the mutation involving the -spectrin nucleation site diminishes the propensity of the mutant allele to be incorporated into the spectrin heterodimer, thereby ameliorating the clinical severity of this mutation. Note the predominant elliptocytosis with some rod-shaped cells (arrow) and virtual absence of poikilocytes. Note the many elliptocytes, spherocytes, as well as numerous fragments and poikilocytes. The patient is a double heterozygote for a structural -spectrin mutant and a presumed -spectrin synthetic defect. If hemolysis is still active after splenectomy, folate should be administered daily. Serial interval ultrasonographic investigations to detect gallstones should be performed in patients with significant hemolysis. Among these peptides, the 80-kDa I domain peptide representing the selfassociation site of the normal -spectrin is among the most prominent. Nearly all - or -spectrin mutations reported are associated with a formation of tryptic peptides of abnormal size and mobility that are generated from the normal 80-kDa I domain peptide. The cleavage sites of the most common abnormal tryptic peptides are found in the third helix of a given triple-helical repetitive segment. The reported mutations reside in the vicinity of these cleavage sites either in the same helix or, less commonly, in helix 1 or 2 of a given repetitive segment. The condition is widespread in certain ethnic groups of Malaysia, Papua New Guinea, the Philippines, and Indonesia. A remarkable feature of ovalocytes is their resistance to in vitro invasion by several strains of malaria parasites, including P. The 56 Lys to Glu substitution represents an asymptomatic polymorphism known as band 3 Memphis. In normal 640 PartV RedBloodCells the band 3 protein, inability to transport sulfate anions, and a markedly restricted lateral and rotational mobility of band 3 protein in the membrane. A useful screening test is the demonstration of the resistance of ovalocytes or their ghosts to changes in shape produced by treatments that produce spiculation in normal cells, such as metabolic depletion or exposure of ghosts to salt solutions. Such particles cluster at the site of parasite invasion, forming a ring around the orifice through which the parasite enters the cell. Acanthocytosis was first described in cases of abetalipoproteinemia and subsequently in severe liver disease, the chorea-acanthocytosis syndrome, the McLeod blood group phenotype, and other conditions. The molecular mechanisms leading to acanthocytosis in abetalipoproteinemia and severe liver disease have been extensively studied and have been attributed to changes in composition of membrane lipids and their altered distribution between the two hemileaflets of the lipid bilayer. Cholesterol also alters membrane permeability and interacts with several membrane skeletal proteins, but the role of these changes in spur cell lesions is unclear. Peripheral blood smears from these patients often reveal target cells that are particularly prominent in obstructive jaundice. In some patients, particularly those with end-stage liver disease, anemia rapidly worsens and spur cells appear in high percentage in the peripheral blood. This is accompanied by worsening jaundice, rapid deterioration of liver function, hepatic encephalopathy, and hemorrhagic diatheses. A similar clinical syndrome has been described in patients with advanced metastatic liver disease, cardiac cirrhosis, Wilson disease, fulminant hepatitis, and infantile cholestatic liver disease. The development of spur cell hemolytic anemia is an ominous sign in most patients, predicting a survival seldom exceeding weeks to months. In theory, splenectomy could provide a marked improvement, because the spleen is the major sequestration site of nondeformable acanthocytes; in reality, splenectomy is seldom considered because of severity of the underlying liver disease. The plasma of patients with severe liver disease contains abnormal lipoproteins that have a high free cholesterol/phospholipid ratio. This extracholesterol accumulates preferentially in the outer bilayer leaflet, as suggested by findings of increased accessibility of cholesterol to cholesterol oxidase and a selective decrease in lipid fluidity of the outer hemileaflet of the lipid bilayer. Subsequently several investigators reported a congenital absence of -lipoprotein, accounting for the diverse manifestations of the disorder. Pathobiology Abetalipoproteinemia is an autosomal recessive disorder found in people of diverse ethnic backgrounds. The primary molecular defect involves a congenital absence of -apolipoprotein in plasma. The B apoproteins (B100 and B48) are generated by alternate transcription of a single gene residing on the short arm of chromosome 2. Erythrocytes have an expanded surface area with irregular contour and targeting, reflecting accumulation of free cholesterol in the membrane, preferentially in the outer bilayer leaflet. Splenic remodeling leads to increasing spheroidicity with longer and more irregular surface projections. In some patients this is because of qualitative or quantitative defects in the microsomal triglyceride transfer protein, which catalyzes the transport of triglyceride, cholesterol ester, and phospholipid from phospholipid surfaces. Microsomal triglyceride transfer protein is the only tissue-specific component, other than apolipoprotein B, required for secretion of apolipoprotein B-containing lipoproteins. As a result, apoprotein B is absent in plasma, as are the individual lipoprotein fractions that contain this apoprotein. These lipoprotein fractions include chylomicrons and very-low-density lipoproteins that transport triglycerides, as well as the low-density lipoproteins that are products of very-low-density lipoproteins and transport cholesterol. Consequently, preformed triglycerides are not transported from the intestinal mucosa, and they are nearly absent in the plasma. Plasma cholesterol and phospholipids are markedly reduced, with a relative increase in sphingomyelin at the expense of lecithin. As is the case in acanthocytosis of liver disease, the acanthocytic lesion is acquired from the plasma. Erythrocyte precursors are of normal shape, and the acanthocytic lesion develops as the cells mature and age in the circulation. The role of membrane lipids in the acanthocyte shape transformation was first established by findings of restoration of biconcave shape after extraction of lipids from the cell membrane by detergents. The molecular basis of the acanthocytic shape is unknown, but several indirect observations suggest that it is related to an increase of the surface area of the outer hemileaflet of the lipid bilayer relative to the inner leaflet. Several other abnormalities have been noted in abetalipoproteinemia, including a decrease in plasma lecithin cholesterol transferase activity and an increased susceptibility of membrane and plasma lipids to oxidation as a result of malabsorption-induced deficiency of vitamin E. The contributions of these abnormalities to the acanthocyte red cell lesions are unknown. NeuroacanthocytosisSyndromes the neuroacanthocytosis syndromes are a group of degenerative neurologic disorders with phenotypic and genetic heterogeneity that share the feature of acanthocytes on peripheral blood smear. Chorea-acanthocytosis syndrome is an autosomal recessive syndrome of adult onset that is manifest by multiple neurologic abnormalities, including limb chorea, progressive orofacial dyskinesia with tics, tongue-biting neurogenic muscle hypotonia, and atrophy. Additional abnormalities of uncertain significance include an uneven distribution of intramembrane particles, impaired phosphorylation of the erythrocyte actin-bundling protein dematin, abnormal accumulation of transglutaminase products, and altered function and structure of band 3. Chorein does not belong to any known human gene family, and computer searches have not identified any known structural motifs or domains. The function of the chorein gene product remains unknown in either erythrocytes or the brain. In yeast, a chorein homologue is involved in protein sorting and transport and in regulation of levels of phosphatidylinositol-4phosphate in cell membranes. In affected males, erythrocytes demonstrate absent Kx antigen and reduced Kell antigens. Because of the susceptibility to alloimmunization, it is important to diagnose affected patients because if they are transfused, they can develop antibodies compatible only with McLeod red cells. The McLeod syndrome has been reported in association with chronic granulomatous disease of childhood, retinitis pigmentosa, and Duchenne muscular dystrophy. This association is caused by the close proximity of the genetic loci for these disorders in the p21 region of the X chromosome (Xp21), suggesting the occurrence of various manifestations because of contiguous gene syndromes. This may explain the occasional findings of either echinocytes or Clinical Manifestations this autosomal recessive disease can become evident in the first few months of life, manifested by fat malabsorption with normal absorption of other nutrients. Intestinal biopsy is diagnostic, revealing engorgement of mucosal cells with lipid droplets. Other features include retinitis pigmentosa and a progressive ataxia with intention tremors that usually develops at 5 to 10 years of age, progressing to death in the second or third decade of life. Occasional patients can have more severe anemia resulting from the nutritional deficiencies (iron and folate) that accompany fat malabsorption. The treatment includes dietary restriction of triglycerides and supplementation with the lipid-soluble vitamins A, K, D, and E. Vitamin E can stabilize or even improve both the retinal and neuromuscular abnormalities. Autosomal recessive abetalipoproteinemia should be distinguished from the homozygous form of familial hypobetalipoproteinemia. Although the clinical presentation of both disorders is similar, the latter disorder is milder, and the parents have occasional acanthocytes on the peripheral blood film, and their plasma low-density lipoprotein levels are decreased. The molecular lesions in familial hypobetalipoproteinemia involve a variety of apoprotein B gene mutations, leading to aberrant apoprotein B gene transcription or translation. Varying degrees of acanthocytosis without anemia have also been described with isolated deficiency of apoprotein B100. Chapter45 RedBloodCellMembraneDisorders 643 stomatocytes in Duchenne dystrophy, or a choreiform disorder in some patients with the McLeod phenotype. The Kell antigen consists of two protein components: a 37-kDa protein that carries the Kx antigen, a precursor molecule necessary for the Kell antigen expression, and a 93-kDa protein that carries the Kell blood group antigen. In K0 cells, only the Kell antigen carrying the 93-kDa glycoprotein is absent, whereas these cells have twice the amount of the Kx antigen. As in the other acanthocytic disorders, the surface projections of acanthocytes may be related to asymmetry of the surface area of the two lipid bilayer hemileaflets, as indicated by correction of the acanthocytosis by agents that expand the inner lipid layer, as well as the finding of an increased rate of exchange of phosphatidylcholine (localized preferentially in the outer lipid hemileaflet) with an exogenous source. Conversely, agents that asymmetrically expand the inner half of the lipid bilayer, such as chlorpromazine, lead to stomatocytic shape transformation. Likewise, a small number of cells with long spicules resembling acanthocytes are found in patients with hypothyroidism, after splenectomy, and with myelodysplasia.

There is one report of successful allogeneic peripheral blood stem cell transplantation in a 19-year-old man with transfusion-dependent hereditary sideroblastic anemia virus 52 generic keftab 750mg with mastercard. Regular administration of packed red cells using white blood cell filters are given to relieve symptoms and permit normal childhood development antimicrobial activity of medicinal plants order keftab australia. Iron overload and secondary hemosiderosis rapidly progress after transfusions begin; chelation therapy with desferrioxamine or oral deferasirox should be initiated from the onset antibiotic for ear infection keftab 750mg sale. Iron removal may be of great benefit for patients who have mild or moderate anemia and evidence of iron overload virus 552 purchase keftab 500mg without prescription. All patients with iron overload should avoid ingestion of ascorbic acid supplements infection prevention society order keftab australia, which enhance iron absorption and increase the tissue toxicity of elemental iron infection 2 cheats purchase keftab 750mg on-line. AcquiredSideroblasticAnemia Acquired sideroblastic anemia is categorized within the myelodysplastic syndromes and may appear de novo or occur after chemotherapy or irradiation (see Table 38. The clonal nature of hemopoiesis in this condition was first suggested by Dacie et al. Acquired idiopathic sideroblastic anemia falls within the diagnostic category of refractory anemia with ring sideroblasts as defined by the French-American-British group and World Health Organization classification. Some indirect evidence exists for a primary mitochondrial lesion, perhaps in the mitochondrial respiratory chain, which impairs the reduction of Fe3+ because Fe2+ is essential for heme synthesis. Family surveys are very useful in distinguishing acquired from hereditary forms of sideroblastic anemia, because the latter may present in late adult life. Prognosis Acquired idiopathic sideroblastic anemia and the related entity of refractory anemia have the most favorable outlook among the myelodysplastic syndromes, with a median survival of 42 to 76 months and 3% to 12% incidence of leukemic progression in different series. First is the severity of the anemia, because repeated transfusions markedly increase iron overload and invariably lead to the organ dysfunction characteristic of secondary hemosiderosis. These cytopenias form the basis of a simple prognostic scoring system in which two or more of the following place the patient in a poor prognostic category: hemoglobin level less than 10 g/dL, neutrophil count less than 1. Thirdly, karyotypic analysis of marrow aspirates provides valuable information, because a normal karyotype carries a more favorable prognosis. Conversely, chromosome 7 abnormalities impart a high probability of transformation to acute myeloid leukemia. Multiple chromosomal abnormalities and del(20q) are also associated with an increased risk for progression to leukemia; in contrast, trisomy 8 has no adverse prognostic significance. Etiology Clonal chromosomal changes are found in bone marrow cells in approximately 60% of patients with acquired sideroblastic anemia. Characteristic changes are monosomy 7; trisomy 8; deletions involving chromosomes 5, 7, 11, or 20; and a number of balanced translocations. This concept is in accord with the view that multiple genetic events underlie the pathogenesis of other myelodysplastic syndromes and acute myeloid leukemia203,216 (see box on Clinical and Laboratory Evaluation of Sideroblastic Anemia). When changes are confined to dyserythropoiesis, the condition has been called refractory anemia with ring sideroblasts. Cytogenetic analysis of marrow aspirates provides important information, because a normal karyotype predicts long survival in any type of acquired sideroblastic anemia. However, few patients with acquired idiopathic sideroblastic anemia respond to this vitamin. If any response is achieved, maintenance therapy with pyridoxine at lower dosage is indicated. Red blood cells show dimorphic morphology; evidence in the marrow of folate deficiency is present in half of cases. The ring sideroblasts gradually disappear over 4 to 12 days when alcohol is withdrawn234; during this period, there may be a rebound erythroid hyperplasia, reticulocytosis, and thrombocytosis. Folic acid should be given for the associated megaloblastic changes after blood is taken for vitamin B12 and folate assays. In some reports, patients present with neurologic symptoms such as paresthesias, weakness, or ataxia; and demyelination is seen on the magnetic resonance image of the brain. Serum copper and ceruloplasmin levels are low, whereas serum iron and transferrin saturation levels are normal. Large quantities of ingested zinc interfere with copper absorption and produce the neutropenia and sideroblastic anemia characteristic of copper deficiency. Sideroblastic anemia has also been ascribed to zinc toxicity arising from the ingestion of coins over a period of many years. Zinc must be discontinued for 9 to 12 weeks for full reversal of the anemia and neutropenia. Isoniazid Administration of the antituberculous drug isoniazid has occasionally been associated with development of a sideroblastic anemia after 1 to 10 months of therapy. The anemia is hypochromic and microcytic, with a dimorphic blood smear and ring sideroblasts in the marrow. This complication is thought to occur only in slow acetylators of isoniazid, allowing this drug to react nonenzymatically with pyridoxal and to form a hydrazone that is rapidly excreted in the urine. The zinc complex of protoporphyrin is produced because ferrochelatase uses Zn2+ during iron-deficient erythropoiesis. This effect is predictable and separate from the rare idiosyncratic side effect of aplastic anemia in approximately 1 of 20,000 exposed persons. Nearly all patients given chloramphenicol (>2 g/day) develop vacuolation of the erythroid precursors and ring sideroblasts. Chloramphenicol inhibits mitochondrial protein synthesis and reduces cytochrome a, a3, and b levels. Hypothermia Thrombocytopenia, erythroid hypoplasia, and ring sideroblasts have been described in patients with hypothermia associated with neurologic disease. The bone marrow aspirate showed a left shift in granulopoiesis with vacuolization of immature granulocytic and erythroid precursors (B, C). Many of the clinical manifestations of lead poisoning may be the result of altered heme biosynthesis. The abdominal pain, constipation, and peripheral neuropathy that occur in lead poisoning are also seen in acute attacks of hepatic porphyria. Neuropathy, seen in lead poisoning, may also be the result of disorders of heme biosynthesis, as in the porphyrias. Furuyama K, Harigae H, Heller T, et al: Arg-452 substitution of the erythroid-specific 5-aminolaevulinate synthase, a hot spot mutation in X-linked sideroblastic anaemia, does not itself affect enzyme activity. In liver disease, there may be increased urinary excretion of coproporphyrin, predominantly isomer I. Harigae H, Furuyama K: Hereditary sideroblastic anemia: pathophysiology and gene mutations. Thunell S, Pomp E, Brun A: Guide to drug porphyrogenicity prediction and drug prescription in the acute porphyrias. Macalpine I, Hunter R, Rimington C: Porphyria in the royal houses of Stuart, Hanover, and Prussia. Chiabrando D, Mercurio S, Tolosano E: Heme and erythropoieis: more than a structural role. Grandchamp B, De Verneuil H, Beaumont C, et al: Tissue-specific expression of porphobilinogen deaminase. Thunell S, Andersson C, Carlmark B, et al: Markers for vulnerability in acute porphyria. Poblete-Gutierrez P, Wiederholt T, Martinez-Mir A, et al: Demystification of Chester porphyria: a nonsense mutation in the Porphobilinogen Deaminase gene. Gross U, Sassa S, Jacob K, et al: 5-Aminolevulinic acid dehydratase deficiency porphyria: a twenty-year clinical and biochemical follow-up. Ishida N, Fujita H, Fukuda Y, et al: Cloning and expression of the defective genes from a patient with delta-aminolevulinate dehydratase porphyria. Biolcati G, Marchesini E, Sorge F, et al: Long-term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria. Akagi R, Inoue R, Muranaka S, et al: Dual gene defects involving delta-aminolaevulinate dehydratase and coproporphyrinogen oxidase in a porphyria patient. A 57-year-old woman with abdominal pain and weakness after gastric bypass surgery. Cacheux V, Martasek P, Fougerousse F, et al: Localization of the human coproporphyrinogen oxidase gene to chromosome band 3q12. Qin X, Tan Y, Wang L, et al: Structural insight into human variegate porphyria disease. Wiman A, Harper P, Floderus Y: Nine novel mutations in the protoporphyrinogen oxidase gene in Swedish families with variegate porphyria. Greaves P, Clothier B, Davies R, et al: Uroporphyria and hepatic carcinogenesis induced by polychlorinated biphenyls-iron interaction: absence in the Cyp1a2(-/-) knockout mouse. Munoz-Santos C, Guilabert A, Moreno N, et al: Familial and sporadic porphyria cutanea tarda: clinical and biochemical features and risk factors in 152 patients. Blauvelt A: Hepatitis C virus and human immunodeficiency virus infection can alter porphyrin metabolism and lead to porphyria cutanea tarda. Koszo F, Morvay M, Dobozy A, et al: Erythrocyte uroporphyrinogen decarboxylase activity in 80 unrelated patients with porphyria cutanea tarda. Goerz G, Bunselmeyer S, Bolsen K, et al: Ferrochelatase activities in patients with erythropoietic protoporphyria and their families. Schneider-Yin X, Gouya L, Dorsey M, et al: Mutations in the ironsulfur cluster ligands of the human ferrochelatase lead to erythropoietic protoporphyria. Wang X, Poh-Fitzpatrick M, Taketani S, et al: Screening for ferrochelatase mutations: molecular heterogeneity of erythropoietic protoporphyria. Romslo I, Brun A, Sandberg S, et al: Sideroblastic anemia with markedly increased free erythrocyte protoporphyrin without dermal photosensitivity. Tuckfield A, Ratnaike S, Hussein S, et al: A novel form of hereditary sideroblastic anaemia with macrocytosis. Cazzola M, Barosi G, Bergamaschi G, et al: Iron loading in congenital dyserythropoietic anaemias and congenital sideroblastic anaemias. Camaschella C, Campanella A, De Falco L, et al: the human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload. Cazzola M, Invernizzi R, Bergamaschi G, et al: Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia. Levi S, Corsi B, Bosisio M, et al: A human mitochondrial ferritin encoded by an intronless gene. Liu G, Guo S, Kang H, et al: Mutation spectrum in Chinese patients affected by congenital sideroblastic anemia and a search for a genotypephenotype relationship. Furuyama K, Harigae H, Heller T, et al: Arg452 substitution of the erythroid-specific 5-aminolaevulinate synthase, a hot spot mutation in X-linked sideroblastic anaemia, does not itself affect enzyme activity. Furuyama K, Fujita H, Nagai T, et al: Pyridoxine refractory X-linked sideroblastic anemia caused by a point mutation in the erythroid 5-aminolevulinate synthase gene. Aoki Y: Multiple enzymatic defects in mitochondria in hematological cells of patients with primary sideroblastic anemia. Tricot G, De Wolf-Peeters C, Hendrickx B, et al: Bone marrow histology in myelodysplastic syndromes. Histological findings in myelodysplastic syndromes and comparison with bone marrow smears. Oishi H, Nomiyama H, Nomiyama K, et al: Comparison between males and females with respect to the porphyrin metabolic disorders found in workers occupationally exposed to lead. Thunell S, Floderus Y, Henrichson A, et al: Alcoholic beverages in acute porphyria. Ashkenazi A, Levin S, Djaldetti M, et al: the syndrome of neonatal copper deficiency. Antony the term megaloblastic anemia is used to describe a group of disorders characterized by a distinct morphologic pattern in hematopoietic cells. The net result of megaloblastosis is a cell whose nuclear maturation is arrested (immature) while its cytoplasmic maturation proceeds normally independently of the nuclear events. The microscopic appearance of this nuclear-cytoplasmic asynchrony (or dissociation) is morphologically described as megaloblastic. This is significantly influenced by the normal patterns of maturation of the affected cell line. The peripheral blood picture is characteristic and reflective of megaloblastic hematopoiesis within the bone marrow. Because of the imperative for conservation of cobalamin within the body, there is a finely tuned mechanism in place to ensure a sequential handover of this precious cargo from one protein to another-from the point of its entry into the mouth through the gut, across the enterocyte, into the circulation with specialized uptake into cells, passage through lysosomes into cytoplasm, and even into mitochondria. Throughout this odyssey, cobalamin is accompanied by several chaperones that sequentially bind, sequester, and thereby ensure that cobalamin does not participate in side reactions. Despite the greater abundance of folate in the diet relative to cobalamin, there are also specialized means to ensure that the natural folates in food are first chopped and diced before being ushered across the enterocyte through specialized pathways. After passage from the portal blood into the general circulation, folate is extracted by cell surface folate receptors, undergoes endocytosis, and is then shunted together with a proton across another channel into the cytoplasm. Indeed, the care with which cobalamin and folate are handled is analogous to the swarm of Secret Service agents escorting a president as he walks by a crowd of well-wishers, their sole aim being to prevent him from getting too close to the public-to shake hands, or hug and kiss a baby, and the like, which could also expose him to potential harm by an ill-wisher-and detract him from doing his primary job as chief executive. A general principle is that the preexisting store of these vitamins will dictate the speed with which overt deficiency develops; this is particularly relevant to pregnant women and children in developing countries with preexisting borderline stores of folate and cobalamin. The pathophysiology of cellular cobalamin and folate deficiency is most readily discerned by the clinician who approaches megaloblastosis with a clear understanding of the physiology of these vitamins. Some strains (such as Pseudomonas denitrificans) produce cobalamin during fermentation, making them excellent and cheap commercial sources for cobalamin used in therapy. Herbivores obtain their dietary quota of cobalamin from plants contaminated with cobalaminproducing soil bacteria (rhizobia) that grow in roots and nodules of legumes. Because rhizobia-related organisms are also found in the large intestine of animals (and humans), volitional or inadvertent coprophagy can lead to intake of cobalamin by herbivores; however, cobalamin from manure that contaminates plants is not likely to be a significant source for humans.

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Although the activity of this enzyme is generally measured together with that of P5N1 infection 8 weeks after giving birth buy cheap keftab 750mg line, it is encoded by a separate gene antibiotics for dogs cheap 500mg keftab with amex, is not strictly pyrimidinespecific antimicrobial for mold order keftab 500mg without prescription, and is unable to compensate for deficient function of P5N1 antibiotic resistance powerpoint buy generic keftab 750mg. The second family had a compound heterozygous mutation and a clinical phenotype of neonatal jaundice antibiotic 500g order keftab. Pfkm null mice show exercise intolerance virus 88 discount keftab 500mg on line, reduced lifespan and progressive cardiac hypertrophy. Although a polymorphism affecting the activity of glutathione peroxidase and acquired decreased activity because of selenium deficiency have been described, neither circumstance was associated with a clinical phenotype. AldolaseDeficiency Aldolase reversibly cleaves fructose-1,6-diphosphate into glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Aldolase deficiency is a very rare cause of chronic nonspherocytic hemolytic anemia; myopathy and mental retardation may also occur. Rarely, severe neuromuscular symptoms, mental retardation and granulocyte dysfunction occur. Deficiency of this X-chromosome encoded enzyme is variably associated with hemolytic anemia, mental retardation, and myoglobinuria. The neuromuscular disease is likely caused by the formation of toxic protein aggregates of glycated proteins formed by elevated byproducts of dihydroxyacetone phosphate. Approximately 40 patients with several different mutations have been reported; however, most patients have the same mutation and are descendants from a common British/French ancestor about 1000 years ago. There is no effective therapy and most patients die in childhood, although there are rare exceptions. Most patients are of northern European extraction, although one case was reported in a Chinese individual. The molecular defect has been characterized in only four patients; two were homozygous. Formation of methemoglobin and it physiologic (open space) and therapeutic reduction (shaded space). Transaldolase deficiency presents in the neonatal period and clinical manifestations include dysmorphic features, hepatosplenomegaly, cirrhosis, cardiac and renal abnormalities, skin manifestations, and thrombocytopenia, although the phenotype is highly variable. Methemoglobin is a derivative of hemoglobin in which the ferrous (Fe2+) irons are oxidized to the ferric (Fe3+) state. Methemoglobin is formed spontaneously at a slow rate by the autoxidation of hemoglobin. Methemoglobin may also be formed from the oxidation of hemoglobin in other reactions with endogenous and exogenous compounds. The ferric hemes of methemoglobin are unable to bind oxygen and, additionally, if a ferriheme subunit is part of a hemoglobin tetramer, the oxygen affinity of the accompanying ferrous hemes in the hemoglobin tetramer is increased. As a result, the oxygen dissociation curve is left-shifted and oxygen delivery is impaired. Methemoglobin is formed continuously, but reducing mechanisms keep the methemoglobin level at about 1% of the total hemoglobin. The consequent left shift of the oxygen dissociation curve increases hemoglobin affinity for oxygen, thus resulting in decreased delivery of oxygen into the peripheral tissues and compensatory polycythemia. Since these electron acceptors are not physiologic, this pathway is only of importance as it is the mechanism by which methylene blue treats acute toxic methemoglobinemia. Epidemiology Most cases of methemoglobinemia are acquired, resulting from increased methemoglobin formation by various exogenous agents. Acute or toxic methemoglobinemia may occur in the setting of overdose or poisoning, but also at standard doses of drugs. Acute methemoglobinemia occurs equally between males and females and over a wide range of ages; however, infants are more susceptible because their erythrocyte b5R activity is normally 50% to 60% of adult activity. Other causes of hereditary methemoglobinemia are the autosomal dominant inheritance of an abnormal hemoglobin in hemoglobin M disease (see Chapter 43) and, very rarely, deficiency of cytochrome b5. Death typically ensues at methemoglobin levels above 70% but can occur at lower levels. Individuals with type I b5R deficiency, which is limited to erythrocytes, have methemoglobin concentrations of 10% to 35% and appear cyanotic but are usually asymptomatic, even with levels up to 40%. Other neurologic symptoms may be present, including microcephaly, opisthotonus, athetoid movements, strabismus, seizures, and spastic quadriparesis. LaboratoryManifestations the laboratory diagnosis of methemoglobinemia is based on analysis of its absorption spectra. A fresh specimen should always be obtained because methemoglobin levels tend to increase with storage. Traditional pulse oximetry is unreliable in the presence of methemoglobinemia because of its light absorbance properties; however, co-oximetry can determine the methemoglobin fraction along with all other substances with the optical density at 630 nm. Methemoglobin detected by co-oximeter should be confirmed by the specific Evelyn-Malloy method if available. This method involves direct spectrophotometric analysis and should be used when methemoglobinemia is suspected. In the Evelyn-Malloy method, blood is lysed in a slightly acid buffer and the optical density is measured at 630 nm before and after adding a small amount of neutralized cyanide Absorption of methemoglobin at this wavelength disappears when it is converted to cyanmethemoglobin. This method remains the most accurate technique for the estimation of methemoglobin concentration. Distinguishing the hereditary forms of congenital methemoglobinemia requires interpretation of family pedigrees as well as biochemical analyses. Cyanosis in successive generations suggests autosomal dominant hemoglobin (Hb) M disease, whereas normal parents but possibly affected siblings implies autosomal recessive b5R deficiency. Because the enzyme defect is found in fibroblasts, analysis of b5R activity in cultured amniotic cells for prenatal diagnosis is possible. Pathobiology Acute Methemoglobinemia Many drugs and toxins have been implicated in acute methemoglobinemia. More common culprits include dapsone, local anesthetics (benzocaine, lidocaine, prilocaine), and derivatives of the anesthetic phenacetin. Exposure to nitrates and nitrites, widely used as food preservatives and found in well water can also cause methemoglobinemia. Nitrates do not oxidize hemoglobin directly but are converted to nitrites by intestinal bacteria. Infants less than 6 months of age may have increased susceptibility to methemoglobinemia at least in part because of their lower b5R activity. Homemade baby food purees of high-nitrate-containing vegetables, well water contaminated by nitrites and diarrheal illness may all cause acute toxic methemoglobinemia in infants. B5R Deficiency In erythrocytes, b5R transfers electrons to methemoglobin to reduce it to hemoglobin. In other cells, b5R transfers electrons from cytochrome b5 to stearyl-CoA in the endoplasmic reticulum, a reaction that has an important role in cholesterol biosynthesis, fatty acid elongation and desaturation, and drug metabolism. The more common type I b5R deficiency is usually caused by missense mutations leading to decreased stability of the enzyme. Other pigments, including methylene blue, may also produce false positive results when methemoglobin is measured by co-oximetry. ClinicalManifestations Methemoglobinemia causes clinically discernible cyanosis when the absolute level of methemoglobin exceeds 1. Methemoglobinemia should be clinically suspected when "cyanosis" occurs in the presence of a normal PaO2. Symptoms develop secondary to impaired tissue oxygenation and the onset may be abrupt. At higher levels, respiratory depression, altered consciousness, shock, seizures, and death may occur. As methemoglobin levels rise above 20% to 30%, Prognosis Acute methemoglobinemia generally resolves promptly with treatment providing the offending cause is discontinued. Therapy Offending agents in cases of acquired methemoglobinemia should be discontinued. However, if the patient is symptomatic or if methemoglobin levels are greater than 20%, specific therapy is indicated. Leukomethylene blue, in turn, nonenzymatically reduces methemoglobin to hemoglobin. In these patients, methylene blue would not only fail to give the desired effect on methemoglobin levels but might compound the situation by inducing an acute hemolytic episode. The cyanosis in hereditary b5R deficiency is of cosmetic significance only but can be treated with methylene blue or ascorbic acid, both of which facilitate the reduction of methemoglobin through alternate pathways. Beutler E: Red cell metabolism: a manual of biochemical methods, ed 3, 1984, Grune & Stratton. A summary of current understanding and management of clinical and metabolic features of pyruvate kinase deficiency. Summary of red cell enzyme defects in descending order of their clinical importance. This review focuses on the impact of energy metabolism of erythrocyte and its pathophysiology. Viprakasit V, Ekwattanakit S, Riolueang S, et al: Mutations in Kruppellike factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression. Review of red cell enzymes with extensive bibliography of original and recent articles. In patients with severely dysfunctional spectrin mutations, the weakened spectrin dimer-dimer self-association disrupts the skeletal lattice, leading to a marked skeletal instability and cell fragments. It is speculated that elliptocytes are permanently deformed cells because the weakened horizontal interactions facilitate a shear stress-induced rearrangement of skeletal proteins, precluding recovery of the normal biconcave shape. Acanthocytosis,Stomatocytosis,andtheBilayer CoupleHypothesis the mechanism of acanthocytosis and stomatocytosis associated with defects of membrane proteins is much less clear. Most forms of acanthocytosis are associated with either acquired or inherited abnormalities of membrane lipids. In rare cases with acanthocytosis, membrane protein abnormalities have been detected, but the associated mechanisms leading to acanthocyte formation are unknown. These abnormalities occur in the McLeod phenotype, the choreaacanthocytosis syndrome, and other rare disorders. In acanthocytosis erythrocytes, agents that interact with the lipids of the inner lipid bilayer leaflet normalize the shape. Vertical interactions, which are perpendicular to the plane of the membrane, stabilize the lipid bilayer. Horizontal interactions, which are parallel to the plane of the membrane, support the structural integrity of erythrocytes after their exposure to shear stress. Horizontal interactions involve the spectrin heterodimer association site, where spectrin heterodimers assemble into tetramers, the principal building blocks of the membrane skeleton, and the contacts of the distal ends of spectrin heterodimers with actin and protein 4. Although interactions between proteins of the erythrocyte membrane are significantly more complex than can be classified by horizontal and vertical interactions, the model serves as a useful starting place for understanding erythrocyte membrane protein interactions, particularly in reference to membrane-related disorders. Consequently, the lipid bilayer membrane is destabilized, leading to release of bilayer lipids from the cells in the form of skeleton-free lipid vesicles. This lipid loss, in turn, results in membrane surface area deficiency and spherocytosis. The lipid bilayer forms the equator of the cross-section with its polar heads (small circles) turned outward. Mutations in the highly conserved region of -spectrin involved in the interaction with protein 4. Thus patients with one normal and one defective -spectrin allele are asymptomatic, because -spectrin production remains in excess of -spectrin synthesis, allowing normal amounts of spectrin heterodimers to be assembled on the membrane. Destabilization of the lipid bilayer facilitates a release of lipids from the membrane, leading to surface area deficiency and formation of poorly deformable spherocytes that are selectively retained and damaged in the spleen. This facilitates disruption of existing protein contacts during shear stress-induced elliptical deformation. In some cases, mutations of the ankyrin promoter leading to decreased ankyrin expression have been found. Approximately 15% to 20% of ankyrin gene mutations reported are de novo mutations. Ankyrin deletions may be part of a contiguous gene syndrome with manifestations of spherocytosis, mental retardation, typical facies, and hypogonadism. A number of band 3 mutations clustered in the membranespanning domain that replace highly conserved arginines have been described. These arginines, which are all located at the cytoplasmic end of a predicted transmembrane helix, exhibit defective cellular trafficking from the endoplasmic reticulum to the plasma membrane. Chapter45 RedBloodCellMembraneDisorders 629 Spectrin/ankyrin deficiency Release of microvesicles pH Macrophage contact Hemolysis Band 3/protein 4. The primary defect in hereditary spherocytosis is a deficiency of membrane surface area. Decreased surface area may be produced by two different mechanisms: (1) Defects of spectrin, ankyrin, or protein 4. Both pathways result in membrane loss, decreased surface area, and formation of spherocytes with decreased deformability. These deformed erythrocytes become trapped in the hostile environment of the spleen where splenic conditioning inflicts further membrane damage, amplifying the cycle of red cell membrane injury. Alleles have been identified that influence band 3 expression and that, when inherited in trans to a band 3 mutation, aggravate band 3 deficiency and worsen the clinical severity of the disease. The loss of membrane material occurs through the release of vesicles containing integral proteins devoid of spectrin. During in vitro incubation, the loss of membrane material is sufficient to augment the surface area deficiency, as evidenced by increased osmotic fragility of the cells after incubation. As a result, areas of the lipid bilayer membrane that are not directly supported by the skeleton are susceptible to release from the cells in the form of microvesicles. Because band 3 protein spans the lipid bilayer membrane many times, it is likely that a substantial amount of "boundary" lipids are released together with the band 3 protein, thus leading to surface area deficiency. Another possible mechanism may involve a formation of band 3-free domains in the membrane, followed by the formation of membrane blebs, which are subsequently released from the cells as microvesicles.

In clinical practice antibiotics used for ear infections purchase generic keftab from india, although nearly all patients with wellcharacterized phagocyte abnormalities have recurrent or unusual infections antimicrobial jersey order discount keftab online, the majority of individuals with histories of persistent or recurrent infections do not have identifiable phagocyte disorders or other immune defects infection prevention jobs discount keftab on line. In some cases infection pathophysiology buy cheap keftab online, these reflect another underlying medical condition or nonimmunologic problem related to an anatomic or obstructive defect antibiotic resistance science project keftab 250mg otc. This article focuses largely on disorders in which a good correlation exists between the clinical condition and an identifiable defect in phagocyte function infection journal impact factor discount 750mg keftab otc. Superoxide is the precursor to numerous microbicidal oxidants, including hydrogen peroxide and hypochlorous acid. These reactions are involved in the production of O2- (reactions 8 and 1) in the conversion of O2- and hydrogen peroxide to other toxic derivatives (reaction 4) or in the detoxification of excess hydrogen peroxide needed to protect the phagocyte during the respiratory burst (reactions 7 and 9). Activated neutrophils can detect as little as a 2% change in the chemoattractant gradient and move to the site of infection. Both oxidative and nonoxidative antimicrobial mechanisms are then used to kill bacteria. The absence of respiratory burst-derived oxidants results in recurrent, often life-threatening bacterial and fungal infections, and is also associated with formation of inflammatory granulomas. The disease was termed fatal granulomatous disease owing to this distinguishing histologic feature and the grim clinical course in most patients. Recent publications on disease manifestations and genotypes in large patient registries are also available and support earlier reports. The history, physical examination, and infections episodes in patients with a possible primary neutrophil dysfunction syndrome are noted. A qualified reference laboratory with special expertise in this area should carry out the neutrophil evaluations. Chemotaxis is very difficult to evaluate clinically and should only be attempted in a qualified research laboratory with extensive experience. The oxidase subunits are referred to by their apparent molecular mass (kDa) and have been given the designation phox, for phagocyte oxidase. A b-type cytochrome known as flavocytochrome b558, a membrane-bound heterodimer composed of gp91phox and p22phox, is the redox center of the oxidase. The p40phox subunit appears to play a selective role in stimulating highlevel superoxide production within phagosomes via membrane-bound phosphatidylinositol-3-phosphate. In about 5% of X-linked cases, gp91phox can be present in normal levels but be nonfunctional (X91+), mutated in such a way that gp91phox is poorly functional (X91-), or expressed in only a small fraction of phagocytes (X91+). The major diagnostic problem faced by the clinician is to determine if the history of infection is unusual enough to warrant consideration of an underlying neutrophil dysfunction defect. The first point to remember is that primary immunodeficiency disorders are rare and primary neutrophil dysfunction syndromes form only a small percentage of all primary immunodeficiency syndromes. Excellent discussions of this problem have been published (see Kyono and Coates2, and Dinauer, Newburger and Borregaard3). Patients with unusual features in at least one of these aspects should alert the clinician to a possible underlying phagocyte disorder. For example, recurrent otitis media in a 2-yearold patient is far less worrisome than a similar history in a 40-year-old patient. The more unusual or severe the infections, the less frequently these have to occur before a phagocyte evaluation is indicated. Infections in unexpected anatomic locations, such as hepatic, pulmonary, and rectal abscesses, may indicate an underlying phagocyte defect. Childhood periodontal disease or gingivitis is distinctly uncommon, and in the absence of neutropenic conditions, strongly suggests underlying neutrophil dysfunction. A history of delayed separation of the umbilical cord is often mentioned as a sign of phagocytic defect. Evaluation Performing a good history and physical examination to eliminate common causes of recurrent infection is important before looking for rare syndromes. For example, is the recurrent pneumonia caused by an aspirated foreign body in the bronchus In general, patients should first be evaluated for lymphocyte or complement defects. Note that testing described in this algorithm is not exhaustive, and patients with truly striking histories of unusual kinds of infections should be referred for further evaluation by specialized research laboratories. Flavocytochrome b558 is the redox center of the enzyme and is located in plasma, specific granule, and phagolysosomal membranes. The soluble regulatory proteins p47phox, p67phox, and p40phox are found in the cytosol until phagocyte activation by soluble or particulate inflammatory stimuli, after which they move to the membrane where p47phox and p67phox bind flavocytochrome b558, binds Rac, and p40phox binds phosphatidylinositol 3-phosphate, a phosphoinositide present on phagosome membranes. This close physical proximity leads to recombination events between the wild-type gene and pseudogene(s). However, one A67+ patient has been reported in which a nonfunctional form of p67phox with an amino acid deletion is expressed but is unable to translocate to the membrane or bind to Rac. The most common types of infections are those that involve sites in contact with the outside world, which is consistent with the role of neutrophils as a first line of defense against infection. In this situation, one treats empirically with the antibiotic that should work and if it fails, one then aggressively pursues more invasive diagnostic procedures looking for one (or more) of the less commonly seen microbes such as Nocardia spp. After their first major infection, some of these patients may be relatively healthy again for another 3 to 10 years before the next severe infection occurs. Individuals with partial respiratory burst activity but less than 10% of normal (most X91- patients; see Table 50. Polymorphisms in oxygen-independent antimicrobial systems or other components regulating the innate immune response are also likely to play an important role in modifying disease severity. Peripheral blood neutrophils and monocytes from a drop of fresh whole blood were made adherent to glass slides and stimulated with phorbol myristate acetate. Am J Med 71:59, 1981; (7) Hayakawa H, Kobayashi N, Yata J: Chronic granulomatous disease in Japan: A summary of the clinical features of 84 registered patients. The infecting organisms are arranged in approximate order of frequency for each type of infection. This organism is a member of the Acetobacteraceae family, which has previously not been linked to invasive human disease. Proven or suspected Aspergillus infections were treated with amphotericin B therapy, but new azole antifungal agents are now typically used. Lymphadenitis is the second most common infection and is usually caused by gram-negative organisms, S. Incision and drainage should not be delayed if the lesion fails to respond to parenteral antibiotics. Most lesions require drainage (needle or surgical) to permit efficient healing to occur. Perirectal abscesses are difficult to treat, even with months of therapy, and can lead to fistula formations. These lesions become granulomas as the host uses lymphocytes and activated macrophages to assist in containing the pathogens. However, this complication is not always clearly linked to persistent infection and in these cases, is speculated to involve a dysregulated inflammatory response, inefficient degradation of debris, or both. In the absence of oxidant production, excessive production of cytokines and delayed neutrophil apoptosis at inflammatory sites appear to contribute as underlying mechanisms. Throughout the body, granuloma formation can lead to dysfunction and obstruction in the esophagus, urinary bladder, and kidneys. In the stomach, the gastric antral narrowing can be severe enough in infants and children to resemble pyloric stenosis. A chronic ileocolitis resembling Crohn disease occurs in about 10% of patients and can range from mild diarrhea to a debilitating syndrome of bloody diarrhea and malabsorption that can necessitate a colectomy. Other types of chronic inflammation include gingivitis, chorioretinitis, destructive white matter lesions in the brain, and glomerulonephritis. Discoid lupus has been reported in 10% to 20% of patients, and occasional patients may develop systemic lupus erythematosus, sarcoidosis, or rheumatoid arthritis. First, about one-fourth of X-linked carriers are at risk of developing mild to moderately severe discoid lupus erythematosus characterized by discoid skin lesions and photosensitivity. However, because the probability of getting an abnormal result is very low, there may be confusion in interpretation because of a lack of experience. Thus, if the index of suspicion is high, consultation should be obtained from a center with extensive experience with the test and with the disorder. A normal blood sample should always be shipped with the patient specimen as a control for problems in specimen handling during transport. It has the advantage of assessing large numbers of cells and can give quantitation of the amount of oxidant production. If the circulating neutrophil population is skewed to the point that fewer than 10% to 15% of the cells function, then the carrier has an increased risk of bacterial infections that in some cases have been severe. Regardless of diagnostic assay used, is important to have Chapter50 DisordersofPhagocyteFunction 699 these tests performed on appropriately handled blood samples and by experienced laboratories to avoid inconclusive or false-normal results. Genetic classification is useful primarily for purposes of genetic counseling and prenatal diagnosis. Genetic testing for the four most common genetic subgroups is commercially available. Laboratories specializing in neutrophil biochemistry can also perform immunoblot analysis of neutrophil extracts, flavocytochrome b spectroscopy, or functional analysis of membrane and cytosol fractions in the cell-free oxidase assay. More importantly, there can be serious problems with development of hemolytic antibodies if these patients are transfused. Cuts and skin abrasions should be cleansed promptly with soap and water and a topical antiseptic applied (2% hydrogen peroxide, Betadine ointment, or both). Frequent brushing, flossing, use of antibacterial mouthwash, and professional cleaning of teeth can help prevent gingivitis. Constipation should be avoided because it can lead to rectal or anal fissures and abscesses. Early anal infections can be treated with soaking in soapy water (with or without Betadine). The frequency of pulmonary infections can be reduced by not using commercially available bedside humidifiers; avoiding smoking (cigarettes and marijuana); and refraining from handling decaying plant materials. Avoidance of construction sites, especially demolition of old buildings that may harbor fungi, is recommended. There have been clear outbreaks of Aspergillus pneumonias in immunosuppressed children visiting hospitals undergoing renovation. Side effects were observed in some of the patients but typically were restricted to mild fever and flu-like symptoms. On average, this group of patients averaged one serious infection per patient every 4 to 5 years. Reasonable attempts to define the source of the infection and the responsible microbe should also begin promptly. If the patient fails to respond, then more aggressive diagnostic procedures should be instituted (computed tomography, bone, and gallium scans; open biopsies if indicated) and empirical changes in the antibiotics used to broaden coverage to Pseudomonas cepacia. If fungus is identified or strongly suspected, amphotericin B has been the drug of choice in the past, but newer azole antifungal agents such as voriconazole are supplanting its use. Even with appropriate antibiotics, certain types of infections respond slowly and may require many months of therapy. Surgical drainage or resection can sometimes play a key role in accelerating healing of certain types of infection such as lymphadenitis, osteomyelitis, and abscesses of visceral organs such as the liver or lung. Finally, granulocyte transfusions may be of benefit in the treatment of stubborn or life-threatening infections. Specific treatment may be indicated, especially if the patient has significant cytopenias or evidence of hepatic dysfunction. Use of corticosteroids should generally be avoided, including extensive topical use, except in cases of severe asthma, esophageal strictures, gastric antral narrowing, granulomatous cystitis, inflammatory bowel disease, or certain cases of pneumonia. Clear evidence shows that corticosteroids are beneficial in these clinical settings because the steroids induce rapid regression of obstructive symptoms at low oral doses. Steroids can be lifesaving in young children with airway obstruction because of inflammation. In these cases, the physician and patient should be aware of the risks of the additional immunosuppression caused by the corticosteroids. Transfusion of patients with McLeod syndrome poses a serious problem because they can develop alloantibodies of wide specificity that can preclude any further transfusions except with Kell-negative blood products. McLeod-matched blood is extremely rare, and patients with this syndrome should have their own blood frozen in case it is needed. Because of the difficulty in finding blood, transfusion with non-McLeod blood is likely to occur. Although management is difficult and use of steroids is necessary, the hemolytic anemia can be managed successfully. The chronic hemolytic anemia is treated by supportive means, including transfusions. This brief burst of O2-, however, appears to be sufficient for adequate microbial killing because the few patients reported have not had problems with recurrent infections. However, they do have congenital hemolytic anemia during periods of oxidant stress caused by diminished levels of glutathione reductase in erythrocytes. Patients with glutathione synthetase deficiency also have intermittent neutropenia (perhaps caused by the acidosis), as well as oxidant-induced hemolysis. In vitro, an impressive defect in killing Candida albicans and hyphal forms of Aspergillus fumigatus is observed. In other instances, clear and major defects were identified in vitro that correlated with the in vivo propensity for infection. Extensive classification systems have been devised to categorize the numerous acquired defects in chemotaxis. The problem in many of these reports is that it is unclear whether the infections were caused by the in vitro chemotactic abnormality or by the medical complications of the underlying disorder.