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Charles Redman MB ChB FRCOG FRCS (Ed)

  • Consultant Gynaecologist, City General, North Staffordshire
  • Hospital, Stoke-on-Trent

Binding to the intermediate conformation overcomes the resistance to imatinib conferred by mutations Y253F treatment 8th february proven trecator sc 250mg, E255K treatment 1st metatarsal fracture buy generic trecator sc 250mg line, and D276G medicine 2016 generic trecator sc 250mg amex, but does not confer activity against cells expressing T315I medications zyprexa buy trecator sc us. Common adverse events observed with bosutinib include gastrointestinal upset (diarrhea medications safe in pregnancy buy trecator sc with a mastercard, vomiting, and abdominal pain), whereas the more common serious adverse events include diarrhea, myelosuppression, and elevated serum lipase and transaminases. Toxicities observed in early clinical trials included pancreatitis and elevation in pancreatic enzymes, fatigue, rash, and elevated aminotransferase levels. However, subsequent trials showed increased arterial thrombosis events in patients randomized to ponatinib arms, leading to limitations in the indications for ponatinib and the requirement for thrombosis prevention strategies in subjects treated with this drug. Ibrutinib binds covalently to a cysteine (Cys 481) in the Btk active site, with potent and irreversible enzymatic activity. Serious adverse events associated with ibrutinib occurred in approximately 10% of patients, including rash, febrile neutropenia, diarrhea, and life threatening bleeding. The diarrhea follows two patterns: an early diarrhea that usually presents in the first weeks of treatment, which can usually be managed with antidiarrheal agents, and a late diarrhea that has an inflammatory bowel component and that may require more aggressive therapies, including corticosteroids and other antiinflammatory therapies. Elevation of liver function tests is also commonly observed, requiring interruption of idelalisib. Serious adverse events include hepatotoxicity occurring in the first 3 months of treatment, diarrhea and colitis, intestinal perforation, pneumonitis, and neutropenia. Frequent adverse events include gastrointestinal complaints (diarrhea, nausea, dyspepsia, gastrointestinal reflux, and anorexia) and fatigue. Severe adverse events include rash, fatigue, elevations in liver function tests, and thrombocytopenia. Improvements in solubility and pharmacokinetic properties led to development of rapamycin analogs (rapalogs), of which everolimus and temsirolimus are available as antineoplastic agents. Metabolic abnormalities are common, including hyperglycemia, hypercholesterolemia, and hypertriglyceridemia. An uncommon pulmonary toxicity manifested as interstitial lung disease has also been observed with rapalogs. Interference with any of these processes can lead to inhibition of Raf activation as well as downstream targets. In addition to their potential intrinsic activity against malignant hematopoietic cells, evidence indicates that such agents might also enhance the activity of conventional cytotoxic drugs. The most common adverse events include gastrointestinal symptoms (nausea, vomiting, diarrhea), visual impairment, asthenia, cough, and myelosuppression (neutropenia, lymphopenia), as well as elevations of hepatic function tests. In the clinical setting, modest response rates of 10% were observed in two studies, suggesting the need to consider combination therapy. The result is either hypersensitivity to cytokine signals or constitutive activation of the kinase. After 3 months of therapy, 44% of patients with splenomegaly experienced a reduction of more than 50%. Importantly, the majority of patients experienced a decrease in constitutional symptoms and improved exercise tolerance and performance status, as well as weight gain. Recent studies have also shown ruxolitinib to be effective in controlling symptoms, spleen size and hematocrit in patients with polycythemia vera. Rapid redevelopment of splenomegaly and symptom exacerbation can occur after abrupt interruption or discontinuation of ruxolitinib. Common side effects of ruxolitinib include myelosuppression, primarily anemia, and thrombocytopenia requiring dose modifications; increased risk of infections and herpes zoster; gastrointestinal symptoms (abdominal pain, diarrhea), fatigue and headache. The main side effects are gastrointestinal, predominantly diarrhea, nausea, vomiting, and abdominal pain, while hematologic adverse events are modest. Early trials in myelofibrosis patients resulted in decreased splenomegaly and improvement in symptoms in the majority of patients treated. Of note, more than one-third of patients with improved splenomegaly had previously been treated with ruxolitinib. The most common side effects included myelosuppression, primarily thrombocytopenia. The maximum tolerated dose has been established at 300 mg/day given continuously in 28-day cycles. Lenalidomide was identified as an analog of thalidomide with more potent immunomodulatory functions but fewer side effects. In addition, lenalidomide induces caspase 8-mediated apoptosis and mitochondrial-mediated cell death. Lenalidomide can cause a similar dose-dependent peripheral neuropathy as thalidomide, and causes more significant myelosuppression, which can be dose limiting. The risk of thrombosis is also increased and the administration of lenalidomide should be accompanied by antithrombotic prophylaxis. Pomalidomide ImmunomodulatoryAgents Thalidomide and its related compounds provide effective oral immunomodulatory (see Chapter 86) therapy for patients with hematologic malignancies, in particular plasma cell dyscrasias and lymphoid malignancies. The lack of a simple mechanism of action has been confusing because it is unclear which, if any, biomarker is an appropriate correlate for clinical success or toxicity. In addition to its immunomodulatory and antiangiogenic activity, pomalidomide has direct activity against myeloma cells, affecting gene expression, and promoting apoptosis and cell cycle arrest. In vitro studies showed that pomalidomide was active in cell lines resistant to thalidomide and lenalidomide. The most common severe adverse events are myelosuppression (anemia, neutropenia, and thrombocytopenia), infections, and fatigue. ProteasomeInhibitors the 26S proteasome is the central proteolytic machinery of the highly conserved ubiquitin proteasome system. Under the sequential action of E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin ligase), ubiquitin is activated and covalently conjugated to potential proteasome substrates via an isopeptide bond between the C-terminal glycine residue of ubiquitin and the -amino group of internal lysine residues in target proteins. The same set of enzymes also catalyzes the formation of the isopeptide bond between G76 and the lysine residue (K48) of previously conjugated ubiquitin, leading to formation of a polyubiquitin chain. The 26S proteasome is a large (2000-kDa) threonine protease present in the nucleus and cytoplasm of all eukaryotic cells. The 19S cap is involved in the recognition, binding, and unfolding of ubiquitinated proteins and in the regulation of the opening of the 20S core. Three different active sites are located inside the cylindrical core within the -subunit rings. At least three distinct proteolytic activities are associated with the proteasome: chymotryptic, tryptic, and peptidylglutamyl. After release from the substrate, the polyubiquitin chain is hydrolyzed into single ubiquitin moieties, and tagged proteins are degraded to small peptides. Synergism between proteasome inhibition and cytotoxic chemotherapy is an area of active research. Transformed cells are much more sensitive to blockade of the proteasome than are normal cells; the exact mechanism of this selective susceptibility is not fully understood. Early studies revealed that proteasomes are abnormally highly expressed in rapidly growing metazoan embryonic and human neoplastic cells, but not in their well-differentiated and normal proliferating cells. However, the clinical relevance of this finding is less certain, as mutations in the B5 subunit have not been identified in myeloma patients who are resistant to proteasome inhibitors. Gene expression signatures associated with bortezomib sensitivity and resistance have been characterized in cell lines derived from animal models of myeloma, yet the clinical relevance of such signatures awaits confirmation in large clinical trials. Bortezomib (pyrazylcarbonyl-Phe-Leu-boronate), the first in this class of agents to enter clinical trials, is a dipeptidyl boronic acid that is a specific and selective inhibitor of the 26S proteasome. The Boron atom interacts reversibly with the catalytic threonine residue of the proteasome, primarily inhibiting its chymotrypsin-like activity. The process of cell death appears to be p53 independent and to result in mitotic catastrophe, although the classical caspase 8-dependent apoptosis pathway has also been implicated. It also suggests a selective mechanism that could explain the emergence of less differentiated myeloma cells with decreased immunoglobulin production during treatment. These processes also increase oxidative stress and contribute to apoptotic signaling, explaining the sensitivity of myeloma cells to proteasome inhibition. Among solid tumor cell lines, those of the prostate, breast, colon, and pancreas were exquisitely sensitive to proteasomal inhibition. Cytotoxic activity was reported as well against Lewis lung carcinoma cells and nasopharyngeal squamous cell carcinoma cells. The unfolded protein response not only was increased in plasma cells producing large quantities of immunoglobulin, but also induced a stress apoptosis response. Importantly, bortezomib demonstrated synergistic activity with dexamethasone, thalidomide, melphalan, and doxorubicin and did not appear to be a substrate for multidrug-resistance transporters. This did not preclude the observation of myelosuppression during treatment of patients with bortezomib as a single agent. The deboronated metabolites have been shown to be inactive in the 20S proteasome assay. Bortezomib specifically and selectively inhibits proteasome function by binding tightly (dissociation constant [Ki] >0. An intermittent but high level of inhibition (>70%) of proteasome activity was better tolerated than sustained inhibition. Nonetheless, this dose schedule is often associated with significant myelosuppression and the onset of peripheral neuropathy. Reducing the dose schedule to a weekly regimen ameliorates these toxicities and appears to increase patient tolerance without jeopardizing clinical efficacy. Second-Generation Proteasome Inhibitors Carfilzomib: Carfilzomib is a second-generation proteasome inhibitor that selectively inhibits the chymotrypsin-like activity of the proteasome and is active in bortezomib-resistant patients. Carfilzomib induces irreversible inhibition (once carfilzomib binds to its active site within the barrel of the proteasome, the proteasome is permanently inactivated and new proteasomes must be synthesized to restore proteasome activity) compared with the reversible effects of bortezomib (duration of proteasome inhibition lasts about 72 h). Carfilzomib was approved in 2012 for the treatment of patients with myeloma who have received at least two prior therapies. Carfilzomib appears to be less likely to cause peripheral neuropathy, and is safe in patients with renal impairment. Early indications suggest that ixazomib may be associated with less neuropathy than bortezomib. Early indications suggest that delanzomib may be associated with less neuropathy than bortezomib but it was noted to cause rash. Since it is not peptide based, marizomib is resistant to degradation by endogenous proteases. It is capable of overcoming bortezomib resistance in vitro; clinical trials are underway but are still in early stages. Dose-limiting toxicities in phase I trials have included cognitive changes, transient hallucinations, and loss of balance, which were reversible. The most common drug-related adverse effects included fatigue, gastrointestinal adverse events, dizziness, and headache. Since marizomib has a different mechanism of action from bortezomib, and a nonoverlapping toxicity profile, combinations of these agents may be evaluated in future studies. This is a very active area of research; there are over 10 structurally distinct classes of proteasome inhibitors in development, with new agents expected to enter clinical testing in the hopes of finding drugs with optimal potency, reduced toxicity and oral bioavailability. The mechanism by which bortezomib produces peripheral neuropathy is unknown, but is hypothesized to be due to aggresome formation and cytoskeletal collapse in dorsal root ganglion sensory neuron axons, alterations in mitochondrial function, or other off-target effects. It is possible that the boron moiety is implicated in the peripheral neuropathy since carfilzomib (which does not contain a boron atom) is much less likely to cause neuropathy than bortezomib. Hematologic Toxicity Hematologic adverse events appear to be a class effect associated with proteasome inhibitors; all agents tested so far are associated with thrombocytopenia, neutropenia, anemia, and lymphopenia. Differences in the tendency of the different agents to cause hematologic toxicity remain to be established as newer agents undergo further testing in clinical trials (there is hope that second-generation drugs may have lower rates of hematologic toxicity). Bortezomib, carfilzomib, and ixazomib cause transient, cyclical thrombocytopenia, with platelet counts dropping and then returning to baseline prior to the next cycle of treatment. The exact mechanism of bortezomib-induced thrombocytopenia remains to be fully elucidated. Herpes Zoster Reactivation Bortezomib has been associated with a significantly increased rate of herpes zoster reactivation. The increased susceptibility to herpes zoster reactivation in patients treated with bortezomib may be due to the effect of bortezomib treatment on the number and function of specific lymphocyte subsets. One of the major motivations for the development of the second-generation agents has been to reduce the occurrence of neuropathy. Proteasome inhibitors may therefore be safer for long-term use/maintenance therapy than other agents. Infusion reactions (chills, fever, and dyspnea) have been observed with carfilzomib. Carfilzomib has been associated with pulmonary complications, renal toxicity, and cardiac events (including congestive heart failure and cardiac arrest) in 7% of treated patients. Chest pain and acute congestive heart failure may have been related to prehydration with normal saline. The toxicities of the newer agents will ultimately be important in determining whether these drugs are suitable for first-line use. TargetingApoptosisSignalingin HematologicMalignancies the processes of cell division and cell death are tightly coupled so that a net increase in cell numbers does not occur. Alterations in the expression or function of the genes controlling cell division and cell death can upset this delicate balance and are hallmarks of cancer.

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An inflammatory background is frequent medicine zolpidem buy trecator sc 250 mg lowest price, consisting of eosinophils medications safe in pregnancy order 250 mg trecator sc otc, plasma cells medicine 3605 order trecator sc cheap online, and histiocytes medications 5113 order trecator sc 250 mg otc. The T-zone variant is composed of small to medium-sized cells that preferentially involve the paracortical regions of the lymph node treatment molluscum contagiosum purchase 250 mg trecator sc visa. Constitutional symptoms, including fever and night sweats, are common, as is pruritus. The clinical course is aggressive, although complete remissions may be obtained with combination chemotherapy. It is likely that individual clinicopathologic entities will be delineated in the future from this broad group of malignancies. The disease has a long latency, and affected individuals are usually exposed to the virus very early in life. The virus may be transmitted in breast milk, and through exposure to blood and blood products. Other clinical findings include lymphadenopathy, hepatosplenomegaly, lytic bone lesions, and hypercalcemia. The acute form of the disease is associated with a poor prognosis and a median survival of less than 2 years. Chronic and smoldering forms of the disease are seen less commonly, and are associated with minimal lymphadenopathy. The predominant clinical manifestation is skin rash, with only small numbers of atypical cells in the peripheral blood. The cells are often markedly polylobated, and have been referred to as flower cells. Peripheral blood involvement is very common, but often in the absence of bone marrow disease. The function of the tumor cells as Treg cells may correlate with the associated immunodeficiency. Because of the sinusoidal location of the tumor cells, and their lobulated nuclear appearance, this disease when first observed was suspected to be of histiocytic origin. Anaplastic large cell lymphoma can show a wide spectrum in cell size, and there is a small cell variant in addition to the more typical common form. The cells (A) include "wreath cells" (center) and "hallmark cells" (bottom right). The cytoplasm is usually abundant, amphophilic, and there are distinct cytoplasmic borders. Small cell and lymphohistiocytic variants constitute part of the entity, and appear to be associated with a more aggressive clinical course. The cells exhibit an aberrant phenotype with loss of many of the T-cell associated antigens. By molecular studies, in most of the cases, a T-cell receptor rearrangement is found, confirming a T-cell origin. Although most patients present with nodal disease, a high incidence of extranodal involvement has been reported (involving skin, bone, and soft tissue). Although these lymphomas have an aggressive natural clinical history, they respond well to chemotherapy. Patients with large tumor masses may develop disseminated disease with lymph node involvement. Because the skin nodules may show spontaneous regression, usually a period of observation is warranted before the institution of any chemotherapy. Lymphadenopathy is usually not present at presentation and, when identified, is associated with a poor prognosis. Aberrant expression of other T-cell antigens may be seen but mainly occurs in the advanced (tumor) stages. Part of the controversy relates to the lack of absolute criteria to recognize these cases. In its early stages the infiltrate may appear deceptively benign, and lesions are often misdiagnosed as panniculitis. In mycosis fungoides, there is a dermal infiltrate with some malignant T cells infiltrating into the epithelium (Pautrier microabscesses) (A). The peripheral nuclear outline is fairly rounded, but the internal nuclear detail shows complex nuclear folding giving rise to a convoluted and cerebriform look. A case of subcutaneous panniculitis-like T-cell lymphoma is illustrated and shows an abnormal lymphoid infiltrate in the subcutaneous fat (C). Admixed reactive histiocytes are frequently present, particularly in areas of fat infiltration and destruction. The cause of the hemophagocytic syndrome appears related to cytokine production by the malignant cells. It is associated with an excellent prognosis, and requires only limited localized therapy, unless multiple skin lesions are present. The clinical course is aggressive, and most patients have multifocal intestinal disease. An association with celiac disease is seen only rarely, and this form of intestinal lymphoma is relatively common in Asia. While skin is the most common presenting site, lymphomas of gamma delta T-cell origin can present in other mainly extranodal sites. In enteropathy-associated T-cell lymphoma (A), there is an abnormal T-lymphoid proliferation with infiltration into the gastrointestinal glandular elements (center right). Although patients may respond initially to chemotherapy, relapse has been seen in the vast majority of cases, and the median survival is less than 3 years. Rare long-term survival has been seen following allogeneic hematopoietic cell transplantation. The pattern of infiltration mimics the homing pattern of gamma-delta T cells with marked sinusoidal infiltration in liver and spleen. Abnormal cells are usually present in the sinusoids of the bone marrow but may be difficult to identify without immunohistochemical stains. The neoplastic cells also have a phenotype that resembles that of normal resting gamma-delta T cells. However, perforin and granzyme B are usually negative, suggesting that these cells are not activated. Isochromosome 7q is a consistent cytogenetic abnormality, and is often seen in association with trisomy 8. All are seen most often in Asian children but are also reported in Central and South America, in individuals of Native American origin. The latter two conditions affect mainly the skin and have a more indolent clinical course, whereas the systemic disease has a very aggressive clinical course with survival measured in weeks. HodgkinLymphomas Hodgkin and non-Hodgkin lymphoma have long been regarded as distinct disease entities based on their differences in pathology, phenotype, clinical features, and response to therapy. Although we have become aware of this closer relationship from the histogenetic point of view (hence the name Hodgkin lymphoma), these disorders are still treated with different modalities. In addition, the presence of somatic mutations indicates transit through the germinal center. The preferred term of Hodgkin lymphoma over Hodgkin disease reflects current knowledge concerning the nature of the neoplastic cell as a lymphocyte. It affects adults (median age 50) and the most common clinical presentation is a destructive nasal or midline facial lesion. The clinical course is usually aggressive, with a slightly improved median survival in patients with localized disease, in which local radiation therapy may be useful. Low-power illustration shows vague expansile nodules that efface the lymph node architecture (A). Progressively transformed germinal centers are often seen in partially involved lymph nodes or other lymph node sites. The background is predominantly lymphocytes with or without epithelioid histiocyte clusters. Small lymphocytes in the nodules are predominantly B cells with a mantlezone phenotype. Patients with advanced stage disease may benefit from treatment regimens used for aggressive B-cell lymphomas. Progression to a process resembling T-cell/histiocyte rich large B-cell lymphoma may also been seen, and recent data suggest that these diseases may be different ends of a spectrum, with a close biologic relationship. The background contains lymphocytes, histiocytes, plasma cells, eosinophils, and neutrophils. Classic Hodgkin Lymphoma, Mixed Cellularity Patients are usually adults; males outnumber females and the stage is often advanced. It frequently presents with abdominal lymphadenopathy, spleen, liver, and bone marrow involvement, without peripheral adenopathy. The infiltrate is diffuse and often appears hypocellular, owing to the presence of diffuse fibrosis and necrosis. Classic Hodgkin Lymphoma, Nodular Sclerosis this variant is most common in adolescents and young adults, but can occur at any age; female cases equal or exceed those in males. In nodular sclerosis Hodgkin Lymphoma, broad bands of sclerosis typically divide the lymph node into cellular nodules (A). The nodules contain a mixed cellular infiltrate and scattered neoplastic cells with lobular nuclei and retracted cytoplasm (B). In mixed cellularity Hodgkin lymphoma, the lymph node is usually diffusely effaced with only fine fibrosis (C). Classic mononuclear, binuclear, and multinuclear Hodgkin and Reed-Sternberg cells are present (D). Hallek M: Chronic lymphocytic leukemia: 2015 update on diagnosis, risk stratification, and treatment. Horn H, Schmelter C, Leich E, et al: Follicular lymphoma grade 3B is a distinct neoplasm according to cytogenetic and immunohistochemical profiles. Van Loo P, Tousseyn T, Vanhentenrijk V, et al: T-cell/histiocyte-rich large B-cell lymphoma shows transcriptional features suggestive of a tolerogenic host immune response. Vater I, Montesinos-Rongen M, Schlesner M, et al: the mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing. Vose J, Armitage J, Weisenburger D: International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. Hartmann S, Doring C, Jakobus C, et al: Nodular lymphocyte predominant Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma - endpoints of a spectrum of one disease Thus the molecular analysis of these cells was hampered until methods became available to isolate these cells by microdissection from tissue sections. Hence it was initially difficult to draw firm conclusions from the study of such lines. B cells are generated in the bone marrow from hematopoietic stem cells in a multistep developmental process. B-cell development is initiated when common lymphoid progenitors undergo gene rearrangements at the Ig gene heavy chain locus. The variable part of the antibody heavy chain is composed of three gene segments: variable (V), diversity (D), and joining (J). A heavy chain can be expressed and the developmental stage of a pre-B cell is reached if the rearrangement is in-frame and productive. If this is not successful, V gene rearrangement processes take place at the light chain locus. Moreover, because of the availability of multiple V, D, and J gene segments and additional diversity generated at the joining sites of the rearranging gene segments, a V(D)J rearrangement (in particular for the heavy chain locus) is unique for each B cell and thus can be used as a clonal marker for B cells deriving from the same mature B cell. The process of somatic hypermutation introduces point mutations and some deletions and duplications at a very high rate into the Ig heavy and light chain V region genes. In the centroblasts, the process of somatic hypermutation is activated, which introduces somatic mutations at a very high rate into rearranged Ig V genes. In some cases, intraclonal diversity of V region genes was observed, indicating ongoing somatic hypermutation during clonal expansion. However, several cases were identified that lacked Ig V gene rearrangements and that showed clonal T-cell receptor gene rearrangements. HodgkinLymphomaCellLines Tumor cell lines are valuable tools for detailed genetic, biochemical, and functional studies of a malignancy. However, later studies showed that this line represents a cell culture contamination. These cells are defined as rare cells that have a particular proliferative potential and that sustain the tumor clone, whereas the bulk of the tumor clone lacks the potential to regrow to a full tumor. It is thus an intriguing question how these two types of cells are related to each other. It was proposed that fusion of two independent cells might be involved in the generation of Reed-Sternberg cells from Hodgkin cells. Notably, the pattern of both shared and distinct V gene mutations in the majority of these cases revealed that the two lymphomas share a common precursor, but developed separately from this precursor. The horizontal line within the cells indicates an Ig V region gene; the vertical lines indicate somatic Ig V gene mutations. In several types of tumors, side population cells were shown to share features with cancer stem cells. There are a few cases where the two lymphomas are not related to each other and hence represent the chance occurrence of two unrelated malignancies developing in parallel in a patient. Thus these composite lymphomas usually do not represent the transformation of one lymphoma into the other but, rather, the parallel development of the two malignant clones from a common, premalignant precursor cell. Therefore composite lymphomas are intriguing models to study the multistep transformation process in lymphomagenesis. In initial studies of several composite lymphomas for shared and distinct transforming events, examples for such genetic lesions were indeed identified. Moreover, the coexpression of multiple master regulators of different hematopoietic cell lineages.

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Some practitioners avoid the prescription of prophylactic antibiotics medications related to the blood purchase trecator sc in united states online, others recommend prophylactic antibiotics for at least 5 years postsplenectomy treatment quadriceps strain discount 250mg trecator sc, and others recommend their use for life treatment urticaria buy trecator sc 250 mg with amex. The recurrence of hemolytic anemia several years after splenectomy should raise the suspicion of development of splenunculi holistic medicine trecator sc 250 mg low price, resulting from autotransplantation of splenic tissue during surgery medicine quotes doctor order trecator sc online from canada. The presence of an accessory spleen or splenunculus is suggested by the absence of both Howell-Jolly bodies and the "pitted" cells with crater-like surface indentations readily seen by interference contrast microscopy. Gene cloning and determination of the primary structure of these proteins was soon followed by reports of mutations in the genes encoding erythrocyte membrane proteins. Both - and -spectrin are elongated flexible molecules consisting of triple-helical repeats connected by nonhelical segments. Spectrin heterodimers associate head to head to form spectrin tetramers, the major structural subunits of the membrane skeleton. Spectrin tetramers in turn are interconnected into a highly ordered two-dimensional lattice through binding, at their distal ends, to actin oligomers with the aid of protein 4. Spectrin dimer-tetramer interconversion is governed by a simple thermodynamic equilibrium that under physiologic conditions strongly favors spectrin tetramers. These mutations create abnormal proteolytic cleavage sites that typically reside in the third helix of a repetitive segment and give rise to abnormal tryptic peptides on two-dimensional tryptic peptide maps of spectrin. All of these mutations open a proteolytic cleavage site residing in the third helix of the combined repetitive segment, which gives rise to a 74-kDa I peptide. Although most spectrin mutations reside in the vicinity of the -spectrin self-association site, a few mutations remote from the self-association site have been described. These mutations are asymptomatic in the simple heterozygous state but cause hemolytic anemia, which can be severe, in homozygous patients. When an upstream initiator methionine is used, isoforms greater than 80 kDa are synthesized. During erythropoiesis, this upstream initiator methionine is spliced out and a downstream initiator methionine is used, leading to the production of the 80-kDa mature erythroid protein 4. In contrast, patients deficient in glycophorin A, the major transmembrane glycoprotein, are asymptomatic. Spectrin is composed of - and -spectrin heterodimers (SpD) that associate in their head regions into tetramers. At their distal ends, SpD bind to the junctional complexes of oligomeric actin (band 5 [5]) and protein 4. Additional proteins found in the junctional complex, such as adducin and tropomyosin, are shown in the lower enlarged area. The membrane skeleton is attached to transmembrane proteins by interactions of -spectrin with ankyrin (protein 2. 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.

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A patient having an aplastic crisis with a reticulocyte count that is recovering is less likely to require urgent transfusion than one with a normal or low absolute reticulocyte count medicine that makes you throw up order trecator sc amex. Bone marrow necrosis treatment for piles buy trecator sc, which also may be the result of parvovirus infection medicine cabinet shelves buy trecator sc with a visa, characterized by fever symptoms hypoglycemia trecator sc 250mg line, bone pain treatment myasthenia gravis purchase trecator sc 250mg free shipping, reticulocytopenia, and a leukoerythroblastic response, also causes aplastic crisis. When transfusion is necessitated by the degree of anemia or cardiorespiratory symptoms, a single transfusion usually will suffice because reticulocytosis resumes spontaneously within a few days. Transfusion may be avoided by keeping severely anemic patients on bed rest to prevent symptoms and by avoiding supraphysiologic oxygen tensions. A Acute splenic sequestration of blood is characterized by acute exacerbation of anemia; persistent reticulocytosis; a tender, enlarging spleen; and sometimes hypovolemia. In one study, 30% of children had splenic sequestration over a 10-year period and 15% of the attacks were fatal. Because splenic sequestration recurs in 50% of cases, splenectomy is recommended after the event has abated. Alternatively, chronic transfusion therapy is used in young children to delay splenectomy until it can be tolerated safely. Because recurrence is possible during transfusion therapy, parents should be trained to detect a rapidly enlarging spleen and to seek immediate medical attention in this event. After alloimmunization, there is a subsequent decrease in antibody titer that can fall below serologically detectable levels. This can result in a delayed hemolytic transfusion reaction produced by the amnestic response of the immune system (as opposed to the immediate hemolytic reaction that occurs with preformed antibody). Bone marrow aspirate in a patient with sickle cell disease and aplastic crisis (A). Note the absence of red blood cell precursors except for the single, large degenerating pronormoblast (lower center). Such pronormoblasts contain large nuclear inclusions (B) as a result of replication of parvovirus B19. The parvovirus can now be recognized immunohistochemically with an immunostain (E). Chapter42 SickleCellDisease 597 bystander effect of destruction of recipient blood (not just donor blood) can result in unanticipated worsening of anemia to levels below that seen before transfusion. Resolution of severe anemia may only occur after withholding further transfusions with subsequent reticulocyte count recovery. Intravenous immunoglobulin can also be considered, with proper attention paid to avoiding iatrogenic fluid overload. Approaches to minimizing this complication include transfusing extended-matched (see Basic Management and Disease Modification), phenotypically compatible blood. By 5 years of age, almost all patients are functionally asplenic, contributing to infectious susceptibility. Historically, pneumococcal sepsis has been the predominant cause of death in those younger than 20 years of age. If suspected, the approach to management should first be to look for an underlying etiology, which may be one of the events listed earlier: aplastic crisis (during the recovery phase when the reticulocyte count may not be decreased), sequestration crisis, delayed hemolytic transfusion reaction, or autoimmune hemolysis. Penicillin Prophylaxis and Pneumonia Vaccination Erythropoietin Deficiency this entity is discussed under Basic Management and Disease Modification. Data and recommendations regarding penicillin prophylaxis and pneumonia vaccination are discussed under Basic Management and Disease Modification. Nutritional Deficiencies: Folate, Iron, or Vitamin B12 Deficiency this entity is discussed under Basic Management and Disease Modification. Staphylococcus aureus OtherPathogens Streptococcus pneumoniae bacteremia is accompanied by leukocytosis, a left shift, aplastic crisis, sometimes disseminated intravascular coagulation, and a 20% to 50% mortality rate. Rapid administration of antibiotics has resulted in a lower incidence of meningitis among patients with bacteremia than 20 years ago when the incidence was 50%. Please see Pulmonary Complications for further discussions regarding pneumonia and acute chest syndrome. Salmonella and Osteomyelitis In this patient population, osteomyelitis is commonly caused by Salmonella spp. It has been reported to cause bone marrow necrosis, acute chest syndrome, pulmonary fat embolism, hepatic sequestration, and glomerulonephritis. Escherichia coli is the most common uropathogen and can cause septicemia in these patients. Smaller arterioles and capillaries demonstrate distension, thrombosis, and vessel-wall necrosis. Even in patients without silent or overt cerebral infarction, cognitive functioning can be impaired. Less well-documented but potentially modifiable risk factors include alcohol or drug use, oral contraceptive use, and sleep-disordered breathing. Intracranial hemorrhage results in the same signs as thrombosis, but in addition, neck stiffness, photophobia, severe headache, vomiting, and altered consciousness may occur. Although the mortality rate may be as high as 50%, the morbidity of survivors is low. Hemorrhage may be subarachnoid, intraparenchymal, or intraventricular, which can be differentiated by angiography. The favorable neurosurgical outcome in subarachnoid hemorrhage caused by ruptured aneurysm justifies an aggressive approach to diagnosis, transfusion, vasodilatory therapy, and surgery. Over a period of more than 2 years, the risk of stroke was reduced to less than 1% per year in the transfused group171 (a risk reduction of >90%). The ability of transfusion to curtail progression of large-vessel stenosis has also been proven with angiography. This trial evaluated discontinuation of transfusion after at least 30 months in children who had not had an overt stroke and in whom the cerebral flow rates decreased to low risk (<170 cm/s) with transfusion. Therefore there is a need for alternatives, especially because some patients and physicians believe that the 10% annual stroke risk does not warrant the risks and burdens of chronic transfusion. Stem cell transplantation has resulted in stabilization of cerebral vasculopathy178 but there is a mortality risk with this procedure of between 6% and 10%. Other modifiable risk factors for stroke (see Cerebrovascular Accidents, Pathophysiology, Incidence, Risk Factors, and Presentation) should be identified and treated. Notably, in the general population, hypertension is particularly associated with a risk for hemorrhagic stroke, and effective treatment of hypertension can produce a relative risk reduction of 26% for ischemic stroke and 49% for hemorrhagic stroke. Patients with systolic pressures in the higher range for the sickle cell group, even with systolic pressures less than 140 mmHg, had an increased risk of first ischemic stroke (there were insufficient events to make firm conclusions regarding hemorrhagic stroke). This treatment also provides incidental protection against pain crises, bacterial infections, acute chest syndrome, and hospitalization. This may not be feasible for administrative reasons or because of allosensitization or iron overload for which the patient is unable or unwilling to undergo treatment. Stem cell transplantation has resulted in stabilization of cerebral vasculopathy,178 but the risk of a second neurologic event is higher in the peritransplant period, and the mortality rate with this procedure is between 6% and 10%. In both thrombosis and hemorrhage, prompt partial-exchange transfusion is performed, and chronic direct transfusion to maintain the Hb S level below 30% is instituted to prevent recurrent events (see also Basic Management and Disease Modification) and promote resolution of arterial stenoses. In one study, 21 of 152 patients in a pediatric clinic had seizures, four of which were related to meperidine therapy. The common acute complications are pneumonia and acute chest syndrome, and the common chronic complication is pulmonary hypertension. Antibiotic therapy for pneumonia or acute chest syndrome should cover these agents in addition to pneumococcus and H. However, it should be borne in mind that the usual etiology might be both vasoocclusion and infection simultaneously, and in almost all cases of acute chest syndrome, antibiotics should be administered. Many episodes in which common pathogens are not cultured are caused by "atypical" agents (Mycoplasma, Legionella, and Chlamydia spp. Pulmonary fat embolus, evidenced by stainable fat in pulmonary macrophages obtained by bronchoalveolar lavage or sputum induction, is found in 44% to 60% of cases of acute chest syndrome. Some patients have a rapidly progressive course associated with a precipitous decrease in arterial oxygen tension; they may require intensive care treatment. If there are clinical signs of respiratory distress or when arterial oxygen tension cannot be maintained above 70 mmHg with inhaled oxygen, partialexchange transfusion is indicated. Chronic complications such as pulmonary hypertension occur in as many as 60% of patients. Blood gas and pulmonary function measurements should be obtained as baseline data for all patients. The level rises after the first decade, possibly as a result of chronic hepatobiliary dysfunction. Alkaline phosphatase levels are elevated in all genotypes until puberty, which occurred later in males and in those with sickle cell anemia. Some have recommended the surgical removal of asymptomatic gallstones to avoid subsequent difficulty in distinguishing gallbladder pain from acute painful episodes. This approach has become more feasible with the availability of laparoscopic cholecystectomy. Acute Hepatic Sequestration Crisis Acute hepatic sequestration crisis presents with acute hepatic enlargement and a dramatic fall in Hb concentration, the most likely mechanism being sequestration of sickled erythrocytes in the liver. Intrahepatic Cholestasis Maternal complications include increased rates of painful episodes, severe anemia caused by iron or folate deficiencies, exaggeration of the physiologic "anemia of pregnancy," increased infections (urinary tract infections, pneumonias, endometritis), preeclampsia, and death. The occurrence of a perinatal death in a previous pregnancy and the presence of twins in the present pregnancy are two major risk factors for an unfavorable outcome. Better fetal and maternal outcomes in recent years are largely attributable to generally improved antenatal and obstetric care. Patients should be followed in a high-risk obstetric clinic in addition to the hematology clinic and receive the usual vitamin, mineral, and folate supplements. There is no specific therapeutic or preventive treatment for intrauterine growth retardation. Some experts recommend prophylactic transfusion, but a large controlled study showed no improvement in fetal outcome from this management option, although maternal symptoms are reduced. If the Hb is between 8 and 10 g/dL and transfusion is indicated for any of the reasons above, partial exchange should be performed. Some experts advise that hypertonic saline injections are contraindicated for elective termination of pregnancy because of the risk of sickling-induced vasoocclusion. There are anecdotal reports of a higher incidence of acute painful episodes after therapeutic abortion; inpatient intravenous hydration before and for the 24 hours after the procedure is recommended. Sickle cell intrahepatic cholestasis results in severe, asymptomatic hyperbilirubinemia without fever, pain, leukocytosis, hepatic failure, or death. Evidence of progressive liver dysfunction should prompt consideration of acute hepatic cell crisis and exchange transfusion. Liver transplantation has been used successfully as therapy for this complication. Pregnancy entails increased risks to the mother and child compared with the general population. Another caution with low-dose estrogen oral contraception is the risk of contraceptive failure with less than excellent compliance. There may be risks to contraception, but against this must be weighed the risks of unintended pregnancy. Sexually active women should have routine pelvic examinations and birth control instructions. Renal Complications Hypertension, proteinuria, hematuria, increasing anemia, and nephrotic syndrome reliably predict progression to renal failure, which are clinical indices to pay attention to because the serum creatinine may be misleading. Patients with sickle cell anemia exhibit an increased proximal tubular secretion of creatinine. Thus patients may have a significant decline in renal function before it is detectable by measuring creatinine clearance. These patients typically survive and recover their renal function with no increased risk of developing chronic renal failure. There are seven well-described nephropathies that affect patients with either sickle cell trait or disease. These are gross hematuria, papillary necrosis, nephrotic syndrome, renal infarction, inability to concentrate urine, pyelonephritis, and renal medullary carcinoma. When water deprived, these patients cannot maximally concentrate their urine and develop hypovolemia and dehydration. Other abnormalities of renal tubular dysfunction found in sickle cell anemia include an incomplete form of distal renal tubular acidosis with hyperchloremic metabolic acidosis and hyperkalemia. Urinary Tract Infections Urinary tract infections and pyelonephritis are discussed under infectious complications. Renal Medullary Carcinoma Renal Endocrine (Erythropoietin) Deficiency this is discussed under Basic Management and Disease Modification. Sickle cell trait has been reported to be associated with renal medullary carcinoma. Gross Hematuria Hematuria may result from microthrombi formation in the peritubular capillaries of the renal medulla or from frank papillary necrosis. Significant hematuria may resolve with high urinary flow through oral hydration and bed rest. These therapies are aimed at changing the acidic, hypertonic environment of the renal medulla that favors erythrocyte dehydration, increased Hb S concentrations, and Hb S polymerization. If bleeding persists for 72 hours despite these measures, then alternative treatment should be considered. Embolization or nephrectomy should be reserved for prolonged, life-threatening cases of hematuria that require multiple transfusions.


  • Omoto R, Yokote Y, Takamoto S, et al: The development of real-time two-dimensional Doppler echocardiography and its clinical significance in acquired valvular diseases. With special reference to the evaluation of valvular regurgitation, Jpn Heart J 25:325-340, 1984.
  • Nakano H, Soda H, Takasu M, et al. Heterogeneity of epidermal growth factor receptor mutations within a mixed adenocarcinoma lung nodule. Lung Cancer 2008;60:136-40.
  • Coen JJ, Paly JJ, Niemierko A, et al: Nomograms predicting response to therapy and outcomes after bladder-preserving trimodality therapy for muscle-invasive bladder cancer, Int J Radiat Oncol Biol Phys 86(2):311n316, 2013.
  • Cooper Jr LT, et al. Usefulness of immunosuppression for giant cell myocarditis. Am J Cardiol 2008;102:1535-1539.
  • Dale RA. Dentoalveolar trauma. Emerg Med Clin North Am 2000;18:521-538.
  • Jahromi AS, Cina CS, Liu Y, et al. Sensitivity and specificity of color duplex ultrasound measurement in the estimation of internal carotid artery stenosis: a systematic review and meta-analysis. J Vasc Surg. 2005;41:962-972.
  • Shook LL, Whittle R, Rose EF. Rectal fist insertion. An unusual form of sexual behaviour. Am J Forensic Med Pathol 1985; 6:319.