Human telomere disease due to disruption of the CCAAT box of the TERC promoter

Mutations in the coding region of telomerase complex genes can result in accelerated telomere attrition and human disease. Manifestations of telomere disease include the bone marrow failure syndromes dyskeratosis congenita and aplastic anemia, acute myeloid leukemia, liver cirrhosis, and pulmonary fibrosis. Here, we describe a mutation in the CCAAT box (GCAAT) of the TERC gene promoter in a family in which multiple members had typical features of telomeropathy. The genetic alteration in this critical regulatory sequence resulted in reduced reporter gene activity and absent binding of transcription factor NF-Y, likely responsible for reduced TERC levels, decreased telomerase activity, and short telomeres. This is the first description of a pathogenic mutation in the highly con-served CCAAT box and the first instance of a mutation in the promoter region of TERC producing a telomeropathy. We propose that current mutation-screening strategies should include gene promoter regions for the diagnosis of telomere diseases. This clinical trial was registered at www.clinicaltrials.gov as #NCT00071045. (Blood. 2012;119(13):3060-3063)

[Pharmacotherapy of hyperthyreosis--adverse drug reactions]

The antithyroid drugs mainly include thioimidazole (carbimazole, methimazole=thiamazole) and propylthiouracil. After absorption, carbimazole is rapidly metabolized to methimazole and thus switching between these two drugs should not be considered in case of side effects. Furthermore, in case of side effects, sometimes even cross reactions between thioimidazoles and propylthiouracil occur. Common and typical adverse reactions of antithyroid drugs include dose dependent hypothyroidism and thus thyroid function should be repeatedly checked while the patient is on antithyroid drugs. Furthermore, pruritus and rash may develop. In this case, one might try to switch from thioimidazoles to propylthiouracil or vice versa. Antithyroid drugs may cause mild dose dependent neutropenia or severe allergy-mediated agranulocytosis, which typically occurs during the first three months of treatment, has an incidence of 3 per 10,000 patients and cross reactivity between thioimidazoles to propylthiouracil may occur. Rarely, antithyroid drugs can cause aplastic anemia. Mainly propylthiouracil, but sometimes also methimazole may lead to an asymptomatic transient increase in liver enzymes or to severe, even lethal liver injury of cholestatic or hepatocellular pattern. Since propylthiouracil associated liver injury was observed increasingly among children and adolescent, it has been suggested to prefer thioimidazoles for these patients. Because of these potential serious adverse effects, physicians should advise patients to immediately seek medical help if they get a fever or sore throat or malaise, abdominal complaints or jaundice, respectively. Furthermore, arthralgias may develop in 1-5% of patients under both antithyroid drugs. Since arthralgias may be the first symptom of more serious immunologic side effects, it is recommended to stop the antithyroid drug in this case. Drug induced polyarthritis mainly develops during the first month of therapy, whereas ANCA-positive vasculitis is generally observed only after long term exposure to propylthiouracil or very rarely with the thioimidazoles. The teratogenic risk of the thioimidazoles is somewhat higher (Aplasia cutis congenita), that is why one generally recommends preferring propylthiouracil during pregnancy. During breast feeding both, thioimidazoles or propylthiouracil, may be administered. Nowadays, perchlorate is only used short term in case of latent hyperthyroidism before administering iodine-containing contrast agents. Therefore, the known side effects, which usually are only observed after long term treatment, are not an issue any more.

Is Acute Fibrinous and Organizing Pneumonia the Expression of Immune Dysregulation?

INTRODUCTION: Acute fibrinous and organizing pneumonia (AFOP) is a recently described histologic pattern of diffuse pulmonary disease. In children, all cases reported to date have been fatal. In this study, we describe the first nonfatal AFOP in a child and review the literature. DESCRIPTION: A 10-year-old boy developed very severe aplastic anemia (VSAA) after being admitted to our hospital with a fulminant hepatic failure of unknown origin. A chest computed tomography scan revealed multiple lung nodules and a biopsy of a pulmonary lesion showed all the signs of AFOP. Infectious workup remained negative. We started immunosuppressive therapy with antithymocyte globulin and cyclosporine to treat VSAA. Subsequent chest computed tomography scans showed a considerable diminution of the lung lesions but the VSAA did not improve until we performed hematopoietic stem cell transplantation 5 months later. CONCLUSIONS: Aplastic anemia is associated with a variety of autoimmune syndromes. The sequence of events in our patient suggests that the hepatic failure, AFOP, and the VSAA may all have been part of an autoimmune syndrome. AFOP could be the result of immune dysregulation in this pediatric case with favorable outcome after immunosuppressive therapy and hematopoietic stem cell transplantation.

Longitudinal data on telomere length in leukocytes from newborn baboons support a marked drop in stem cell turnover around 1 year of age

Stem cells of various tissues are typically defined as multipotent cells with 'self-renewal' properties. Despite the increasing interest in stem cells, surprisingly little is known about the number of times stem cells can or do divide over a lifetime. Based on telomere-length measurements of hematopoietic cells, we previously proposed that the self-renewal capacity of hematopoietic stem cells is limited by progressive telomere attrition and that such cells divide very rapidly during the first year of life. Recent studies of patients with aplastic anemia resulting from inherited mutations in telomerase genes support the notion that the replicative potential of hematopoietic stem cells is directly related to telomere length, which is indirectly related to telomerase levels. To revisit conclusions about stem cell turnover based on cross-sectional studies of telomere length, we performed a longitudinal study of telomere length in leukocytes from newborn baboons. All four individual animals studied showed a rapid decline in telomere length (approximately 2-3 kb) in granulocytes and lymphocytes in the first year after birth. After 50-70 weeks the telomere length appeared to stabilize in all cell types. These observations suggest that hematopoietic stem cells, after an initial phase of rapid expansion, switch at around 1 year of age to a different functional mode characterized by a markedly decreased turnover rate.

Effects of high-yield thrombocytapheresis on the quality of platelet products

BACKGROUND: The steadily increasing demands for single-donor apheresis platelet (PLT) concentrates (APCs) are a challenge to the PLT supply system. Therefore, efforts to improve plateletpheresis yield, allowing apheresis products to be split into 2 or more units, are valuable strategies. No data to demonstrate in vivo transfusion efficacy of these high-yield split-APCs are currently available, however. STUDY DESIGN AND METHODS: The transfusion efficacy of APCs produced by two apheresis methods involving different harvest and storing procedures and varying PLT yields was investigated. Efficacy measures were the 1-hour percent PLT recovery (PPR(1h)) and the 1-hour corrected count increment (CCI(1h)). In total, 400 APCs, produced with either an Amicus device (Baxter) and stored in PLT additive solution (T-Sol; Amicus method [AM], n = 107) or a Trima device (Gambro) and stored in plasma (Trima method [TM], n = 293), were transfused to 55 children (31 girls; median age, 9.5 years; range, 0.2-18.5 years) with thrombocytopenia due to chemotherapy or aplastic anemia (median, 4 APCs per child; range, 1-68). RESULTS: Transfusion efficacy was significantly lower for AM-APCs than for TM-APCs (median PPR(1h), 17 and 33%; median CCI(1h), 7.9 and 15.6, respectively; p < 0.001). Reduced transfusion efficacy correlated in a yield-dependent manner with high apheresis PLT yields (>/=6 x 10(11)) for AM-APCs (p < 0.001). CONCLUSION: Although in vitro validation of AM- and TM-APCs has been performed, only by evaluating transfusion efficacy in vivo did the AM turn out to be not suitable for high-yield thrombocytapheresis. This study recommends the implementation of in vivo transfusion efficacy studies for high-yield APC apheresis donations.

Transfusion efficacy of ABO major-mismatched platelets (PLTs) in children is inferior to that of ABO-identical PLTs

BACKGROUND: ABO major compatibility is essential in transfusions of red blood cells but is not requisite in PLT transfusions. In adults there is some evidence that transfusion efficacy of ABO blood group-identical platelets (PLTs) is superior to major-mismatched PLTs. However, in children this question has not been investigated for more than 30 years. STUDY DESIGN AND METHODS: In a prospective study, the efficacy (based on the 1-hour percentage of PLT recovery [PPR(1hr)]) of 400 eligible ABO blood group-identical or out-of-group apheresis PLT concentrates (APCs), transfused mainly prophylactically to 50 children with hematologic malignancies, solid tumors, or aplastic anemia was investigated. The primary objective was to compare PPR(1hr) between ABO-identical and major-mismatched transfusions. RESULTS: After ABO major-mismatched transfusions, PPR(1hr) was significantly lower than after ABO blood group-identical transfusions (median 21% vs. 32%; p = 0.034). Multivariate analysis showed major-mismatched transfusions to be significantly more often unsuccessful than identical transfusions (odds ratio [OR], 3.97; 95% confidence interval [CI], 1.52-10.39; p = 0.005). Using flow cytometry and fluorescent microscopy, it could be demonstrated that PLTs of subgroup A(1), significantly expressing A antigen on their surface, were rapidly cleared from the circulation of group O or B recipients. In contrast, major-mismatched transfusions of A(2) PLTs, expressing no detectable A antigen, were as successful as identical transfusions (OR, 1.13; 95% CI, 0.16-7.88; p = 0.90). CONCLUSION: These data clearly indicate that in children ABO major-mismatched PLT transfusions result in inferior transfusion efficacy, with the only exception of group A(2) PLTs. ABO minor-mismatched PLTs showed comparable efficacy to identical transfusions.

BENZENE TOXICITY AND THE OCCURRENCE OF BENZENE IN THE AMBIENT AIR OF THE HOUSTON AREA

This study was conducted by either literature review or actual field survey. Results are summarized as follows: (1) Long-term occupational exposure of workers to benzene vapor at levels of 3-7 ppm, 2-3 ppm and 1.6 ppm may result in a decreased level of leucocyte alkaline phosphates, an increased incidence of chromosome aberrations and an increased level of ALA in erythrocytes, respectively; (2) Benzene is capable of causing fetotoxic effects in animals at levels as low as 10 ppm by volume; (3) Exposure of animals to or less than 1 ppm benzene vapor may result in leucopenia, an inverse ratio of muscle antagonist chronaxy and a decreased level of ascorbic acid in fetus's and mother's liver as well as whole embryo; (4) Benzene is causally associated with the increased incidence of pancytopenia, including unicytopenia, bicytopenia and aplastic anemia, and chromosome aberrations in occupational exposure population, and at best benzene must also be considered as a leukemogen; (5) Since it can be emitted into the atmosphere from both man-made and natural sources, benzene in some concentrations is present everywhere in the various compartments of the environment; (6) The findings of the emission of benzene from certain natural sources indicate that reducing benzene to a zero-level of exposure is theoretically impossible; (7) The annual average of benzene concentration detected in the Houston ambient air is 2.50 ppb, which is about 2.4 times higher than the nation-wide annual average exposure level and may have been some health implications to the general public; (8) In the Houston area, stationary sources are more important than mobile sources in contributing to benzene in the ambient air. ^

Study of chronic hemolytic anaemia patients in Rio de Janeiro: prevalence of anti-human parvovirus B19 IgG antibodies and the developement aplastic crises

The prevalence of anti-human parvovirus B19 IgG antibodies was determined in sera from 165 chronic hemolytic anemia patients, receiving medical care at Instituto Estadual de Hematologia (IEHE), Rio de Janeiro, during the year of 1994. This sample represents around 10% of the chronic hemolytic anemia patients attending at IEHE. Most of these patients (140) have sickle cell disease. Anti-B19 IgG antibodies were detected in 32.1% of patients. No statistically significant difference (p > 0.05) was seen between IgG antibody prevalence in male (27.8%) and female (35.5%) patients. Anti-B19 IgG antibodies were more frequent in older (37.6%) than younger (28.2%) than 20 years old patients, although this difference had no statistical significance (p > 0.05). Anti-B19 IgG antibody prevalence showed that 67.9% of patients enrolled in the study were susceptible to B19 acute infection. With the aim to detect acute B19 infection, patients follow up continued until February 1996. During this period four patients presented transient aplastic crisis due to human parvovirus B19 as confirmed by the detection of specific IgM antibodies. All four patients were younger than 20 years old, and 3 were younger than 10 years old. Three of them were sickle cell disease patients. Three of the four acute B19 infection occurred during 1994 springtime.

Aplastic crisis caused by parvovirus B19 in an adult patient with sickle-cell disease

We describe a case of aplastic crisis caused by parvovirus B19 in an adult sickle-cell patient presenting with paleness, tiredness, fainting and dyspnea. The absence of reticulocytes lead to the diagnosis. Anti-B19 IgM and IgG were detected. Reticulocytopenia in patients with hereditary hemolytic anemia suggests B19 infection.

Farmacocinética e farmacodinâmica de derivado ftalimídico planejado para o tratamento da anemia falciforme

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Prominent Role Of Platelets In The Formation Of Circulating Neutrophil-red Cell Heterocellular Aggregates In Sickle Cell Anemia.

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Evaluation Of Red Cell And Reticulocyte Parameters As Indicative Of Iron Deficiency In Patients With Anemia Of Chronic Disease.

The purpose of this study was to evaluate the effectiveness of mature red cell and reticulocyte parameters under three conditions: iron deficiency anemia, anemia of chronic disease, and anemia of chronic disease associated with absolute iron deficiency. Peripheral blood cells from 117 adult patients with anemia were classified according to iron status, and inflammatory activity, and the results of a hemoglobinopathy investigation as: iron deficiency anemia (n=42), anemia of chronic disease (n=28), anemia of chronic disease associated with iron deficiency anemia (n=22), and heterozygous β thalassemia (n=25). The percentage of microcytic red cells, hypochromic red cells, and levels of hemoglobin content in both reticulocytes and mature red cells were determined. Receiver operating characteristic analysis was used to evaluate the accuracy of the parameters in differentiating between the different types of anemia. There was no significant difference between the iron deficient group and anemia of chronic disease associated with absolute iron deficiency in respect to any parameter. The percentage of hypochromic red cells was the best parameter to discriminate anemia of chronic disease with and without absolute iron deficiency (area under curve=0.785; 95% confidence interval: 0.661-0.909, with sensitivity of 72.7%, and specificity of 70.4%; cut-off value 1.8%). The formula microcytic red cells minus hypochromic red cells was very accurate in differentiating iron deficiency anemia and heterozygous β thalassemia (area under curve=0.977; 95% confidence interval: 0.950-1.005; with sensitivity of 96.2%, and specificity of 92.7%; cut-off value 13.8). The indices related to red cells and reticulocytes have a moderate performance in identifying absolute iron deficiency in patients with anemia of chronic disease.

Guidelines On The Treatment Of Anemia Of Chronic Renal Failure Using Recombinant Human Erythropoietin: Associação Brasileira De Hematologia, Hemoterapia E Terapia Celular Guidelines Project: Associação Médica Brasileira - 2014.

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Unusual Erythrocyte Split Chimerism In Pregnancy After Allogeneic Stem Cell Transplantation.

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Necrose cerebelar extensa na anemia falciforme: relato de um caso

A 6 month-old mulatto boy was admitted on account of acute gastroenteritis, malnutrition and dehydration. In the hospital, the child developed septicemia, and temperature reached up to 38.6°C. Despite intensive antibiotic treatment, the patient died 12 days after admission. Necropsy disclosed bilateral bronchopneumonia, bilateral fronto-parietal subarachnoid hemorrhage, and extensive necrosis of the inferior half of both cerebellar hemispheres. On histopathological examination of the necrotic cerebellar cortex, numerous sickled erythrocytes were observed in petechial hemorrhages and, in lesser quantities, inside capillaries. Lesions of the central nervous system in sickle cell anemia most often involve the cerebral cortex, and a single extensive cerebellar infarction as present in this case seems extremely rare. The pathogenetic mechanism of the necrosis is unclear, since thrombosis was not observed either in large blood vessels or in capillaries. Possible contributory factors were the infectious condition (septicemia), fever, and anoxia caused by the extensive bronchopneumonia.