Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019045 (hemoglobinopathies)
 2,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Achieving long-term pancellular expression of a transferred gene at therapeutic level in a given hematopoietic lineage remains an important goal of gene therapy. Advances have recently been made in the genetic correction of the hemoglobinopathies by means of lentiviral vectors and large locus control region (LCR) derivatives. However, panerythroid beta globin gene expression has not yet been achieved in beta thalassemic mice because of incomplete transduction of the hematopoietic stem cell compartment and position effect variegation of proviruses integrated at a single copy per genome. Here, we report the permanent, panerythroid correction of severe beta thalassemia in mice, resulting from a homozygous deletion of the beta major globin gene, by transplantation of syngeneic bone marrow transduced with an HIV-1-derived [beta globin gene/LCR] lentiviral vector also containing the Rev responsive element and the central polypurine tract/DNA flap. The viral titers produced were high enough to achieve transduction of virtually all of the hematopoietic stem cells in the graft with an average of three integrated proviral copies per genome in all transplanted mice; the transduction was sustained for >7 months in both primary and secondary transplants, at which time approximately 95% of the red blood cells in all mice contained human beta globin contributing to 32 +/- 4% of all beta-like globin chains. Hematological parameters approached complete phenotypic correction, as assessed by hemoglobin levels and reticulocyte and red blood cell counts. All circulating red blood cells became and remained normocytic and normochromic, and their density was normalized. Free alpha globin chains were completely cleared from red blood cell membranes, splenomegaly abated, and iron deposit was almost eliminated in liver sections. These findings indicate that virtually complete transduction of the hematopoietic stem cell compartment can be achieved by high-titer lentiviral vectors and that position effect variegation can be mitigated by multiple events of proviral integration to yield balanced, panerythroid expression. These results provide a solid foundation for the initiation of human clinical trials in beta thalassemia patients.
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PMID:Permanent and panerythroid correction of murine beta thalassemia by multiple lentiviral integration in hematopoietic stem cells. 1239 30

In order to test the accuracy of glycated hemoglobin (HbA1c) in predicting mean glycemia in HIV-infected patients, we recorded consecutive HbA1c measurements from 1238 non-HIV-infected and 112 HIV-infected patients, all devoid of any hemoglobinopathy, in a retrospective, transversal study. Mean fasting glycemia from the six previous weeks (measured-Gly) and HbA1c-estimated glycemia [HbA1c-Gly (1.85x%HbA1c-4.78) mM] were compared. Mean hemoglobin, red cell volume, serum creatinine, CD4 count, and HIV viral load from the same period were collected in HIV-infected patients. Although measured-Gly was not significantly different between non-HIV-infected (6.95+/-3.23 mM) and HIV-infected patients (6.62+/-2.42 mM), HbA1c underestimated the mean fasting glycemia by 12.3% in HIV-infected as compared to non-HIV-infected patients (p=0.0001). The difference "measured-Gly-HbA1c-Gly" was correlated with the red cell volume (p<0.0001) in HIV-infected patients. We then searched for the presence of subclinical hemolysis, a cause of both macrocytosis and reduced HbA1c levels, in HIV-infected patients. To this end, we prospectively measured serum haptoglobin in 249 consecutive samples from HIV-infected subjects without any known cause of hemolysis. A very low haptoglobin level, a marker of hemolysis, was frequent and negatively correlated with the red cell volume in these patients. Treatment with nucleoside analogues was significantly associated with macrocytosis and low haptoglobin. In conclusion, HbA1c could be inappropriately low in HIV-infected patients. Its underestimation of mean fasting glycemia could be due to an antiretroviral-induced subclinical hemolysis, but further studies are needed to explore this hypothesis. Self-monitoring of blood glucose and search for latent hemolysis should be promoted in diabetic HIV-infected patients.
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PMID:Inappropriately low glycated hemoglobin values and hemolysis in HIV-infected patients. 1720 66

Modern health care has greatly increased longevity for patients with congenital hemolytic anemias (such as sickle cell disease and thalassemia) and human immunodeficiency virus (HIV) infection. It is estimated that 10% of patients with hemoglobinopathies and 0.5% of patients with HIV infection develop moderate to severe pulmonary hypertension. Pulmonary hypertension is a relentlessly progressive disease leading to right heart failure and death. Worldwide, there are an estimated 30 million patients with sickle cell disease or thalassemia and 40 million patients with HIV disease. Considering the prevalence of pulmonary vascular disease in these populations, sickle cell disease and HIV disease may be the most common causes of pulmonary hypertension worldwide. In this review, the available data on epidemiology, hemodynamics, mechanisms, and therapeutic strategies for these diseases are summarized. Because therapy is likely to reduce morbidity and prolong survival, efforts to screen, diagnose, and treat these patients represent a global health opportunity.
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PMID:Pulmonary hypertension: an increasingly recognized complication of hereditary hemolytic anemias and HIV infection. 1846 Jun 61

Muscle compromise associated with diabetes includes muscle infarction, myositis, pyomyositis, and abscess formation. These conditions may also be seen in various other conditions, such as trauma, alcoholism, neoplasia, vasculopathy, HIV infection, and other immunocompromised states and hemoglobinopathies. Due to recent advances in imaging technology, these entities are readily detected and treated at an earlier stage. Different diagnostic modalities may be used, particularly magnetic resonance imaging (MRI), which is best for soft-tissue pathologies. Muscle infarction appears with acute edema and inflammatory changes on T1- and T2-weighted images, enhancing peripherally postcontrast, and nonenhancing central areas suggestive of necrosis, lacking focal fluid collections. The latter feature may help to exclude abscesses, as these mostly present with fluid collections. Pyomyositis in its early period demonstrates ill-defined muscle enlargement with increased signal on T2-weighted images. Myositis shows no signal changes or mild hypointensity on T1-weighted images, but diffuse hyperintensity on T2-weighted images, with no or minimal enhancement following intravenous contrast media. Recognition of these pathologies is important, since management approaches vary depending on the etiology of the muscle involvement and overall status of the patient.
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PMID:Muscle compromise in diabetes. 1856 60

Based on biochemical evidence, a high prevalence of biochemical evidence of vitamin B12 or folate deficiency has been reported in a number of areas in the world. The evidence that these biochemical abnormalities lead to a comparable prevalence of anemia is reviewed. The overall contribution of vitamin B12 deficiency to the global burden of anemia is probably not significant, except perhaps in women and their infants and children in vegetarian communities. In developed countries, folate-deficiency anemia is uncommon. In some developing countries, this anemia is still seen, but there are no comprehensive data on the relative prevalence compared with anemia due to malaria, iron-deficiency, hemoglobinopathy, and HIV disease. It seems unlikely that folate deficiency makes a major contribution to the burden of anemia in developing countries. Iron-deficiency anemia may coexist with vitamin B12 and especially folate deficiency, and may confound the hematological features of the vitamin deficiencies whose prevalence would then be underestimated. Supplementation of the diet of pregnant women with folic acid can virtually eliminate folate-deficiency anemia in these women. There are very few data on the hematological effect of vitamin B12 supplementation or fortification at the population level. The addition of vitamin B12 to the supplementation of the diet of pregnant women with iron and folic acid does not produce an increased hematological response, at least in nonvegetarian populations. There are numerous reports of the effect of folic acid fortification of food on tests of folate status, but only a single published report on the hematological response was found.
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PMID:A high prevalence of biochemical evidence of vitamin B12 or folate deficiency does not translate into a comparable prevalence of anemia. 1870 83

After the approval of suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza) for the treatment of cutaneous T cell lymphoma (CTCL), a number of HDAC inhibitors (HDACi) are currently in Phase II or III clinical trials (alone or in combination) for the treatment of a great number of tumors. In addition to these cancer uses, HDACi can be successfully used in non-cancer diseases. In this review we focused on the uses of HDACi in some infectious diseases and beta-hemoglobinopaties. In C. albicans cultures, HDACi increased the frequency of cell switching (a relevant virulence trait) in the white-to-opaque transition, reduced the azole trailing effect through reduction in azole-dependent upregulation of CDR and ERG genes, and inhibited the fluconazole-dependent resistance induction. Moreover, they inhibited germination in several strains, and caused 90% reduction in the adherence of C. albicans to human cultured pneumocytes. In HIV-1-infected cells, the treatment with HDACi reactivates the HIV-1 expression in latent cellular reservoirs. Thus, the use of HDACi as adjuvant to highly active antiretroviral therapy (HAART) can represent a new potential therapeutic strategy to eradicate the viral infection. A number of HDACi have been reported as active against P. falciparum infection. Two recent papers show some 2-aminosuberic acid-based compounds as well as a series of phenylthiazolyl suberoyl hydroxamates as very potent and selective antimalarial agents. Among the many agents capable to perform post-natal reactivation of fetal hemoglobin production, HDACi for their capacity to de-repress gamma-globin gene expression in adult red cell, are presently considered promising molecules for personalized therapy of beta-hemoglobinopathies.
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PMID:Non-cancer uses of histone deacetylase inhibitors: effects on infectious diseases and beta-hemoglobinopathies. 1935 91

We report a human immunodeficiency virus-1 (HIV-1)-infected couple, where the woman in the 11th week of gestation, carried a Hb E trait. She and her spouse were referred to the hemoglobinopathy counselors. Her spouse's blood was subsequently tested and showed an increased Hb A(2) value. However, his red cell indices and osmotic fragility test were different from those found in beta-thalassemia (beta-thal) carriers. The beta-thal genes were investigated further and no mutations were observed. Therefore, it is unlikely that he is a beta-thal carrier and the increased Hb A(2) value is a result of receiving antiretroviral drugs. As antenatal thalassemia screening becomes more widespread, measuring the Hb A(2) values should be taken in all HIV-1-infected couples before the initiation of antiretroviral drugs to rule out misdiagnosis of beta-thal. However, if these tests are not available, the results of the red cell indices and osmotic fragility test should be considered as they may provide great value for beta-thal investigations.
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PMID:Increased Hb A2 values in an HIV-1-infected patient receiving antiretroviral drugs: a pitfall for thalassemia antenatal diagnosis. 1937 94

We conducted an empirical pilot study to assess the attitudes of health care professionals (HCPs) to the personal identification of heterozygote carrier status for two autosomal recessive conditions (cystic fibrosis and a hemoglobinopathy) and for an X-linked disorder (Duchenne muscular dystrophy) using the Health Orientation Scale (HOS) and a modified HIV Stigma Scale. Attitudes towards carrier identification of children were also assessed. Three hundred and ten of 742 (42%) eligible HCPs fully or partly completed the survey. As measured with the HOS and the modified HIV scale, respondents had a more negative reaction to the hypothetical discovery of being a carrier for an autosomal recessive genetic condition that was less likely given their self-identified ancestry. Female respondents had a more negative reaction on both scales to being a carrier for an X-linked disorder than men thought their partners would feel. However, the differences found on the HOS and modified HIV scale are small and their clinical relevance unknown. Fifty-seven percent of respondents agreed that parents should tell their children to keep their carrier status private with many (44%) agreeing that children who learn that they are carriers may suffer from a decrease in self-esteem. The vast majority of respondents would inform immediate family members and HCPs of their carrier status, but would be unlikely to share this information with neighbors or employers. Further study is needed to develop a heterozygote genetic carrier stigma scale.
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PMID:A pilot study to determine whether health care professionals perceive stigma in heterozygote carrier identification and disclosure decisions. 2173 84

Recognition of causes of pulmonary hypertension other than congenital heart disease is increasing in children. Diagnosis and treatment of any underlying cause of pulmonary hypertension is crucial for optimal management of pulmonary hypertension. This article discusses the available knowledge regarding several disorders associated with pulmonary hypertension in children: idiopathic pulmonary arterial hypertension (IPAH), pulmonary capillary hemangiomatosis, pulmonary veno-occlusive disease, hemoglobinopathies, hepatopulmonary syndrome, portopulmonary hypertension and HIV. Three classes of drugs have been extensively studied for the treatment of IPAH in adults: prostanoids (epoprostenol, treprostinil, iloprost, beraprost), endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan), and phosphodiesterase inhibitors (Sildenafil, tadalafil). These medications have been used in treatment of children with pulmonary arterial hypertension, although randomized clinical trial data is lacking. As pulmonary vasodilator therapy in certain diseases may be associated with adverse outcomes, further study of these medications is needed before widespread use is encouraged.
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PMID:Non-congenital heart disease associated pediatric pulmonary arterial hypertension. 2185 94

The aim of this study is to review over a period of 5 years the clinical spectrum of rheumatic diseases seen in a tertiary hospital in Ouagadougou, Burkina Faso. A retrospective study of case records was conducted from March 1, 2006 to March 30, 2011 in the Rheumatology service, Department of Internal Medicine of the University Hospital Yalgado Ouedraogo. Of the 4,084 patients seen, 2,381 were women (58.30%) and 1,703 were men (41.70%). The mean age at disease onset was 42.12 years, ranging from 3 to 92 years. Among the rheumatologic conditions, mechanical and degenerative disorders were the most common, found in 3,053 cases (74.76%). Among these cases, spinal pathology predominated, especially low back pain (19.93 %). The frequency of osteoarthritis was 19.70 % (804 cases) with a predominance of knee osteoarthritis (657 cases). Infectious pathology was dominated by osteoarticular tuberculosis (48 cases), particularly Pott's disease (43.68% of infectious diseases). Among the cases of inflammatory arthritides, rheumatoid arthritis was the leading cause (116 cases or 2.84%). It was followed by spondyloarthropathies in which arthritis related to HIV predominated (21 out of 81 cases). Metabolic diseases were mainly represented by the gout (162 cases or 3.96%) with male predominance. Comorbidities included high blood pressure (46.57%), diabetes mellitus (13.78%), hemoglobinopathies (9.66%), epigastric pain (7.25%), and peptic ulcer confirmed by endoscopy (6.75%). Rheumatology in Burkina Faso is booming. The profile of rheumatologic diseases in Burkina Faso, after 5 years of practice, confirms the diversity and importance of these conditions dominated by a degenerative pathology of the spine and limbs, including infectious diseases such as Pott's disease and the inflammatory and metabolic diseases.
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PMID:Clinical spectrum of rheumatologic diseases in a department of rheumatology in Ouagadougou (Burkina Faso). 2471 17


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