Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preventive measures for single-gene disorders are currently based on carrier screening in pregnancy and prenatal diagnosis. Although this has been extremely effective for preventing new cases of common inherited conditions, the major limitation is still termination of 25% of wanted pregnancies following detection of affected fetuses. To overcome this important problem, we developed a method for prepregnancy genetic testing that involves DNA analysis of the first and second polar bodies, which are extruded during maturation and fertilization of oocytes. We offered this option to 28 couples at risk for having children with single-gene disorders. Fifty clinical cycles were performed from these patients for the following conditions: 20 for cystic fibrosis, 18 for thalassemia, 6 for sickle cell disease, 2 each for Gaucher disease and LCHAD (long-chain 3-hydroxyacyl-COA dehydrogenase deficiency), and 1 each for hemophilia B and phenylketonuria. Oocytes obtained from these patients using in vitro fertilization procedures (IVF) were tested by a sequential multiplex nested PCR analysis of the first and second polar body to detect the gene involved simultaneously with linked polymorphic markers. A total of 191 of 399 oocytes with predicted genotype were mutation free and preselected for fertilization and transfer. In all but three cycles, one to three unaffected embryos with predicted unaffected genotypes were transferred, resulting in 20 pregnancies, from which 19 healthy children have been born. The follow-up analysis of embryos resulting from oocytes with predicted affected genotype, confirmed the diagnosis in 97% of cases, demonstrating the reliability of prepregnancy diagnosis of single-gene defects by polar body analysis.
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PMID:Prepregnancy testing for single-gene disorders by polar body analysis. 1046 66

Sodium 4-phenylbutyrate (PBA), a short-chain fatty acid, has been approved to treat patients with urea cycle enzyme deficiencies and is being evaluated in the management of sickle cell disease, thalassemia, cancer, and cystic fibrosis (CF). Because relatively little is known about the effects of PBA on the expression and function of the wild-type CF transmembrane conductance regulator (wt CFTR), the goal of this study was to examine the effects of PBA and related compounds on wt CFTR-mediated Cl(-) secretion. To this end, we studied Calu-3 cells, a human airway cell line that expresses endogenous wt CFTR and has a serous cell phenotype. We report that chronic treatment of Calu-3 cells with a high concentration (5 mM) of PBA, sodium butyrate, or sodium valproate but not of sodium acetate reduced basal and 8-(4-chlorophenylthio)-cAMP-stimulated Cl(-) secretion. Paradoxically, PBA enhanced CFTR protein expression 6- to 10-fold and increased the intensity of CFTR staining in the apical plasma membrane. PBA also increased protein expression of Na(+)-K(+)-ATPase. PBA reduced CFTR Cl(-) currents across the apical membrane but had no effect on Na(+)-K(+)-ATPase activity in the basolateral membrane. Thus a high concentration of PBA (5 mM) reduces Cl(-) secretion by inhibiting CFTR Cl(-) currents across the apical membrane. In contrast, lower therapeutic concentrations of PBA (0.05-2 mM) had no effect on cAMP-stimulated Cl(-) secretion across Calu-3 cells. We conclude that PBA concentrations in the therapeutic range are unlikely to have a negative effect on Cl(-) secretion. However, concentrations >5 mM might reduce transepithelial Cl(-) secretion by serous cells in submucosal glands in individuals expressing wt CFTR.
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PMID:PBA increases CFTR expression but at high doses inhibits Cl(-) secretion in Calu-3 airway epithelial cells. 1051 10

Just as metabolites, hormones and proteins are measured in newborn screening tests, DNA has become an analyte that is important in the screens for certain disorders. DNA confirmatory testing on the original dried blood specimen reduces the age at diagnostic confirmation and antibiotic prophylaxis initiation for neonates with sickle cell disease. Molecular genetic analysis of the initial specimens from newborns with elevated immunoreactive trypsinogen (IRT) for cystic fibrosis (CF) screening permits reduction of the IRT threshold value, improving specificity without compromising sensitivity. Because of this cost reduction, CF neonatal screening programs routinely incorporate DNA confirmatory testing into their initial CF screening algorithm. DNA analysis is also a valuable adjunct in screening programs for congenital adrenal hyperplasia (CAH), improving sensitivity and specificity. Incorporation of DNA into newborn screening programs will continue to be stimulated by development of robust, high throughput technologies for evaluation of this analyte. New paradigms for neonatal screening are evolving, including hearing screening in the newborn nursery. DNA testing, such as for mutations in the connexin 26 gene, may have a role in the evaluation of those screened positive. Newborn screening dried blood specimens are DNA databases. Therefore, there are significant ethical, legal and social issues that must be considered in the storage and utilization of neonatal screening specimens.
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PMID:State-of-the-art for DNA technology in newborn screening. 1062 81

Children with chronic illness live with the specific consequences of their illness, as well as secondary endocrine abnormalities that further compromise growth and pubertal development. These secondary abnormalities may significantly add to their physiologic and psychological burden. Although these endocrine abnormalities theoretically arise as adaptations to the chronic illness, they may have deleterious effects if they persist untreated. Children with HIV infection and other wasting disorders, for example, show growth suppression out of proportion to the severity of their primary illness as a result of growth hormone resistance and enhanced cortisol secretion. In hematologic conditions such as sickle cell anemia, thalassemia, or bone marrow transplant, damage to the hypothalamus and/or pituitary may lead to growth hormone deficiency, gonadal insufficiency, and hypothyroidism. Growth and pubertal delay are also common among children with cystic fibrosis, along with insulin-dependent diabetes mellitus caused by pancreatic fibrosis. Similarly, children receiving long-term steroid therapy have delays in growth and pubertal development, accompanied by risk for osteoporosis, whereas chronic renal disease is associated with growth and pubertal delay, as well as secondary hyperparathyroidism. Recognition of potential endocrinopathies in children with chronic illness is an important aspect of the care of these children because the disturbances are frequently amenable to treatment, permitting full or partial restoration of normal growth and development in these children. In this chapter, the endocrine consequences of common chronic conditions of childhood are reviewed, as well as the etiology of the endocrine disturbance, the clinical consequences, and recommendations for treatment.
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PMID:Advances in the recognition and treatment of endocrine complications in children with chronic illness. 1064 63

Advances in technology provide new challenges to public health to implement screening programs that are effective, cost-efficient, and available to all infants regardless of ability to pay. The Newborn Metabolic Disorder Screening Program (NMDSP) of the Oklahoma State Department of Health is evaluating the expansion of newborn screening for the disorders of cystic fibrosis, congenital adrenal hyperplasia, and medium-chain acyl coenzyme A dehydrogenase deficiency (MCAD) to the current screening battery of disorders (phenylketonuria, congenital hypothyroidism, galactosemia, and sickle cell disease). The challenge is to offer these new screening tests in a cost-efficient manner that ensures all newborns have access to screening and that an infrastructure exists to diagnose and provide the specialized comprehensive care affected infants will require to reduce the morbidity, mortality, and disability associated with these disorders. Essential components of an effective newborn screening system include the smooth integration of sample collection, laboratory testing, follow-up, diagnosis, timely treatment, and tracking components. The NMDSP has recommended that screening should be expanded, but issues of cost and the establishment of a sustainable infrastructure of comprehensive medical services must be addressed.
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PMID:Public health explores expanding newborn screening for cystic fibrosis, congenital adrenal hyperplasia, and medium-chain acyl coenzyme A dehydrogenase deficiency (MCAD). 1139 80

Sclerosing cholangitis in childhood is a heterogeneous condition, which has different aetiologies. Sclerosing cholangitis may be inherited and diagnosed in the neonatal period (neonatal sclerosing cholangitis); it may present later with features of autoimmunity (autoimmune sclerosing cholangitis); or it may be associated with a variety of disorders, including Langerhans cell histiocytosis, immunodeficiency, psoriasis, cystic fibrosis, reticulum cell sarcoma and sickle cell anaemia. In contrast to the experience in adult patients, sclerosing cholangitis occurring as an individual disease (primary sclerosing cholangitis) is rare. The initiating events and possible pathogenic mechanisms differ in the various forms of sclerosing cholangitis and are still obscure. Treatment and prognosis depend on the type of sclerosing cholangitis present.
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PMID:Sclerosing cholangitis in the paediatric patient. 1149 76

The issues relating to assisted reproduction in women with severe medical disease can be divided into the likely effect of pregnancy upon the medical condition, and how the medical condition may adversely affect pregnancy outcome. In addition, consideration of the hazards relating to the process of assisted conception, in particular the risk of ovarian hyperstimulation syndrome and multiple pregnancy, must be remembered. In some women, successful assisted reproduction may result in a life-threatening pregnancy. Clinicians advising women about assisted conception should be aware of the medical conditions that are absolute contra-indications to pregnancy. Some women with severe medical disease may have a significantly reduced life expectancy, in which case ethical issues regarding the future welfare of the child must be considered. Examples include sickle cell disease, cystic fibrosis and HIV. One of the biggest advantages of assisted reproduction for women with severe medical disorders is that the pregnancy is planned. Thus, there is an opportunity for the patient to be informed fully about any risks, both to herself and her fetus. This article reviews the general management of women with severe medical disorders who seek assisted reproduction and gives specific guidelines for the more common conditions.
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PMID:Hazards of assisted conception in women with severe medical disease. 1171 19

This review discusses the Ca2+-activated K+ channels of intermediate conductance (IK channels), and their historical discovery in erythrocytes, their classical biophysical characteristics, physiological function, molecular biology as well as their role as possible molecular targets for pharmacological intervention in various diseases. The first described Ca2+-activated K+ channel ever - the so-called Gard6s channel from human erythrocytes--is an IK channel. The "I" denominates the intermediate conductance that distinguishes the IK channels from the related Ca2+-activated K+ channels of small (SK) or large (BK) conductance. The recent cloning of the human IK channel gene (KCNN4) enabled a detailed mapping of the expression in various tissues. IK channel expression is found predominantly in cells of the blood, in epithelia and endothelia. An important physiological role of IK channels is to set the membrane potential at fairly negative values and thereby to build up large electrical gradients for the passive transport of ions such as Cl- efflux driving water and Na+ secretion from epithelia, and Ca2+ influx controlling T-lymphocyte proliferation. The molecular cloning of IK and SK channels has revealed that both channels gain their Ca2+-sensitivity from tightly bound calmodulin (CaM). The IK channel is potently blocked by the scorpion toxin charybdotoxin (ChTx) and the antimycotic clotrimazole (CLT). CLT has been in clinical trials for the treatment of sickle cell disease, diarrhea and ameliorates the symptoms of rheumatoid arthritis. However, inhibition of cytochrome P450 enzymes by CLT limits its therapeutic value, but new drug candidates are entering the stage. It is discussed whether pharmacological modulation of IK channels may be beneficial in sickle cell anemia, cystic fibrosis, secretory diarrhea, craft-versus-host disease and autoimmune diseases.
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PMID:The Ca2+-activated K+ channel of intermediate conductance: a molecular target for novel treatments? 1173 39

Protein aggregation occurs in vivo as a result of improper folding or misfolding. Diverse diseases arise from protein misfolding and are now grouped under the term "protein conformational diseases", including most of the neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, the prion encephalopathies and Huntington's disease, as well as cystic fibrosis, sickle cell anemia and other less common conditions. The hallmark event in these diseases is a change in the secondary and/or tertiary structure of a normal, functional protein, leading to the formation of protein aggregates with various supramolecular organizations. In most cases the aggregates are organized in structurally well-defined fibrils forming amyloid deposits. The crucial feature of the amyloidogenic proteins is their structural instability induced either by mutations, post-translational modifications, or local conditions, such as pH, temperature, and co-solutes. The conformational change may promote the disease either by gain of a toxic activity or by the lack of biological function of the natively folded protein. As different molecular mechanisms are involved in the formation of the various forms of protein aggregates, the laboratory diagnostic approach remains frequently elusive.
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PMID:Protein aggregation. 1183 22

Reproductive technology comprises abortion, contraception, amniocentesis (more than 40 genetic disorders can be diagnosed), chorionic villus sampling, genetic screening (to reduce the risk of chromosomal defects such as Down syndrome, sickle cell anemia, Tay-Sachs disease, and cystic fibrosis), in vitro fertilization, artificial insemination by spouse or donor, the development of sperm banks, storage of frozen sperm (cryopreservation), the development of artificial wombs, techniques for predetermining the sex of a fetus, and nursery environments to maintain a fetus removed from the womb in the 1st trimester. In recent years, the demand for these services has increased because of higher infertility and the drop in the number of babies available for adoption. Surrogacy is especially controversial: it has become a symbol of the dehumanization of modern life and the exploitation of women. The feminist perspective discloses how patriarchal values about the subordinate status of women, about the nature of motherhood, infertility, and the family are both implicit and explicit in prevailing thinking about reproduction. The new technology offers women who wish to remain unmarried the opportunity to have a family, and it enables lesbian women to bear children. The research literature favors a Eurocentric nuclear family without any awareness that in Canada, and in the Western world, new forms of family life have been evolving as couples marry, divorce, and remarry. There is no awareness either that in other cultures this Eurocentric nuclear model is dysfunctional. Because of the rigid notion of the 2-parent nuclear family, the 3rd parties who are involved in either surrogate relationships or artificial insemination are deprecated. The feminist literature is more critical of the nuclear family, but it has been sometimes inconsistent on the relevant issues.
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PMID:Public policies and reproductive technology: a feminist critique. 1231 72


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