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)

Three broad classes of Ca(2+)-activated potassium channels are defined by their respective single channel conductances, i.e. the small, intermediate, and large conductance channels, often termed the SK, IK, and BK channels, respectively. SK channels are likely encoded by three genes, Kcnn1-3, whereas IK and most BK channels are most likely products of the Kcnn4 and Slo (Kcnma1) genes, respectively. IK channels are prominently expressed in cells of the hematopoietic system and in organs involved in salt and fluid transport, including the colon, lung, and salivary glands. IK channels likely underlie the K(+) permeability in red blood cells that is associated with water loss, which is a contributing factor in the pathophysiology of sickle cell disease. IK channels are also involved in the activation of T lymphocytes. The fluid-secreting acinar cells of the parotid gland express both IK and BK channels, raising questions about their particular respective roles. To test the physiological roles of channels encoded by the Kcnn4 gene, we constructed a mouse deficient in its expression. Kcnn4 null mice were of normal appearance and fertility, their parotid acinar cells expressed no IK channels, and their red blood cells lost K(+) permeability. The volume regulation of T lymphocytes and erythrocytes was severely impaired in Kcnn4 null mice but was normal in parotid acinar cells. Despite the loss of IK channels, activated fluid secretion from parotid glands was normal. These results confirm that IK channels in red blood cells, T lymphocytes, and parotid acinar cells are indeed encoded by the Kcnn4 gene. The role of these channels in water movement and the subsequent volume changes in red blood cells and T lymphocytes is also confirmed. Surprisingly, Kcnn4 channels appear to play no required role in fluid secretion and regulatory volume decrease in the parotid gland.
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PMID:Physiological roles of the intermediate conductance, Ca2+-activated potassium channel Kcnn4. 1534 67

Much progress has been made during the past several decades in gaining understanding about the natural history of sickle cell disease and management approaches aimed at treating or even preventing certain disease complications. The characterization of the human genome now offers the opportunity to understand relationships regarding how gene polymorphisms as well as how environmental factors affect the sickle cell disease phenotype, i.e., the individual patient's overall clinical severity as well as their specific organ function. This chapter explores some of these recent advances in knowledge. In Section I, Dr. Michael DeBaun characterizes the problem of silent stroke in sickle cell disease, comparing and contrasting its clinical and neuroimaging features with overt stroke. Combined, these events affect virtually 40% of children with sickle cell anemia. New understanding of risk factors, associated clinical findings, and imaging technologies are impacting substantially on treatment options. The appreciable cognitive dysfunction and other sequelae of silent infarct demand more effective treatments and ultimate prevention. In Section II, Dr. Charles Quinn addresses the conundrum of why some patients with sickle cell disease do well whereas others fare poorly. Some risk factors have been known for years, based upon careful study of hundreds of patients by the Cooperative Study for Sickle Cell Disease and investigators studying the Jamaican newborn cohort. Other prognostic measures have only recently been defined. Dr. Quinn devotes special attention to stroke and chest syndrome as organ-related complications but also describes attempts to measure overall disease severity and to predict survival. Recently, investigators have attempted to predict factors responsible for early mortality in children and following onset of pulmonary hypertension in adults. In Section III, Dr. Martin Steinberg reviews pharmacologic approaches to sickle cell disease and the rationale for their use. In addition to the inhibition of hemoglobin S polymerization, newer targets have been defined during the past one to two decades. These include the erythrocyte membrane, changes in the red cell intracellular content (especially loss of water), endothelial injury, and free radical production. Hydroxyurea treatment attracted the greatest interest, but many uncertainties remain about its long-term benefits and toxicities. Newer "anti-sickling" agents such as decitabine and short-chain fatty acids also receive attention. Prevention of red cell dehydration, "anti-endothelial" therapy, and marshalling the potentially beneficial effects of nitric oxide are other new and exciting approaches.
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PMID:Sickle cell disease. 1556 75

FLOCOR (purified poloxamer 188) is a surfactant molecule that represents a new class of pharmacological agent. FLOCOR is different in that its activity does not depend on high affinity receptor binding but rather on altering the way cells and molecules interact with water. Extensive preclinical studies in models of vascular occlusive disorders, including circulatory shock, acute stroke, and myocardial infarction (MI), suggest that iv. administration of poloxamer 188 improves microvascular blood flow in ischaemic tissues by inhibiting adhesive interactions, lowering blood viscosity and reducing friction along the vessel wall. In clinical studies, poloxamer 188 demonstrated statistically significant benefits in patients with acute myocardial infarction (AMI) and acute vaso-occlusive crisis of sickle cell disease. However, these studies were conducted with commercial grades of poloxamer 188 that contained nephrotoxic impurities, and elevated creatinine was observed in a small percentage of patients. A new highly purified version of poloxamer 188 free from impurities has been developed. Highly purified poloxamer 188 (trade name FLOCOR) is better tolerated in models of renal failure and is anticipated to have a significantly improved therapeutic index compared to commercial grade poloxamer 188. Clinical studies are now in progress in order to confirm the therapeutic benefits of FLOCOR (purified poloxamer 188).
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PMID:FLOCOR: a new anti-adhesive, rheologic agent. 1599 24

The epizootiology, transmission dynamics, and survival strategies employed by two mosquito-parasitic microsporidia that utilize copepods as intermediate hosts are examined in relation to the biological attributes of their hosts and the environments in which they inhabit. Amblyospora connecticus Andreadis, 1988, a parasite of Ochlerotatus cantator (Coquillett) and Acanthocyclops vernalis (Fischer) is found in an unstable salt marsh environment that is subject to periodic flooding and drying. Both hosts have distinct non-overlapping generations. A. connecticus exhibits a well-defined seasonal transmission cycle that relies heavily on maternal-mediated transovarial transmission by female O. cantator during the summer, and horizontal transmission via the copepod host during the spring (copepod to mosquito) and fall (mosquito to copepod). Its survival strategies include: delayed virulence, low pathogenicity and high tissue specificity that allow for transstadial transmission of horizontally acquired infections and maximum spore production, reliance on living hosts throughout most of its life cycle with overwintering in the copepod, polymorphic development that is well synchronized with host physiology, and production and dissemination of infectious spores that are coincident with the seasonal occurrence of susceptible stages in each host. Hyalinocysta chapmani Hazard et Oldacre, 1975, a parasite of Culiseta melanura (Coquillett) and Orthocyclops modestus (Herrick) is found in a comparatively stable, subterranean habitat that is inundated with water throughout the year. Copepods are omnipresent and C. melanura has overlapping broods. H. chapmani is maintained in a continuous cycle of horizontal transmission between each host throughout the summer and fall but lacks a developmental sequence leading to transovarial transmission in the mosquito host. It relies on living hosts for most of its life cycle and overwinters in diapausing mosquito larvae. Transstadial transmission does not occur and there is no dimorphic development in the mosquito host. The spatial and temporal overlap of both mosquito and copepod hosts during the summer and fall affords abundant opportunity for continuous horizontal transmission and increases the likelihood that H. chapmani will find a target host, thus negating the need for a transovarial route. It is hypothesized that natural selection has favoured the production of meiospores in larval female mosquitoes rather than congenital transfer of infection to progeny via ovarian infection as a strategy for achieving greater transmission success. Analysis of the molecular phylogeny data suggest that (1) transovarial transmission and the developmental sequence leading to ovarian infection have been secondarily lost in H. chapmani, as they occur in all other closely related genera, (2) the ancestral state included complex life cycles involving transovarial transmission and an intermediate host, and (3) mosquito-parasitic microsporidia are adjusting their life cycles to accommodate host ecological conditions.
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PMID:Evolutionary strategies and adaptations for survival between mosquito-parasitic microsporidia and their intermediate copepod hosts: a comparative examination of Amblyospora connecticus and Hyalinocysta chapmani (Microsporidia: Amblyosporidae). 1600 61

Liver iron measurements using biosusceptometers have been validated on two low-TC SQUID (Superconducting Quantum Interference Device) systems (New York and Hamburg) built in the 1980's. Recently, two new instruments have been installed in Torino, Italy (2001), and Oakland, California (2003). The design of the Oakland system is similar to those in Hamburg and Torino. Improvements were made to adjust for significant environmental noise, moreover, an active electronic noise cancellation, a computer controlled water coupling reference system using a pressure feedback and a faster data acquisition system using software lockin amplifiers have been implemented. All 3 systems (Hamburg, Torino, Oakland) are using the same standardized operational protocol. Presented herein are the data collected from 276 patients measured with the SQUID biosusceptometer at Oakland since installation. The results from 149 patients with beta-thalassemia (beta-Thal, age: 2-66 y), 76 patients with sickle-cell disease (SCD, age: 5-55 y), 35 patients with various rare diseases (RD, age: 2-80 y), and 16 patients with hereditary hemochromatosis (HHC, age: 6-74 y) are reported. The liver iron concentration in the different groups are 222 - 7570 (beta-Thal), 518 - 7918 (SCD), 511 - 6234 (RD), 258 - 2041 (HHC) microg/g-liver (in vivo wet weight). The long-term reproducibility (12 months) in a patient on constant treatment regimen demonstrated a mean liver iron of 1141 +/- 133 microg/g-liver. The new SQUID Ferritometer located on the US West coast will give more patients access to this non-invasive liver iron assessment.
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PMID:The new SQUID biosusceptometer at Oakland: first year of experience. 1601

Exposure of red blood cells (RBC) to the K+ -ionophore valinomycin (val), causes loss of KCl and water, resulting in cell dehydration, manifested by increased cell density. While almost all normal val-treated RBC dehydrate, in sickle cell anemia (SCA) a portion of the RBC fail to dehydrate and maintain a light density, indicating the existence of val-resistant (val-res) RBC. In thalassemia and sickle cell disease (SCD), although the primary lesion is in the globin genes, damage to the RBC is partly mediated by oxidative stress. We previously showed that such RBC are under oxidative stress, having more reactive oxygen species (ROS) and less reduced glutathione than normal RBC. We now report a relationship between the phenomenon of val-res and the RBC oxidative status: Treatment with oxidants that increase ROS, also increased the frequency of val-res cells. Val-res cells had higher oxidative status than other RBC in the sample. Similar to SCA, thalassemic blood has more val-res cells than does normal blood. Val-res cells in thalassemic and sickle blood showed a higher oxidative status than normal val-res cells. Thus, oxidative stress might be involved in generation of val-res cells. Further studies are required to elucidate the origin and significance of these cells.
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PMID:Oxidative status of valinomycin-resistant normal, beta-thalassemia and sickle red blood cells. 1658 Jul 76

Clotrimazole, a poorly water-soluble antimycotic agent, is a promising agent for various diseases including cancer and sickle cell anemia. To improve the oral bioavailability of clotrimazole, the inclusion compound of clotrimazole with beta-cyclodextrin was prepared by spray-drying method and characterized by phase solubility, differential scanning calorimetry and dissolution. Furthermore, the pharmacokinetics after oral administration in rats was then performed compared with clotrimazole powder. The solubility of clotrimazole increased linearly as a function of beta-cyclodextrin concentration, resulting in A(L) type phase solubility diagram which revealed a formation of inclusion compound in a molar ratio of 1:2, with the apparent association constant of 230.2 M(-1). The dissolution rate of clotrimazole in the inclusion compound increased greatly compared to clotrimazole powder in pH 7.4 phosphate buffer solution. The inclusion compound gave significantly higher initial plasma concentrations, Cmax and AUC of clotrimazole than did clotrimazole powder when they were administered as suspension form, indicating that the drug from inclusion compound could be more orally absorbed in rats. Thus, the oral bioavailability of clotrimazole could be improved markedly by inclusion complexation, possibly due to an increased dissolution rate.
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PMID:Enhanced bioavailability of poorly water-soluble clotrimazole by inclusion with beta-cyclodextrin. 1736 48

During the screening of a variety of plant sources for their anti-obesity activity, it was found that a water-soluble extract, named PG105, prepared from stem parts of Cucurbita moschata, contains potent anti-obesity activities in a high fat diet-induced obesity mouse model. In this animal model, increases in body weight and fat storage were suppressed by 8-week oral administration of PG105 at 500 mg/kg, while the overall amount of food intake was not affected. Furthermore, PG105 protected the development of fatty liver and increased the hepatic beta-oxidation activity. Results from blood analysis showed that the levels of triglyceride and cholesterol were significantly lowered by PG105 administration, and also that the level of leptin was reduced, while that of adiponectin was increased. To understand the underlying mechanism at the molecular level, the effects of PG105 were examined on the expression of the genes involved in lipid metabolism by Northern blot analysis. In the liver of PG105-treated mice, the mRNA level of lipogenic genes such as SREBP-1c and SCD-1 was decreased, while that of lipolytic genes such as PPARalpha, ACO-1, CPT-1, and UCP-2 was modestly increased. Our data suggest that PG105 may have great potential as a novel anti-obesity agent in that both inhibition of lipid synthesis and acceleration of fatty acid breakdown are induced by this reagent.
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PMID:A water-soluble extract from Cucurbita moschata shows anti-obesity effects by controlling lipid metabolism in a high fat diet-induced obesity mouse model. 1754 58

Sickle cell anaemia is associated with a mutant haemoglobin, HbS, which forms polymers in the red blood cells of patients. The primary role of the HbS polymerization for the pathophysiology has been questioned: observations in patients and model organisms contradict deterministic scenarios of sickling crises triggered by polymerization. However, results with knock-out sickle-cell mice, which were cured by delaying HbS polymerization, reconfirm polymerization's primary role. To reconcile the contradictory observations, this article reviews recent findings on two steps in polymerization: homogeneous nucleation of fibres, and their growth. The fibre growth is faster by far than for any other protein ordered structure. This is due to a negligible free-energy barrier for incorporation into a fibre, determined by an entropy gain, stemming from the release of water molecules structured around HbS. The kinetics of fibre nucleation have shown that the formation of the polymer nucleus is preceded by a metastable droplet of a dense liquid. The properties of the dense liquid are sensitive functions of solution composition, including components in micro- and nanomolar amounts. This mechanism allows low-concentration solution components to strongly affect the nucleation kinetics, accounting for the high variability of the disease. These insights can potentially be utilized for control of HbS polymerization and treatment of the disease.
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PMID:Sickle-cell haemoglobin polymerization: is it the primary pathogenic event of sickle-cell anaemia? 1789 93

In sickle cell anaemia, red cell dehydration increases intracellular HbS concentration and promotes sickling. Higher erythrocyte magnesium reduces water loss through negative regulation of membrane transporters. Hydroxycarbamide (also known as hydroxyurea) reduces sickling partly by increasing intracellular HbF. Combining drugs with distinct mechanisms could offer additive effects. A phase I trial combining oral magnesium pidolate and hydroxycarbamide was performed to estimate the maximum tolerated dose (MTD) and toxicity of magnesium. Cohorts of three children with HbSS, who were on a stable dose of hydroxycarbamide (median 28.5 mg/kg/d), received magnesium pidolate for 6 months beginning at 83 mg/kg/d. The dose was escalated by 50% for subsequent cohorts. Laboratory evaluations were performed at 0, 3, 6 and 9 months. Sixteen children (aged 4-12 years) participated. All four dose-limiting toxicities (grade III diarrhoea and abdominal pain) occurred within the first month of starting magnesium. Additionally, diarrhoea grades I (n = 1) and II (n = 3), and abdominal pain grade II (n = 3) occurred. Hydroxycarbamide dose reduction or interruption was not required. The MTD for magnesium pidolate used in combination with hydroxycarbamide was 125 mg/kg/d. KCl co-transporter activity declined after 3 months of magnesium pidolate (P = 0.02). A phase II study is needed to investigate the efficacy of this drug combination.
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PMID:Phase I study of magnesium pidolate in combination with hydroxycarbamide for children with sickle cell anaemia. 1799 Dec 98


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