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)

To determine whether tumor necrosis factor (TNF) and interleukin-1 (IL-1) might be involved in the pathogenesis of sickle cell disease and its complications, TNF-alpha and IL-1-alpha were measured using enzyme-linked immunosorbent assay in 59 plasma samples from 34 adult subjects with Hb SS or Hb SC who did not have documented infections. Tumor necrosis factor was elevated on at least one occasion in 27 subjects, including 18 of 21 subjects in the steady state and 13 of 19 subjects during painful crisis. Interleukin-1 was elevated on at least one occasion in 6 subjects, including 3 subjects in the steady state and 3 subjects in crisis. All subjects with elevated IL-1 also had elevated TNF. Tumor necrosis factor and IL-1 were similarly elevated in the steady state and during painful crisis. No correlation was noted between TNF or IL-1 levels and the extent of activation of coagulation, as measured by plasma levels of the fibrin D-dimer fragment, the overall severity of vascular occlusive disease in each subject, or the presence of specific vascular occlusive complications. We conclude that plasma TNF is frequently elevated in subjects with sickle cell disease, and IL-1 is also elevated in some subjects. A direct role for these cytokines in the pathogenesis of vascular occlusion in sickle cell disease was not demonstrated, but an indirect role was not excluded.
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PMID:Elevated immunoreactive tumor necrosis factor and interleukin-1 in sickle cell disease. 162 25

The development of genetic epidemiology methods using recent human genetic map together with the growing availability of candidate genes have led to substantial advances in the identification of host genes in human malaria. Investigation of these genes has progressed along two complementary ways: 1) The search for genes influencing the severe malaria clinical phenotype by means of population based case-control studies which showed the protective role of several red cell genetic defects (sickle cell anemia, a-thalassaemia ...) and that some polymorphisms of the TNF-alpha promoter region could predispose to cerebral malaria; 2) The investigation of the genetic regulation of malaria-related biological phenotypes (infection levels, immune response) by means of familial studies which underlined the influence of the 5q31-q33 chromosomal region in the control of Plasmodium falciparum blood parasitemia and the role of major histocompatibility complex (MHC) and non-MHC genes in the regulation of humoral and cellular response to various malarial antigens. Ongoing studies will precise the role of these genes and probably reveal the existence of other genes not identified yet. The impact of these findings on the understanding of malaria pathogenesis and on the design of future preventive and therapeutic strategies should be considerable.
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PMID:[Genetic epidemiology in the study of susceptibility/resistance to malaria in the human population]. 1057 61

Increased adherence of sickle red blood cells (RBC) to endothelium is implicated as an initiating event of vaso-occlusion in sickle cell disease. Although much is known about the humoral influences of this interaction, there has been little investigation regarding endothelial contributions. Endothelial derived nitric oxide (NO) inhibits adhesion of platelets and leukocytes to endothelium and decreases expression of VCAM-1, an endothelial adhesion site implicated in sickle RBC/endothelial adherence. However, whether NO inhibits RBC adherence to endothelium is unexplored. We tested this hypothesis with endothelial monolayers exposed to RBC from normal (Hb AA) and sickle cell (Hb SS) volunteers in a parallel plate flow chamber. To decrease NO production, endothelial monolayers were exposed to 100 microM nitro-L-arginine (NLA), an inhibitor of nitric oxide synthase, resulting in an 87% increase in normal RBC adherence (P = 0.002). Because adherence of normal RBC to endothelium was low, the effect of DETA-NO, an NO donor, was tested after activation of endothelium with TNF-alpha increased adherence by 130% (P < 0.001). Subsequent addition of 2 mM DETA-NO produced a 75% decrease in adherence of normal RBC to endothelium (P = 0.03). At baseline, sickle RBC were significantly more adherent than normal RBC (P < 0.001) and DETA-NO decreased sickle RBC adherence by 54% (P = 0.04). Thus, NO inhibits both normal and sickle RBC adherence to endothelium. Strategies that enhance NO activity may be therapeutic in sickle cell disease.
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PMID:Nitric oxide attenuates normal and sickle red blood cell adherence to pulmonary endothelium. 1070 64

Steady-state sickle cell disease (SCD) patients may have increased plasma levels of acute phase reactants and pro-inflammatory cytokines because of subclinical inflammation. We have estimated TNF-alpha levels in the plasma and in supernatants following peripheral blood mononuclear cell (PBMC) activation with phytohemagglutinin (PHA) in a group of Kuwaiti SCD patients using ELISA. The group consisted of 28 SS, 8 Sbeta-thal, and 2 SD patients all in steady state; 5 SS patients were studied during 7 episodes of painful crisis. The subjects were aged 2 to 16 years, with a mean of 7.3 +/- 3.5 years. The beta(S)-globin gene cluster haplotype, alpha-tha1 status, and spleen function were determined in the SS group using standard techniques. Most (82%) were homozygous for the Saudi Arabia/India haplotype and had elevated Hb F levels ranging from 15% to 35%. There were 24 controls (Hb AA or AS), of whom 14 were healthy and 10 were acutely ill at the time of the study. None of the children with SCD (either in steady state or crisis) had detectable plasma TNF-alpha, but four controls (3 acutely ill and one healthy) had levels ranging from 61.7 to 249.8 pg/mL. Following PHA stimulation most subjects responded with high levels of TNF-alpha, with the median level among the steady-state SS patients being significantly higher than that in the controls (both the acutely ill or healthy). It therefore appears that because of the mild disease among our Arab SS children, TNF-alpha is not detectable in their plasma in steady state; these children, however, had a significantly higher response than controls following PBMC activation.
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PMID:Tumor necrosis factor-alpha is undetectable in the plasma of SS patients with elevated Hb F. 1081 86

Previously published work has shown that sera from healthy sickle cell disease (SCD) patients inhibits normal lymphocyte response to phytohemagglutinin (PHA) in vitro. The objective of the current study is to ascertain what the combined effects of SCD sera plus penicillin have on normal lymphocyte cytokine production and mitogenic response to PHA. Steady state sera from 20 SCD patients not on penicillin prophylaxis and 20 comparable healthy controls were used in all experiments. Four normal healthy individuals were used as donors for obtaining peripheral blood mononuclear cells (PBMC), by density gradient. PBMC with or without penicillin were PHA stimulated by standard in vitro culture for mitogenic response and cytokine production. Supernatant cytokine levels for interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and interleukin (IL)2 were quantified by ELISA technique. Results revealed suppression of mitogenic response in the SCD group with or without penicillin, compared to control sera (P < .001). Cytokine production in the SCD sera group showed increased production of IFN-gamma and TNF-alpha in the absence of penicillin, but suppression at all doses of penicillin. The control group results were as follows: no significant difference in IFN-gamma production with or without penicillin, mean TNF-alpha levels were the opposite of SCD sera with lower levels in the absence of penicillin. IL-2 production demonstrated a similar pattern for both groups of sera. IL-2 production was low without penicillin, but there was increased production with penicillin, which appeared dose related. The data suggests that sera from healthy SCD patients and in vitro added penicillin may have a combined suppressive effect on normal lymphocyte in vitro production of IFN-gamma and TNF-alpha. The current study results suggest that penicillin has the beneficial effect of decreasing TNF-alpha production and increasing IL-2 production when combined with SCD steady state sera. However, this in vitro benefit must be weighed against suppression of IFN-gamma production and ultimately, perhaps the long-term utility of penicillin prophylaxis in patients with SCD.
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PMID:Combined effects of in vitro penicillin and sickle cell disease sera on normal lymphocyte functions. 1215 23

Patients with sickle cell disease often seek treatment for rapid periorbital swelling due to infarction of the orbital bones. Because of resulting orbital compression syndrome, treatment with corticosteroids and antibiotics is advisable. If spinal tuberculosis occurs in patients with sickle cell anemia, radiologic signs will be a combination of the two conditions. The diagnosis of juvenile rheumatoid arthritis is usually delayed in patients with sickle cell disease. Sulphasalazine is the disease-modifying drug of choice for treating juvenile rheumatoid arthritis, because it also reduces the adhesiveness of sickled red cells. TNF-alpha inhibitors may also be useful for treating these patients. A volumetric method to determine the size and special distribution of the necrotic lesions of the femoral head has been developed using magnetic resonance imaging scans. With this method it will be easier to determine which early lesions require core decompression, or which ones should be treated conservatively. Osteomyelitis can be differentiated from bone infarction with the use of segmental radionuclide bone-marrow and bone scans. Reduction in frequency of painful crises can be achieved by increasing fetal hemoglobin with the use of hydroxyurea. The treatment of the actual pain requires decisions about the analgesics that are used as well as the route of their administration. Ketorolac monotherapy is likely to fail in the presence of an initial high pain score or with involvement of four or more pain sites.
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PMID:Musculoskeletal manifestations of hemoglobinopathies. 1249 9

Autonomic functions, such as increased sympathetic and parasympathetic activity and the brain's suprachiasmatic nucleus, higher nervous centres, depression, hostility and aggression appear to be important determinants of heart rate variability (HRV), which is, itself, an important risk factor of myocardial infarction, arrhythmias, sudden death, heart failure and atherosclerosis. The circadian rhythm of these complications with an increased occurrence in the second quarter of the day may be due to autonomic dysfunction as well as to the presence of excitatory brain and heart tissues. While increased sympathetic activity is associated with increased levels of cortisol, catecholamines, serotonin, renin, aldosterone, angiotensin and free radicals; increased parasympathetic activity may be associated with greater levels of acetylecholine, dopamine, nitric oxide, endorphins, coenzyme Q10, antioxidants and other protective factors. Recent studies indicate that hyperglycemia, diabetes, hyperlipidemia, ambient pollution, insulin resistance and mental stress can increase the risk of low HRV. These risk factors, which are known to favour cardiovascular disease, seem to act by decreasing HRV. There is evidence that regular fasting may modulate HRV and other risk factors of heart attack. While exercise is known to decrease HRV, exercise training may not have any adverse effect on HRV. In a recent study among 202 patients with acute myocardial infarction (AMI), the incidence of onset of chest pain was highest in the second quarter of the day (41.0%), mainly between 4.0-8.0 AM, followed by the fourth quarter, usually after large meals (28.2%). Emotion was the second most common trigger (43.5%). Cold weather was a predisposing factor in 29.2% and hot temperature (> 40 degrees celsius) was common in 24.7% of the patients. Dietary n-3 fatty acids and coenzyme Q10 have been found to prevent the increased circadian occurrence of cardiac events in our randomized controlled trials, possibly by increasing HRV. We have also found that n-3 fatty acids plus CoQ can decrease TNF-alpha and IL-6 in AMI which are pro-inflammatory agents. There is evidence that dietary n-3 fatty acids canenhance hippocampal acetylecholine levels, which may be protective. Similarly, the stimulation of the vagus nerve may inhibit TNF synthesis in the liver and acetylecholine, the principal vagal neurotransmitter, significantly attenuates the release of pro-inflammatory cytokines TNF-alpha, interleukin 1,6 and 18, but not the anti-inflammatory cytokine IL-10 in experiments. Therefore, any agent which can enhance brain acetylecholine levels, may be used as a therapeutic agent in protecting the suprachiasmatic nucleus, higher nervous centres, vagal activity and sympathetic nerve activity which are known to regulate the body clock and HRV and the risk of SCD and heart attack.
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PMID:Brain-heart connection and the risk of heart attack. 1265 78

Microvascular complications in sickle cell disease occur as a result of obstruction of small vessels by deoxygenated sickle cells. Cerebrovascular complications are also common and result from obstruction of large blood vessels by thrombosis with changes in vessels that have some similarity to those found in arteriosclerotic vascular disease. Endothelial damage and activation from sickle cell-endothelial interactions may contribute to both. We find that endothelial cells have increased expression of VCAM-1, E-selectin, and ICAM-1 when exposed to sickle blood cells. The concentration-dependent, sickle-induced, adhesion molecule expression is significantly greater than that promoted by normal cells. The time course of Cell Adhesion Molecule (CAM) expression is similar to that induced by TNF-alpha and IL1. Studies after white cell enrichment and reduction suggest leukocytes are the primary mediators. CAM expression by endothelial cells appears stimulated by soluble factors. Antibody inhibition studies support TNF-alpha and IL-1, produced by sickle leukocytes, as the primary soluble factors responsible for the observed CAM expression. Both the induction of endothelial CAM expression and subsequent endothelial adherence of sickle erythrocytes may play significant roles in the pathophysiology of sickle-related complications, and reduction in CAM expression may provide a new approach to treatment.
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PMID:Activation of vascular endothelial cell adhesion molecule expression by sickle blood cells. 1267 44

Monocytes from patients with sickle cell disease (SCD) are in an activated state. However, the mechanism of activation of monocytes in SCD is not known. Our studies showed that placenta growth factor (PlGF) activated monocytes and increased mRNA levels of cytokines (tumor necrosis factor-alpha [TNF-alpha] and interleukin-1beta [IL-1beta]) and chemokines (monocyte chemotactic protein-1 [MCP-1], IL-8, and macrophage inflammatory protein-1beta [MIP-1beta]) in both normal monocytes and in the THP-1 monocytic cell line. This increase in mRNA expression of cytochemokines was also reflected in monocytes derived from subjects with SCD. We studied the PlGF-mediated downstream cellular signaling events that caused increased transcription of inflammatory cytochemokines and chemotaxis of THP-1 monocytes. PlGF-mediated cytochemokine mRNA and protein expression was inhibited by PD98059 and wortmannin, inhibitors of mitogen-activated protein kinase kinase (MAPK/MEK) kinase and phosphatidylinositol-3 (PI3) kinase, respectively, but not by SB203580, a p38 kinase inhibitor. PlGF caused a time-dependent transient increase in phosphorylation of extracellular signal-regulated kinase-1/2 (ERK-1/2), which was completely inhibited by wortmannin, indicating that activation of PI3 kinase preceded MEK activation. PlGF also induced transient phosphorylation of AKT. MEK and PI3 kinase inhibitors and antibody to Flt-1 abrogated PlGF-induced chemotaxis of THP-1 monocytes. Overexpression of a dominant-negative AKT or a dominant-negative PI3 kinase p85 subunit in THP-1 monocytes attenuated the PlGF-mediated phosphorylation of ERK-1/2, cytochemokine secretion, and chemotaxis. Taken together, these data show that activation of monocytes by PlGF occurs via activation of Flt-1, which results in activation of PI3 kinase/AKT and ERK-1/2 pathways. Therefore, we propose that increased levels of PlGF in circulation play an important role in the inflammation observed in SCD via its effects on monocytes.
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PMID:Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor. 1268 30

Hydroxyurea (HU), a chemotherapeutic agent, used increasingly in the treatment of sickle cell disease (SCD) stimulates the release of a tumor necrosis factor (TNF-alpha) from human macrophages in vitro and the concentration of TNF-alpha is greater than normal in subjects affected by SCD. It is widely accepted that HU may inhibit vaso-occlusive crisis (VOC) by stimulating the production of fetal hemoglobin (HbF) and nitric oxide (NO) in SCD; however, the beneficial effects of HU in vivo may be counteracted by the release of TNF-alpha and, in turn, the expression of a vascular cell adhesion molecule (VCAM-1) on leukocytes. Previous studies have shown that the severity of SCD increases with the leukocyte count. Therefore, we examined the relationship between plasma levels of TNF-alpha and HbF in SCD patients during steady-state (StSt) conditions (in the absence of VOC) and during VOC conditions after the acute administration of HU. Venous blood was collected in SCD patients over 6 h after administering a single dose of HU. Plasma TNF-alpha was found to be greater in SCD subjects than in reported normal adult controls (p<0.05). TNF-alpha in the StSt group was not significantly different than in the VOC group; however, the plasma TNF-alpha tended to greater in the VOC group (p>0.1). An increase in the HbF concentration after acute administration of HU (p<0.01) was not associated with a significant change in plasma TNF-alpha (p>0.1). Contrary to the results of in vitro studies, HU did not increase the plasma concentration of TNF-alpha. These findings suggest that a HU-induced increase in TNF-alpha does not contribute to VOC and sickle cell patients can be counseled that the HU-induced increase in TNF-alpha does not counteract the beneficial effects of HU in SCD.
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PMID:Plasma levels of TNF-alpha in sickle cell patients receiving hydroxyurea. 1496 70


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