Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Butyrate analogues have been shown to increase fetal hemoglobin (HbF) production in vitro and in vivo. Sodium phenylbutyrate (SPB), an oral agent used to treat individuals with urea-cycle disorders, has been shown to increase HbF in nonanemic individuals and in individuals with sickle cell disease. We have treated eleven patients with homozygous beta thalassemia (three transfusion dependent) and one sickle-beta-thalassemia patient with 20 g/d (forty 500-mg tablets) of SPB for 41 to 460 days. All patients showed an increase in the percent of F reticulocytes associated with treatment, but only four patients responded by increasing their Hb levels by greater than 1 g/dL (mean increase, 2.1 g/dL; range, 1.2 to 2.8 g/dL). None of the transfusion-dependent thalassemia subjects responded. Increase in Hb was associated with an increase in red blood cell number (mean increase, 0.62 x 10(12)/L), and mean corpuscular volume (mean increase, 6 fL). Changes in percent HbF, absolute HbF levels, or alpha- to non-alpha-globin ratios as measured by levels of mRNA and globin protein in peripheral blood did not correlate with response to treatment. Response to treatment was not associated with the type of beta-globin mutation, but baseline erythropoietin levels of greater than 120 mU/mL was seen in all responders and only two of eight nonresponders to SPB. Compliance with treatment was greater than 90% as measured by pill counts. Side effects of the drug included weight gain and/or edema caused by increase salt load in 2/12, transient epigastric discomfort in 7/12, and abnormal body odor in 3/12 subjects. Two splenectomized patients who were not on prophylactic antibiotics developed sepsis while on treatment. We conclude that SPB increases Hb in some patients with thalassemia, but the precise mechanism of action is unknown.
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PMID:Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial. 752 72

The effects of L-arginine on the adrenergic responses to either electrical transmural stimulation or phenylephrine were studied in isolated endothelium-denuded strips of rat tail arteries treated with lipopolysaccharide for 6 h in vitro. L-arginine did not relax the strips precontracted by phenylephrine. However, the adrenergic contractions induced by electrical transmural stimulation were significantly inhibited by the addition of L-arginine. This inhibitory effect was reversed by NG-nitro-L-arginine (a nitric oxide synthase inhibitor) or methylene blue (a soluble guanylate cyclase inhibitor) but was not affected by hemoglobin (a scavenger of nitric oxide). These results indicate that the adrenergic neurogenic contractions may be directly modulated by nitric oxide derived from the sympathetic nerves and/or neighboring cells in the lipopolysaccharide-treated rat tail arteries, and the nitric oxide production may be associated with the reduction of sympathetic tone in sepsis.
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PMID:Selective inhibition of sympathetic nerve-mediated contraction by L-arginine in lipopolysaccharide-treated tail artery of rats. 753 6

Nitric oxide (.NO) is synthesized by the enzyme nitric oxide synthase (NOS). There are 2 constitutive forms of NOS (cNOS) and 1 inducible form (iNOS). Cells containing cNOS rapidly and transiently produce small amounts of NO in response to agonists that raise cytosolic levels of free Ca2+, whereas cells expressing inducible iNOS produce large amounts of .NO for extended periods after a lag of several hours during which time the enzyme is induced. Until recently, the 2 constitutive isoforms of NOS were thought to be confined to endothelial cells (eNOS) and brain (bNOS or nNOS). However, eNOS and bNOS have been identified in an increasing variety of additional cells. Many, if not most, types of cells are capable of expressing iNOS in response to cytokines, endotoxin, and phagocytosis. Regulation of iNOS occurs at transcriptional, translational, and posttranslational levels. Because .NO is rapidly diffusible and soluble in hydrophobic and aqueous environments, it is well suited to its role as an intercellular messenger with the unique ability to penetrate solid tissue. However, it is rapidly inactivated by hemoglobin. The biochemistry of .NO is dominated by its rapid reaction with oxygen and transitional metals, notably iron. The former reaction may be protective, as when neutralizing superoxide (.O2-), or harmful in forming additional highly damaging radicals such as peroxynitrite. Interaction of .NO with iron-containing proteins has a number of sequelae, including the activation of guanylate cyclase, inhibition of mitochondrial respiration, and inhibition of cell division. Nitric oxide has been implicated in a number of conditions of orthopaedic interest, including inflammation, arthritis, osteoporosis, sepsis, ligament healing, and aseptic loosening of joint prostheses.
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PMID:Nitric oxide and its role in orthopaedic disease. 754 92

Heme oxygenase (HO) catalyzes the rate-limiting step in the degradation of heme to bilirubin. HO-1 is highly induced by heme, its major substrate, and nonheme products, including metal ions and hormones. Interest in HO-1 has been stimulated recently by observations that HO-1 is also highly induced in response to oxidative stress in vitro. The physiologic significance of HO-1 induction following oxidant injury in vivo, however, is poorly understood. In a rat model of lipopolysaccharide endotoxin (LPS)-induced lung injury and sepsis, we demonstrate that the lung responds to LPS by expressing high levels of HO-1 mRNA and enzyme activity. We hypothesize that this HO-1 induction could play a critical role in the lung's defense against LPS. Pretreatment of rats with hemoglobin, a potent inducer of HO-1, resulted in HO-1 induction and more importantly provided complete protection against subsequent lethal endotoxemia (100% survival). Tin protoporphyrin, a competitive inhibitor of HO, blocked this protective effect of hemoglobin and rendered the rats more susceptible to a lethal dose of LPS. Taken together, these data strongly implicate HO-1 in playing an important role in the defense against endotoxic shock, with potential therapeutic implications.
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PMID:Hemoglobin provides protection against lethal endotoxemia in rats: the role of heme oxygenase-1. 757 96

In Sandaun Province in Papua New Guinea, health professionals at the health center serving the people of Aitape District (Raihu Health Centre) compared data on deliveries before arrival (DBA) at the regional hospital in Wewak with data on 635 deliveries at Raihu Health Centre (HC) to examine differences in pregnancy complications and outcomes between the DBA and HC groups. All the deliveries occurred between 1990 and mid-1992. HC delivery cases were more likely to have had prenatal care than DBA delivery cases (90% vs. 52%). Multiple births were high (4% for DBA and 3.5% for HC), as was expected in Aitape District, where multiple births are common. The multiple births accounted for a high breech delivery rate (3.5-5.4%). Proper supervision during delivery would have likely reduced the high rate of retained placentas in the DBA group (21% vs. 1.3%). Other pregnancy complications more common in the DBA group than the HC group included postpartum hemorrhage (16% vs. 4.3%), need for blood transfusion (15% vs. 2.5%), and puerperal sepsis (18% vs. 4.3%). The DBA group also had a lower hemoglobin level and a higher gonorrhea rate and stayed in the hospital longer than the HC group (7.78 vs. 8.77 g/dl, 17% vs. 8%, and 6.54 vs. 5.4 days, respectively). Infants in the DBA group were more likely than those in the HC group to die in utero (10.5% vs. 2.3%) and die during the first week postpartum (4% vs. 2.5%), develop neonatal sepsis (17.2% vs. 8.4%), and weigh less (2.68 vs. 2.81 kg). These findings suggest that mothers who receive prenatal care and deliver at a health center experience fewer complications and have bigger and healthier newborns than mothers who deliver at home.
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PMID:A comparison between health centre deliveries and deliveries born before arrival in the Aitape district. 766 55

The incidence of functional asplenia in sickle-hemoglobin C (SC) disease has not been defined, and the use of prophylactic penicillin to prevent life-threatening septicemia in this disorder is controversial. The percentage of red blood cells with pits (pit count) is a reliable assay of splenic function in other disorders but has not been validated in hemoglobin SC disease. To address these issues, we conducted a prospective, multicenter study of splenic function in persons with hemoglobin SC disease. Baseline clinical data were recorded, and red blood cell pit counts were performed on 201 subjects, aged 6 months to 90 years, with hemoglobin SC; 43 subjects underwent radionuclide liver-spleen scanning. Pit counts greater than 20% were associated with functional asplenia as assessed by liver-spleen scan, whereas pit counts less than 20% were found in subjects with preserved splenic function. Pit counts greater than 20% were present in 0 of 59 subjects (0%) less than 4 years of age, in 19 of 86 subjects (22%) 4 to 12 years of age, and in 25 of 56 subjects (45%) greater than 12 years of age. Other subjects with hemoglobin SC, who had previously undergone surgical splenectomy, had higher pit counts (59.7% +/- 9.5%) than splenectomized subjects without hemoglobinopathy (38.5% +/- 8.8%) or with sickle cell anemia (20.5% +/- 1.9%; P < .001). Two subjects with hemoglobin SC disease (not splenectomized), ages 14 and 15 years, with pit counts of 40.3% and 41.7% died from pneumococcal septicemia. These data indicate that functional asplenia occurs in many patients with hemoglobin SC disease, but its development is usually delayed until after 4 years of age. The pit count is a reliable measure of splenic function in hemoglobin SC disease, but values indicative of functional asplenia (> 20% in our laboratory) are higher than in other disorders. The routine administration of prophylactic penicillin to infants and young children with hemoglobin SC disease may not be necessary.
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PMID:Functional asplenia in hemoglobin SC disease. 771 96

13 premature babies (gestational age 31.1 +/- 0.9 weeks and birth weight 1586 +/- 261 g) were randomly assigned to receive recombinant human erythropoietin (200 U/kg i.v. three times a week during 4 weeks) or no (13 babies) as soon as haematocrit decrease < 30% between second and seventh week (TO). The two groups had similar gestational age, birth weight, Apgar score 1' and 5', O2-therapy, IPPV and volume of packed erythrocytes transfused before TO. Treatment was started at 30 +/- 0.5 days (range 21-42). At TO all subjects had not cardiopulmonary compromission, sepsis, O2-dependence, GMH-IVH > or = 2 degree grade and received iron and Vit. E by i.m. Result were evaluated through determination of hemoglobin, haematocrit, reticulocytes and volume of packed erythrocytes before and on days 7, 14, 21 and 28 of therapy. After rHuEPO the number of reticulocytes increased on days 21 and 28 of therapy (on day 21: 92.4 +/- 34.2 x 1000/L vs. 71.8 +/- 21.0, p < 0.10; on day 28: 116.2 +/- 42.9 vs. 83.8 +/- 23.2, p < 0.05); otherwise the number of transfusion (0.2 +/- 0.4 vs. 1.0 +/- 1.2, p < 0.10) and volume of packed erythrocytes (3.0 +/- 6.3 ml/kg vs. 14.9 +/- 15.9, p < 0.05) were reduced. Serum erythropoietin levels did not change during treatment, probably because, reducing the lowering of hemoglobin, hypoxic stimulus to increase of erythropoietin was suppressed.
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PMID:[Effects of recombinant human erythropoietin in the treatment of anemia of prematurity]. 773 26

A 55-year-old female presented with sore throat and slight fever. The patient was admitted to our hospital on December 13, 1993. Full blood count showed hemoglobin 10.7 g/dl, white cell count 960/microliters (neutrophils 14%, lymphocytes 82%, blasts 2%) and platelets 13,000/microliters. Bone marrow examination showed hypocellularity with 4.5% of myeloblast positive for peroxidase. The bone marrow specimens on Dec. 20 showed 15.5% of myeloblasts, some of which had Auer rods. These findings led to the diagnosis of refractory anemia with excess myeloblast in transformation (RAEB-T) of French-American-British Cooperative Group. The patient was transfused and treated with cytarabine ocfosfate (SP-AC) (100 mg tid) and 6-mercaptopurine (50 mg tid) for 14 days. During chemotherapy she complained of nausea and anorexia, but they were managed easily with medication. On Feb. 7, 1994, forty-two days after the start of administration, peripheral blood and bone marrow aspirate were compatible with a complete remission. Although complete remission was sustained with courses of chemotherapy for 4 months, relapse occurred and the patient died of septicemia on August 29, 1994 after induction failure. Observation suggested that oral SPAC in combination with 6-mercaptopurine had a good antileukemic effect on the myelodysplastic syndrome. However, the duration response was short, and further improvement of the therapy is needed.
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PMID:[Refractory anemia with excess myeloblast in transformation induced remission by combined oral administration of cytarabine ocfosfate and 6-mercaptopurine]. 779 1

Lipids are a class of molecules which self-assemble into a variety of phase-dependent morphologies. We have employed self-assembled lipid microstructures in the development of a number of biomedical material applications. The blood substitute, liposome encapsulated hemoglobin, is being investigated for the in vivo delivery of hemoglobin without many of the inherent toxicities associated with the delivery of free hemoglobin. This investigation is currently focused on demonstrations of efficacy in stressed animal models and on the safety of administering this material in models of sepsis. The synthetic modification of phospholipids to include photopolymerizable moieties such as diacetylenes has resulted in the spontaneous self-assembly of a hollow microcylinder which we are investigating for the controlled release of growth factors in soft tissue regeneration. Self-assembled monolayers are also being explored for the ability to surface modify biomaterials for improved cell adhesion. Photolithographic techniques have been combined with monolayer deposition to fabricate coplanar patterns of cell adhesion and inhibiting moieties. This results in the ability to spatially control the adhesion of cells to biomaterial surfaces. These cell patterns can form the basis for understanding two- and three-dimensional cellular events on the biomaterial surface and for the fabrication of improved cell-based biocompatible surfaces. The spontaneous self-assembly of lipids to form structures of biotechnological interest presents a unique opportunity to exploit this class of molecules for biomaterial applications.
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PMID:Biomaterial biotechnology using self-assembled lipid microstructures. 782 78

Administration of purified hemoglobin (Hb) as a cell-free resuscitation fluid is associated with multiple organ toxicities. Many of these toxicities are characteristic of the pathophysiological effects of bacterial endotoxins (lipopolysaccharide, LPS). To better understand the potential role of LPS in the observed in vivo toxicities of Hb, we examined mixtures of Hb and LPS for evidence of LPS-Hb complex formation. LPS-Hb complexes were demonstrated by three techniques: ultrafiltration through 300 kDa cut-off membranes, which distinguished LPS in complexes (87-89% < 300 kDa) from LPS alone (90% > 300 kDa); density centrifugation through sucrose, which distinguished denser LPS alone from LPS-Hb complexes; and precipitation by 67% ethanol, which demonstrated 2-3 fold increased precipitability of Hb in complexes compared to Hb alone. Interaction of LPS with Hb was also associated with markedly increased biological activity of LPS, as manifested by enhancement of LPS activation of Limulus amebocyte lysate (LAL), increased release of human mononuclear cell tissue factor, and enhanced production of human endothelial cell tissue factor. These results demonstrated that hemoglobin can serve as an endotoxin binding protein, and that this interaction results in the alteration of several of the physical characteristics of LPS and enhancement of the biological activities of LPS. These findings suggest that a mechanism for the toxicity of infused Hb in vivo may involve potentiation of the biological effects of LPS. In addition, these observations suggest a mechanism by which LPS-related morbidity during sepsis could be enhanced by erythrocyte hemolysis.
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PMID:Hemoglobin: a newly recognized binding protein for bacterial endotoxins (LPS). 783 56


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