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)

Gemtuzumab ozogamicin (Mylotarg) targets leukemia cells expressing the CD33 receptor by means of a monoclonal antibody conjugated to a cytotoxic agent, calicheamicin. Treatment of acute myeloid leukemia (AML) with gemtuzumab ozogamicin may result in liver injury. We reviewed the course of 23 patients who were given gemtuzumab ozogamicin for AML that had relapsed after hematopoietic cell transplantation. Liver toxicity was assessed through physical examination, serum tests, histologic examination, and hepatic venous pressure measurements. Liver injury developed in 11 patients after gemtuzumab ozogamicin administration; it was manifested as weight gain, ascites, and jaundice in 7 patients. Seven patients died with persistent liver dysfunction and either multiorgan failure or sepsis at a median of 40 days after gemtuzumab ozogamicin infusion. Portal pressure measurements were elevated in 2 patients. Results of liver histologic examination in 5 patients showed sinusoidal injury with extensive sinusoidal fibrosis, centrilobular congestion, and hepatocyte necrosis. Six patients experienced AML remission that was sustained for at least 60 days after gemtuzumab ozogamicin infusion. In summary, hepatic sinusoidal liver injury developed after gemtuzumab ozogamicin infusion. Histology showed striking deposition of sinusoidal collagen, suggesting that gemtuzumab ozogamicin targets CD33(+) cells residing in hepatic sinusoids as the mechanism for its hepatic toxicity.
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PMID:Hepatic sinusoidal obstruction after gemtuzumab ozogamicin (Mylotarg) therapy. 1189 61

Lactoferrin (Lf) is an iron-binding protein of external secretions and neutrophil secondary granules with antimicrobial and immunomodulatory activities. To further define these properties of Lf, we have investigated the response to Staphylococcus aureus infection in transgenic mice carrying a functional human Lf gene. The transgenic mice cleared bacteria significantly better than congenic littermates, associated with a trend to reduced incidence of arthritis, septicemia, and mortality. We identified two pathways by which S. aureus clearance was enhanced. First, human Lf directly inhibited the growth of S. aureus LS-1 in vitro. Second, S. aureus-infected transgenic mice exhibited enhanced Th1 immune polarization. Thus, spleen cells from infected transgenic mice produced higher levels of TNF-alpha and IFN-gamma and less IL-5 and IL-10 upon stimulation ex vivo with the exotoxin toxic shock syndrome toxin-1 compared with congenic controls. To confirm that these effects of Lf transgene expression could occur in the absence of live bacterial infection, we also showed that Lf-transgenic DBA/1 mice exhibited enhanced severity of collagen-induced arthritis, an established model of Th1-induced articular inflammation. Higher levels of stainable iron in the spleens of transgenic mice correlated with human Lf distribution, but all other parameters of iron metabolism did not differ between transgenic mice and wild-type littermates. These results demonstrate that human Lf can mediate both antimicrobial and immunomodulatory activities with downstream effects on the outcome of immune pathology in infectious and inflammatory disease.
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PMID:Enhanced Th1 response to Staphylococcus aureus infection in human lactoferrin-transgenic mice. 1193 51

Nitric oxide (NO) plays an important role in various physiological processes. Excessive NO production is closely related to inflammatory and autoimmune diseases such as septic shock and rheumatoid arthritis. Suppression of excess NO formation in participating cells may be helpful in improving disease status. In this study, we examined the effects of a newly synthesized imidazole derivative, 3-(2,4-difluorophenyl)-6-[2-[4-(1H-imidazol-1-ylmethyl) phenoxy]ethoxy]-2-phenylpyridine (PPA250), on NO production in vitro and in vivo, as well as on the dimerization of inducible nitric-oxide synthase (iNOS). PPA250 at concentrations of 25 nM and higher inhibited NO production in activated mouse macrophage-like RAW264.7 cells. The IC(50) was approximately 82 nM. Western blot analysis revealed that PPA250 prevents dimerization of iNOS but has no effect on transcription and translation. In addition, oral administration of PPA250 (10 mg/kg and higher) reduced the NO concentration in serum from mice in which sepsis was induced by bacterial lipopolysaccharide. Since the inhibitory activity was observed not only in vitro but also in vivo, we examined the therapeutic potential of PPA250 in two animal models of arthritis, collagen-induced arthritis in mice and adjuvant arthritis in rats. PPA250 suppressed the development of a destructive polyarthritis in both models after the appearance of clinical signs. These results indicate that inhibitors of iNOS homodimerization, including PPA250, could be useful therapeutic agents for inflammatory and autoimmune diseases, such as rheumatoid arthritis, in which NO is involved.
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PMID:PPA250 [3-(2,4-difluorophenyl)-6-[2-[4-(1H-imidazol-1-ylmethyl) phenoxy]ethoxy]-2-phenylpyridine], a novel orally effective inhibitor of the dimerization of inducible nitric-oxide synthase, exhibits an anti-inflammatory effect in animal models of chronic arthritis. 1223 32

Incomplete septal cirrhosis, which is included in the spectrum of hepatoportal sclerosis, is characterized by parenchymal nodularity, incomplete fibrous septa, clustered or dispersed portal tract remnants, and abnormal spacing of portal tracts and hepatic veins. Hepatoportal sclerosis is known to be associated with collagen vascular diseases. Here, we describe a 73 year-old-female with incomplete septal cirrhosis. At 57 years, she presented with respiratory symptoms, and lung biopsy disclosed active arteritis with granuloma. Perinuclear antineutrophilic cytoplasmic antibody was also positive. Immunosuppressive therapy was done under the diagnosis of Wegener's granulomatosis. At 63 years, liver dysfunction was noted, and laparoscopy revealed uneven surface of the liver and dilatation of the umbilical vein. Liver dysfunction progressed, and she developed encephalopathy and massive ascites. She died of sepsis at 73 years. At autopsy the liver (700 g) was macronodular with several deep depressions. The parenchyma showed fine and diffuse nodularity. Grossly visible portal and hepatic veins were patent. The above-mentioned histologic features characterizing incomplete septal cirrhosis were found. This is the first report of incomplete septal cirrhosis associated with Wegener's granulomatosis implying that vascular and extravascular lesions of Wegener's granulomatosis might have been related to the pathogenesis of incomplete septal cirrhosis.
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PMID:Incomplete septal cirrhosis associated with Wegener's granulomatosis. 1239 Apr 74

Glutamine and glutamate with proline, histidine, arginine and ornithine, comprise 25% of the dietary amino acid intake and constitute the "glutamate family" of amino acids, which are disposed of through conversion to glutamate. Although glutamine has been classified as a nonessential amino acid, in major trauma, major surgery, sepsis, bone marrow transplantation, intense chemotherapy and radiotherapy, when its consumption exceeds its synthesis, it becomes a conditionally essential amino acid. In mammals the physiological levels of glutamine is 650 micromol/l and it is one of the most important substrate for ammoniagenesis in the gut and in the kidney due to its important role in the regulation of acid-base homeostasis. In cells, glutamine is a key link between carbon metabolism of carbohydrates and proteins and plays an important role in the growth of fibroblasts, lymphocytes and enterocytes. It improves nitrogen balance and preserves the concentration of glutamine in skeletal muscle. Deamidation of glutamine via glutaminase produces glutamate a precursor of gamma-amino butyric acid, a neurotransmission inhibitor. L-Glutamic acid is a ubiquitous amino acid present in many foods either in free form or in peptides and proteins. Animal protein may contain from 11 to 22% and plants protein as much as 40% glutamate by weight. The sodium salt of glutamic acid is added to several foods to enhance flavor. L-Glutamate is the most abundant free amino acid in brain and it is the major excitatory neurotransmitter of the vertebrate central nervous system. Most free L-glutamic acid in brain is derived from local synthesis from L-glutamine and Kreb's cycle intermediates. It clearly plays an important role in neuronal differentiation, migration and survival in the developing brain via facilitated Ca++ transport. Glutamate also plays a critical role in synaptic maintenance and plasticity. It contributes to learning and memory through use-dependent changes in synaptic efficacy and plays a role in the formation and function of the cytoskeleton. Glutamine via glutamate is converted to alpha-ketoglutarate, an integral component of the citric acid cycle. It is a component of the antioxidant glutathione and of the polyglutamated folic acid. The cyclization of glutamate produces proline, an amino acid important for synthesis of collagen and connective tissue. Our aim here is to review on some amino acids with high functional priority such as glutamine and to define their effective activity in human health and pathologies.
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PMID:II. Glutamine and glutamate. 1248 81

Auto transplantation of the spleen can be performed in the patients with traumatic rupture of the spleen, in whom spleen could not be conserved in the other way. The right indication for this method is isolated rupture of the spleen (concvasation or complete devascularisation). This method is not recommended in the endangered patients, patients with previous disease of the spleen as well as in the patients with the perforation of the other abdominal organs at the same time. Auto transplantation was performed in 12 patients with isolated splenic rupture and hematoperitoneum, 11 men and one woman. The majority of patients are younger. In 8 patients, autotransplant was placed into big omentum, in three into lipomatous tissue surrounding left kidney, and in one into anterior abdominal wall. In all the patients from this group, following analysis were taken: MCV (middle volume of erythrocytes), HTC, Hb, Le, Glucose, urea, creatinin, sodium, potassium, alkali phosphatasis, target cells, Howell Jolly's bodies, Heinz's bodies, IgG, IgA, IgM, C3, C4, T3, T4, T8, B, segmentated, eosinophiles, lymphocytes, reticulocytes, thrombocytes, fibrinogen, PT, APTT, aggregation of thrombocytes and aggregation of thrombocytes on collagen. The same parameters were taken in 12 patients with surgery similar to splenectomy and in 12 after splenectomy. After splenectomy, there was decrease of the immunologic defending abilities of the organism because of the loss of the childrens function of the spleen, decreased level of the opsonines and tutsin, which leads to the impaired phagocytosis, decreased concentration of IgM and T and B lymphocytes, while in patients after auto transplantation the results were physiological. The most important thing in the assessment of the function of the autotransplanted spleen is scintigraphic investigation using 99mTc-denaturated red blood cells. In our study, auto transplant function was assessed in 10/12 patients by scintigraphy. Five years after surgery, no one patient was proved to have postsplenectomic sepsis.
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PMID:[Autotransplantation of the spleen]. 1258 57

Severe illness with acute renal failure, leukopenia, thrombocytopenia, and coagulopathy frequently occurs with hemolytic uremic syndrome/thrombotic thrombocytopenic purpura, hematological malignancies, sepsis, and collagen-vascular diseases. We present a 16-year-old male fast-food worker with underlying chronic renal insufficiency who manifested these abnormalities as a result of Ehrlichia chaffeensis sepsis. Doxycycline therapy and aggressive supportive care led to complete recovery.
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PMID:Renal, hepatic, and marrow dysfunction in a patient with chronic renal insufficiency. 1264 28

Between 1985 and 2000, a total of 871 patients underwent surgical treatment for infrarenal abdominal aortic aneurysm (AAA), including 98 (11.2%) presenting with ruptured abdominal aortic aneurysms (RAAA). An optimized operative protocol was used to treat 77 RAAA starting in January 1989. The main features of the optimized protocol are routine use of intraoperative autotransfusion, revascularization by aortoaortic bypass, absence of systemic heparinization, and use of a collagen-impregnated prosthesis. Intraoperative mortality (IOM) was 3.8%. Postoperative mortality at 1 month (POM1) was 25.9% and postoperative mortality at 3 months (POM3) was 33.7%. Heart failure (p <0.001), hemodynamic shock (p <0.001), and hemorrhage (p = 0.04) were the only complications correlated with POM1. Pneumonia (p = 0.01) and sepsis (p = 0.01) were the only complications correlated with POM3. Isolated acute renal insufficiency was not a significant risk factor for postoperative mortality. Using a cutoff of 75 years, there was a significant age-related difference (p = 0.025) for POM1 but not for IOM and POM3. The findings of this study show that optimizing the operative protocol decreases mortality related to RAAA. The main predictor of POM1 was hemodynamic status while the main predictor of POM3 was infection. Isolated acute renal insufficiency was not a risk factor for mortality. Age should not be considered a contraindication for operative treatment.
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PMID:Ruptured aneurysm of the infrarenal abdominal aorta: impact of age and postoperative complications on mortality. 1270 41

In this study we aimed to investigate the findings in patients with adult-onset Still's disease (AOSD) admitted with fever of unknown origin (FUO) during the last 18 years in our unit, in order to discover the ratio of such patients to all patients with FUO during the same period, and to determine the clinical features of AOSD in FUO. The number and the aetiologies of the patients with FUO diagnosed between 1984 and 2001, and the clinical features of those with AOSD, were taken from the patient files. The diagnosis of AOSD was reanalysed according to the diagnostic criteria of Cush et al. [11]. The presumed diagnoses before a diagnosis of AOSD was established were also noted. The chi(2) and Fisher's exact tests were used for statistical analysis. We studied 130 patients with a diagnosis of FUO, 36 (28%) of whom had collagen vascular diseases. Of these 36 patients, 20 (56%, 12 female, 8 male, mean age 34 years, range 16-65) had AOSD. Clinical and laboratory findings were as follows: fever (100%), arthralgia (90%), rash (85%), sore throat (75%), arthritis (65%), myalgia (60%), splenomegaly (40%), hepatomegaly (25%), lymphadenopathy (15%), anaemia (65%), neutrophilic leukocytosis (90%), increased erythrocyte sedimentation rate (100%), elevated transaminase levels (65%), a negative RF (100%), and a negative FANA (80%). Antibiotics had been prescribed in 18 (90%) of cases. The presumed infectious diagnoses were streptococcal tonsillitis/pharyngitis (50%), infective endocarditis (four patients), sepsis (two patients) and acute bacterial meningitis (two patients). The presumed non-infectious diagnoses were acute rheumatic fever (three patients), seronegative rheumatoid arthritis (two patients) and polymyositis (two patients). Sixteen patients were followed for a mean duration of 30 months (range 2-59). A remission was obtained with indomethacin in three cases (19%), and with prednisolone in the remainder. Relapse was detected in three cases (19%). AOSD is one of the most frequent aetiologies of FUO. During the diagnostic course of a patient with FUO, a maculopapular rash and/or arthralgia and/or sore throat should raise the suspicion of AOSD. Because the disease has heterogeneous clinical findings, certain bacterial infections (e.g. streptococcal pharyngitis and sepsis) are generally considered and the prescribing of antibiotics is common.
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PMID:Fever of unknown origin: a review of 20 patients with adult-onset Still's disease. 1274 Jun 70

An acute septic inflammatory response with access to the portal circulation was created in a rat model using an intra-abdominal abscess composed of a sterile agar pellet, or one contaminated with 102 Escherichia coli (E. coli) and 109 Bacteriodes fragilis (B. fragilis). After 3 days postimplantation, a well-formed intra-abdominal abscess occurred whose wall showed IL-6 DNA by PCR and IL-6 mRNA by in situ hybridization. Portal venous blood draining into the liver from the intra-abdominal abscess had increased levels of TNF-alpha, IL-1beta, and IL-6 in both sterile and septic groups compared with a control normal animal group. Increased levels of these cytokines were also found in suprahepatic inferior vena caval blood, but were correlated with the higher portal vein levels, suggesting a gradient from abscess wall to portal vein into the systemic circulation via the liver. Liver histology demonstrated sinusoidal congestion centering on the central vein, growing worse with progression from normal in control, to sterile, to septic. Similarly, the degree of intrahepatic myeloperoxidase-positive inflammatory cell infiltration and hepatocellular lipid deposition and apoptosis also increased from control, to sterile, to septic. Gene expression by in situ hybridization demonstrated a significant increase in IL-6 and fibrinogen mRNAs in cells surrounding the central vein in sterile and septic animals, being greatest in animals with sepsis, associated with an increased deposition of collagen in the central vein area, most prominent in the septic liver. The pericentral vein cells with IL-6 and fibrinogen mRNA increases paralleled the increases in cells containing IL-6 and fibrinogen mRNAs in the abscess walls of sterile and septic animals, respectively. The data suggest that an intra-abdominal abscess, especially when contaminated with gram-negative bacteria, induces mRNA-generated cytokine responses in the abscess wall that are related to increased portal venous levels of the inflammatory cytokines TNF-alpha, IL-1beta, and IL-6 perfusing the liver. These, in turn, induce localized production of IL-6 and fibrinogen mRNAs in cells at the central vein area with resultant outflow fibrosis and increased inflammatory cell sequestration within the liver lobular sinuses. This is associated with a generalized inflammatory response and intrahepatic portal sinusoid congestion. There is also increased hepatocellular lipid deposition and apoptosis. Thus, the cytokine production of the abscess wall itself appears to be a major mediator of the septic hepatic response.
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PMID:The septic abscess wall: a cytokine-generating organ associated with portal venous cytokinemia, hepatic outflow fibrosis, sinusoidal congestion, inflammatory cell sequestration, hepatocellular lipid deposition, and focal cell death. 1281 73


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