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)

We have shown that immune cells from septic mice exhibit a suppressed response to exogenous stimuli in vitro. The suppressors of the cytokine signaling (SOCS) family are proteins that block intracellular signaling and can be induced by inflammatory mediators. Therefore, we hypothesized that SOCS-3 is up-regulated in immune cells in response to a septic challenge induced by cecal ligation and puncture (CLP). Mice were subjected to CLP or sham-CLP, and 2-48 h later, the blood, thymus, spleen, lung, and peritoneal leukocytes were harvested and examined. SOCS-3 was undetectable in thymocytes or blood leukocytes. In contrast, SOCS-3 was up-regulated in the spleen, lung, and peritoneal leukocytes in a time-dependent manner. Further examination revealed that only the macrophages and neutrophils expressed SOCS-3. These data suggest that cytokines and bacterial toxins present during sepsis have the ability to suppress the cytokine and/or lipopolysaccharide response and the function of immune cells by up-regulating SOCS-3.
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PMID:Sepsis-induced SOCS-3 expression is immunologically restricted to phagocytes. 1296 Feb 86

Four renal homotransplants were carried out between cadaver donors and four recipients, all of whom were in terminal chronic renal failure. Immune suppression was attempted with azathioprine (Imuran), actinomycin C and prednisone; no radiation was used, nor were the recipient's kidneys, spleen or thymus removed. One patient died with disseminated histoplasmosis at two weeks; another with irreversible homograft rejection at 30 days; a third patient died of septicemia after 9(1/2) weeks with stable renal function. The fourth patient, whose transplant had been ischemic for 190 minutes and had not functioned for 2(1/2) weeks thereafter, eventually achieved good function which remained unchanged to 7(1/2) months. Changes in urinary enzyme excretion and in the I(131) renogram and meralluride scan were of value in assessing homograft rejection.
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PMID:CADAVER RENAL HOMOTRANSPLANTS: INITIAL EXPERIENCES. 1421 12

Using the cecal ligation/puncture (CLP) model of sepsis in rodents, evidence was obtained for excessive activation of the complement system, which leads to nearly total loss of innate immune protective functions of blood neutrophils. These defects are associated with profound defects in chemotaxis, respiratory burst (H2O2 production) and phagocytosis. The molecular mechanisms of these defects are linked to the complement activation product C5a. In CLP rats and mice, the C5a receptor (C5aR) is widely up-regulated in organs, in part owing to the production of interleukin-6 (IL-6). The up-regulation of C5aR in the thymus is linked to C5a-dependent induction of apoptosis in thymocytes, as revealed by caspase activation, increased binding of C5a and DNA laddering. Such events in thymocytes are prevented if rats first are treated with anti-C5a or with anti-C5aR at the time of CLP. Treatment of CLP rats and mice with anti-C5a, anti-IL-6 or anti-C5aR dramatically improves survival rates after CLP, indicating a linkage between C5a and C5aR in the harmful outcomes of sepsis in rodents. Studies are underway in humans with sepsis to determine whether similar mechanisms are in play.
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PMID:Anti-complement strategies in experimental sepsis. 1462 Jan 41

SCH351591, a novel phosphodiesterase-4 inhibitor under investigation as a potential therapeutic for asthma and chronic obstructive pulmonary disease (COPD), was evaluated in a 3-month rising-dose study in Cynomolgus monkeys. Four groups, containing four monkeys/sex, received vehicle control or rising doses up to 12, 24, or 48 mg/kg of SCH351591 daily. Although initial exposure produced clinical signs of emesis, reduced food intake, and reduced body weight, tachyphylaxis to the emesis allowed dose escalation up to 48 mg/kg/day. Two monkeys died and 3 were sacrificed in moribund condition over the course of the study. Early mortality, involving monkeys dosed with 12 or 24 mg/kg, was attributed to sepsis (2 monkeys) or colon inflammation (3 monkeys). Leukocyte function assays on low- and mid-dose group survivors revealed an inhibition of T lymphocyte proliferation for 12 mg/kg group males and 24 mg/kg group monkeys of both sexes. Necropsy findings, unassociated with early mortality, included reduced size and weight of the thymus, depletion of body fat, red discoloration of the gastric mucosa, and perivascular hemorrhage of the stomach and heart. Stomach and heart gross findings were present in the high-dose group only. Histopathologic lesions, in addition to those attributed to concurrent bacterial infection, included thymic atrophy, serous atrophy of fat, myocardial degeneration and acute to chronic inflammation of small to medium-sized arteries in various organs and tissues including the heart, kidneys, stomach, salivary glands, pancreas, esophagus, gallbladder, and mesentery. The findings of this study demonstrate the potential of a PDE4 inhibitor to alter immunologic response as well as to produce arteriopathy in nonhuman primates.
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PMID:The toxicity of SCH 351591, a novel phosphodiesterase-4 inhibitor, in Cynomolgus monkeys. 1520 71

In vitro studies have shown that induction of heat shock before an inflammatory stimulus is cytoprotective, whereas induction of heat shock after an inflammatory stimulus can lead to apoptosis (the "heat shock paradox"). We sought to determine whether induction of the heat shock response in vivo caused similar, order-dependent effects on survival, and if so, by what mechanism. ND4 and C57BL/6 mice were used to calibrate the response to hyperthermia at 41.5 degrees C via induction of inducible heat shock protein 70. Sequences of heat shock and septic stresses were studied in murine models of hyperthermia (41.5 degrees C for 20 min) and cecal ligation and puncture (CLP), respectively. Previous heat shock to 41.5 degrees C did not protect CLP mice when compared with control CLP animals heated to 37 degrees C, but heat shock increased mortality when activated after CLP compared with controls. This effect of heat shock on CLP mortality was strain independent, and did not involve alterations in CLP-induced thymus, spleen, or intestinal apoptosis. We conclude that the heat shock paradox can occur in vitro and in vivo, and that the negative effects of heat shock on survival after CLP appeared to be strain independent. Furthermore, the stress of general anesthesia and warming also altered CLP mortality unexpectedly. The cellular mechanisms responsible for these "stressor" paradoxes in vivo are not known, but do not involve altered sepsis-induced apoptosis.
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PMID:Sequence makes a difference: paradoxical effects of stress in vivo. 1531 92

We report the case of a 9-year-old girl who died from sepsis from cellulitis of the neck caused by a right ear injury. The autopsy findings showed severe involution of the thymus and atrophy of lymphoid tissues. The impairment of T- and B-cell functions was demonstrated both histologically and immunohistologically. Thymic involution caused by child abuse might lead to secondary immunodeficiency.
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PMID:Immunodeficiency induced by child abuse. 1533 22

Neonatal sepsis and chorioamnionitis induce morphologic modifications and shrinkage of the thymus. We show fetal and neonatal morphologic modifications of the spleen in the same autopsy subjects as previously used to describe thymus shrinkage, including 10 preterm or full-term neonates who died of proven sepsis within 48 hours after birth and 20 fetuses spontaneously aborted because of extensive ascending chorioamnionitis. Control subjects included 10 fetuses from induced termination of pregnancy and 10 neonates who died suddenly during the perinatal period without evidence of chorioamnionitis. Spleen cell populations were studied by means of immunohistochemical analysis. Neonatal sepsis occurred with severe spleen depletion, involving both B and T lymphocytes (P < .001). Fetuses with chorioamnionitis also showed spleen cell depletion. These observations, to our knowledge not described before, indicate that preterm and term neonates show an inflammatory reaction similar to that of adult patients and that severe chorioamnionitis is associated with a nonspecific inflammatory response comparable to that of sepsis.
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PMID:Spleen depletion in neonatal sepsis and chorioamnionitis. 1549 73

Lymphopenia and lymphoid depletion occur in adults dying of sepsis. Prolactin increases Bcl-2 expression, suppresses stress-induced lymphocyte apoptosis, and improves survival from experimental sepsis. We hypothesized that prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia occur in children dying with sepsis and multiple organ failure (MOF). Fifty-eight critically ill children with and 55 without MOF admitted to a university hospital pediatric intensive care unit were enrolled in a prospective, longitudinal, observational clinical study. Prolactin levels and absolute lymphocyte count were measured on days 1, 3, 7, 14, and 21. Lymph node, thymus, and spleen autopsy specimens were examined for lymphoid depletion, with immunohistochemical staining for CD4, CD20, and CD21 and for lymphoid apoptosis. Prolonged lymphopenia (absolute lymphocyte count < 1000 for >7 days) occurred only in children with MOF (29 vs 0%, p < 0.05) and was associated independently with nosocomial infection (odds ratio (OR), 5.5, 95% confidence interval (CI), 1.7-17, p < 0.05), death (OR, 6.8, 95% CI, 1.3-34, p < 0.05), and splenic and lymph node hypocellularity (OR, 42, 95% CI, 3.7-473, p < 0.05). Lymphocyte apoptosis and ante/postmortem infection were observed only in children with lymphoid depletion. Prolonged hypoprolactinemia (>7 days) was more common in children with MOF (17 vs 2%, p < 0.05) and was associated independently with prolonged lymphopenia (OR, 8.3, 95% CI, 2.1-33, p < 0.05) and lymphoid depletion (OR, 12.2, 95% CI, 2.2-65, p < 0.05). Prolonged lymphopenia and apoptosis-associated depletion of lymphoid organs play a role in nosocomial sepsis-related death in critically ill children. Prolonged hypoprolactinemia is a previously unrecognized risk factor for this syndrome.
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PMID:Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. 1574 17

Chylothorax and chylopericardium are rare conditions occurring in infants and children. Both may be traumatic or nontraumatic in origin. We reviewed our experiences with the management of sixteen pediatric cases (10 males, 6 females; 11-days to 14-years old) of chylothorax and chylopericardium from 1997 to 2003. There were fifteen cases of chylothorax (9 left, 2 right, 4 bilateral) and two cases of chylopericardium (1 isolated and 1 associated with chylothorax), and their incidences of occurrence after cardiothoracic surgery were 0.89% and 0.12%, respectively. Of the fifteen cases occurring after cardiothoracic surgery, thirteen patients had corrective or palliative surgery for complex congenital heart disease, and two patients had removal of thymolipoma and neuroblastoma, respectively. Included also in this review was an 11-day old preterm infant with hydrops fetalis and congenital heart disease who developed chylothorax. Characteristics of chylous effusion included a presence of whitish opaque fluid in the pleural cavity and the pericardial cavity, having a triglyceride content ranging from 59 to 1689 mg/dl which was higher than a plasma triglyceride, a protein content of 2.4 to 7.4 g/dl, and a presence of lymphocyte predominance. The average latent period for diagnosis of chylothorax or chylopericardium was 13 days (range 3-30). All patients were treated primarily with nutritional modification using medium-chain triglycerides (MCT) instead of long-chain triglycerides in their diet; and only a few cases needed bowel rest with total parenteral nutrition (TPN). Twelve patients completely responded to a MCT-rich diet; two cases resolved after switching to TPN and another case needed surgery for ligation of lymphatic vessels around the thymus gland. The mean duration of lymph drainage was 12.1 days (range 3-29) and the average length of time of continued conservative treatment (MCT-rich diet and TPN) was 29.8 days (range 18-47). Fourteen patients (87.25%) had good outcome, i.e. resolution from chylothorax or chylopericardium and return to normal diet. Two of the fourteen patients developed severe infections; one was diagnosed with suspected bacterial endocarditis and the other had candidemia. However, both responded well to antibacterial and antifungal drugs, respectively. One case succeeded after surgery. A case that had low compliance with dietary recommendations and required repeated placement of drainage devices died due to infection with enterococcal septicemia. Early and good compliance with MCT-rich diet is essential for achieving a favorable outcome in the management of chylothorax and chylopericardium in children.
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PMID:Management of chylothorax and chylopericardium in pediatric patients: experiences at Siriraj Hospital, Bangkok. 1592 38

Although studies have shown increased evidence of death receptor-driven apoptosis in intestinal lymphoid cells, splenocytes, and the liver following the onset of polymicrobial sepsis, little is known about the mediators controlling this process or their pathologic contribution. We therefore attempted to test the hypothesis that the hydrodynamic administration of small interfering RNA (siRNA) against the death receptor, Fas or caspase-8, should attenuate the onset of morbidity and mortality seen in sepsis, as produced by cecal ligation and puncture (CLP). We initially show that in vivo administration of green fluorescent protein (GFP) siRNA in GFP transgenic mice results in a decrease in GFP fluorescence in most tissues. Subsequently, we also found that treating septic nontransgenic mice with siRNA targeting Fas or caspase-8 but not GFP (used as a control here) decreased the mRNA, in a sustained fashion up to 10 days, and protein expression of Fas and caspase-8, respectively. In addition, transferase-mediated dUTP (deoxyuridine triphosphate) nick end labeling (TUNEL) and active caspase-3 analyses revealed a decrease in apoptosis in the liver and spleen but not the thymus following siRNA treatment. Indices of liver damage were also decreased. Finally, the injection of Fas or caspase-8 given not only 30 minutes but up to 12 hours after CLP significantly improved the survival of septic mice.
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PMID:In vivo delivery of caspase-8 or Fas siRNA improves the survival of septic mice. 1594 15


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