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

We report a 65-year-old Japanese woman with Kaposi's sarcoma (KS). The eruption first occurred on the legs while she was admitted for treatment of poorly differentiated lung cancer. Approximately eight months after the evolution, cutaneous tumors rapidly spread to the forearms, trunk, and pharynx. At that time, the patient had received systemic corticosteroid (10-40 mg/day of prednisolone) for about three months to reduce pulmonary inflammation. The laboratory data showed anemia, lymphopenia, hypogammaglobulinemia, and a decreased T cell count, although the serological test for HIV infection was negative. The patient was treated with radiation (X-ray for KS of pharynx and electron beam for KS of lower legs) and local intralesional injection of vinblastine. Although both therapies were very effective and well tolerated, she died of bacterial pneumonia and sepsis. Autopsy revealed KS tumors, unknown before death, in both lungs, the esophagus, and the stomach. The left lung cancer had disseminated and metastasized to the right lung, pleura, mediastinum, and abdominal cavity. It is suspected that chronic respiratory distress and systemic use of corticosteroids might have induced the rapid extension of KS.
 ...
PMID:Kaposi's sarcoma associated with lung cancer and immunosuppression. 885 91

Histopathological examination revealed multifocal acute to chronic adrenal necrosis in 74 of 162 (45%) Pacific harbor seal pups (Phoca vitulina richardsi) dying during rehabilitation following live stranding along the coast of central and northern California (USA). Necrotic adrenal cells contained amphophilic, smudgy intranuclear inclusion bodies that were stained positive for DNA. Fifty of these seals also had lesions typical of sepsis, bacterial omphalophlebitis, pneumonia or gastroenteritis. Twenty four seals had no lesions other than thymic atrophy and occasional multifocal hepatic necrosis. Prior to death, affected seals had a marked lymphopenia. Electron microscopy revealed unenveloped intranuclear hexagonal to round viral particles approximately 100 nm in diameter, and cytoplasmic enveloped virions approximately 160 nm in diameter. These were morphologically consistent with herpesvirus. Inoculation of phocine adrenal and kidney cell lines with an adrenal tissue homogenate from affected animals produced a cytopathic effect in 5 days. Electron microscopy of cell cultures showing this cytopathic effect revealed similar viral particles to those observed in affected adrenal glands. Cases with characteristic inclusion bodies were observed in 42 of 95 (44%) male and 32 of 67 (47%) female seals. Affected animals had been in rehabilitation 0 to 63 days and were below average birth weight for this species.
 ...
PMID:Herpesvirus infection in stranded Pacific harbor seals of coastal California. 924 89

A Phase I dose escalation trial of i.v. administered recombinant human interleukin 12 (rhIL-12) was performed to determine its toxicity, maximum tolerated dose (MTD), pharmacokinetics, and biological and potential antineoplastic effects. Cohorts of four to six patients with advanced cancer, Karnofsky performance >/=70%, and normal organ function received escalating doses (3-1000 ng/kg/day) of rhIL-12 (Genetics Institute, Inc.) by bolus i.v. injection once as an inpatient and then, after a 2-week rest period, once daily for five days every 3 weeks as an outpatient. Therapy was withheld for grade 3 toxicity (grade 4 hyperbilirubinemia or neutropenia), and dose escalation was halted if three of six patients experienced a dose-limiting toxicity (DLT). After establishment of the MTD, eight more patients were enrolled to further assess the safety, pharmacokinetics, and immunobiology of this dose. Forty patients were enrolled, including 20 with renal cancer, 12 with melanoma, and 5 with colon cancer; 25 patients had received prior systemic therapy. Common toxicities included fever/chills, fatigue, nausea, vomiting, and headache. Fever was first observed at the 3 ng/kg dose level, typically occurred 8-12 h after rhIL-12 administration, and was incompletely suppressed with nonsteroidal anti-inflammatory drugs. Routine laboratory changes included anemia, neutropenia, lymphopenia, hyperglycemia, thrombocytopenia, and hypoalbuminemia. DLTs included oral stomatitis and liver function test abnormalities, predominantly elevated transaminases, which occurred in three of four patients at the 1000 ng/kg dose level. The 500 ng/kg dose level was determined to be the MTD. This dose, administered by this schedule, was associated with asymptomatic hepatic function test abnormalities in three patients and an onstudy death due to Clostridia perfringens septicemia but was otherwise well tolerated by the 14 patients treated in the dose escalation and safety phases. The T1/2 elimination of rhIL-12 was calculated to be 5.3-9.6 h. Biological effects included dose-dependent increases in circulating IFN-gamma, which exhibited attenuation with subsequent cycles. Serum neopterin rose in a reproducible fashion regardless of dose or cycle. Tumor necrosis factor alpha was not detected by ELISA. One of 40 patients developed a low titer antibody to rhIL-12. Lymphopenia was observed at all dose levels, with recovery occurring within several days of completing treatment without rebound lymphocytosis. There was one partial response (renal cell cancer) and one transient complete response (melanoma), both in previously untreated patients. Four additional patients received all proposed treatment without disease progression. rhIL-12 administered according to this schedule is biologically and clinically active at doses tolerable by most patients in an outpatient setting. Nonetheless, additional Phase I studies examining different schedules and the mechanisms of the specific DLTs are indicated before proceeding to Phase II testing.
 ...
PMID:Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. 981 99

Sepsis remains a serious clinical problem despite intense efforts to improve survival. Experimental animal models of sepsis have responded dramatically to immunotherapy blocking the activity of cytokines. Despite these preclinical successes, human clinical trials have not demonstrated any improvement in survival. We directly compared the mortality, morbidity, and immunopathology in two models of sepsis, one due to lipopolysaccharide (LPS) and the other to cecal ligation and puncture (CLP). BALB/c mice were injected intraperitoneally with 250 microg of LPS or subjected to CLP with an 18-gauge needle. Both models yielded similar mortality (> 85%) and morbidity. Additionally, neutropenia and lymphopenia developed in both groups. Plasma and peritoneal levels of cytokines (TNF, IL-1, IL-6, and the chemokines KC and MIP-2) were measured at 1.5, 4, and 8 h after challenge. LPS induced substantially higher levels of cytokines in both compartments with peak levels between 1.5 and 4 h that began to decline at 8 h. In contrast, cytokine levels in the CLP model were continuing to increase at the 8 h-time point and often exceeded the LPS-induced values at this time. Our data demonstrate that the LPS and CLP models have similar mortality but significant differences in the kinetics and magnitude of cytokine production. Immunotherapy for sepsis based on cytokine production after LPS challenge is misdirected because the LPS model does not accurately reproduce the cytokine profile of sepsis.
 ...
PMID:Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. 1067 Aug 40

It is not known why respiratory syncytial virus (RSV) is associated with prolonged sequelae in many children. Measles virus (also a paramyxovirus), acute stress in sepsis, and cardiac bypass all cause lymphopenia. Using a retrospective analysis of records of children in Bristol with RSV infections over 5 years, we found that children with RSV had lower lymphocyte counts than unstressed, stable children prior to cardiac surgery. Children who required intensive care had the lowest lymphocyte counts. Neutrophil counts were raised in RSV-infected children. These data may offer an insight into pathological mechanisms, and suggest new research avenues.
 ...
PMID:Peripheral blood lymphopenia and neutrophilia in children with severe respiratory syncytial virus disease. 1211 79

The role of lymphocyte apoptosis in septic shock remains a controversial issue. Using Annexin V and flow cytometry analysis on freshly isolated cells, we evaluated circulating lymphocyte apoptosis in 23 septic shock, 25 sepsis without shock, 7 nonseptic critically ill, and 25 control patients. In patients with sepsis, we compared day 1 lymphocyte apoptosis (i.e., within 3 days of the onset of infection) with that observed 5-7 days after (day 6) according to shock state, mortality, and seventy factors. At day 1, patients in septic shock exhibited higher lymphocyte apoptosis than that present in controls (16.5% +/- 3.5% vs. 3% +/- 0.5%, respectively, P = 0.0001). At day 6, patients with sepsis without shock restored undamaged CD4+ T and CD8+ T lymphocyte counts, whereas patients in septic shock increased only CD4+ T cells. Similarly, survivors restored undamaged lymphocyte count at day 6 (+70%, P < 0.001), whereas nonsurvivors did not. Day 6 undamaged lymphocyte count negatively correlated with day 1 SAPS II, day 6 LOD score, mechanical ventilation, and ICU stay duration. We observed no apoptotic effect of septic shock plasma or septic shock circulating mononuclear cells on target lymphoid cell lines. We found no alteration in any death receptors Fas, TRAIL-R1, TRAIL-R2, or in their ligands on circulating blood cells. Catecholamines and interleukin 10 levels significantly increased in patients with septic shock, but did not correlate with apoptosis levels. We conclude that lymphocyte apoptosis is rapidly increased in blood of patients in septic shock and that lymphocyte apoptosis leads to a profound and persistent lymphopenia associated with poor outcome. These results suggest that lymphocyte apoptosis is one of the main components of human septic shock immune dysfunction and could be related more to microcirculatory disturbance than to circulating factors.
 ...
PMID:Early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome. 1246 54

Phytohemagglutinin (PHA) elicited expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in primary human T cells via the PPARgamma3 promoter, as shown by reverse transcription-polymerase chain reaction. Electrophoretic mobility shift assay demonstrated no correlation between PPARgamma expression and its activation. However, addition of specific PPARgamma agonists such as ciglitazone or 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) for 1 h following PHA pretreatment provoked PPARgamma activation verified by supershift analysis. Taking the proapoptotic properties of PPARgamma into consideration, we analyzed induction of apoptosis in activated T cells in response to PPARgamma agonists. Cells exposed to PPARgamma agonists alone revealed minor cell death compared with controls, whereas treatment with 15d-PGJ(2) or ciglitazone for 4 h subsequent to PHA stimulation significantly increased cell demise, which was attenuated by the pan-caspase inhibitor zVAD, pointing to apoptosis as the underlying mechanism. These data may be relevant for pathophysiological conditions accompanied with lymphopenia of T cells under conditions such as sepsis.
 ...
PMID:Activation-induced PPARgamma expression sensitizes primary human T cells toward apoptosis. 1271 82

The characteristics of severe neutropenia with a delayed onset following administration of rituximab have been evaluated in 53 consecutively treated patients. All but one patient received rituximab for the treatment of non-Hodgkin's lymphoma. Eight episodes of grade 4 neutropenia were detected between 1 and 5 months after rituximab, when administered alone on five occasions, and on three occasions in combination with chemotherapy, where neutrophil counts had recovered prior to the development of neutropenia. In three episodes, the patients presented with sepsis. Development of neutropenia did not correlate with either the presence of detectable disease or the administration of further treatment. Neutropenia was associated with selective depletion of neutrophil precursors in all but one episode, where it was associated with generalized bone marrow hypoplasia. All episodes developed after a period of either normal or mildly depressed neutrophil counts following treatment with rituximab, and persisted for between several days and several months, before undergoing spontaneous recovery in four instances, and after administration of filgrastim in the remainder. Episodes of neutropenia were associated with disordered immune status manifested by lymphopenia and hypogammaglobulinaemia, raising the possibility that either disturbance of the balance of lymphocyte subsets or an immune dyscrasia induced by rituximab resulted in the development of this type of neutropenia.
 ...
PMID:Delayed-onset neutropenia associated with rituximab therapy. 1278 3

Sepsis causes lymphopenia which is inversely correlated with patient survival. The role of apoptosis-specific immune-activation and activation-induced cell-death in sepsis is incompletely understood. Fifteen septic patients and 20 healthy controls were included. T-cell proliferation was measured by [3H]thymidine uptake. Apoptosis and cell phenotype were determined by FACS. sTNFR1, sCD95, interleukin-1beta converting enzyme (sICE), and interleukin (IL)-10 were measured by ELISA. PHA and CD3-driven T-cell proliferation were significantly decreased in septic patients. The percentages of CD3(+) and CD4(+) T cells and CD19(+) B cells were significantly reduced. Percent memory T-cells (CD45RO(+)) and cells undergoing apoptosis (CD95(+)/annexin-V(+)) were significantly increased in sepsis. Moreover, sCD95, sTNFRI, and ICE were significantly increased. Anti-CD3 antibody triggering induced a 56% increase of CD4 T-cell death in septic patients vs. 7.5% in controls relative to IgG. Serum level of IL-10, a Th2 cytokine, was enhanced. These findings strongly suggest that in septic patients Th1 T-cells are selectively susceptible to undergo apoptosis. This observation provides an additional pathophysiological concept in the genesis of Th2 dominance.
 ...
PMID:Susceptibility to programmed cell death in T-lymphocytes from septic patients: a mechanism for lymphopenia and Th2 predominance. 1292 95

Vibrio vulnificus causes severe sepsis in humans. There are several reports about the relationship between host immunity and bacterial growth in V. vulnificus infection. However, the effect on leukocytes of V. vulnificus infection in vivo has not been elucidated. A murine model of V. vulnificus infection was used to investigate its effects on leukocytes in this study. Bacteria were recovered from the blood of mice 3 h after subcutaneous injection in the right lower flank. They were detected in 87.5 % (n = 7/8) of mice at 6 h, but this value decreased to 12.5 % (n = 1/8) at 12 h. In contrast, the number of lymphocytes in peripheral blood had already started to decrease at 3 h, and reached a minimum at 6-9 h post-inoculation. Typical DNA laddering, a hallmark of apoptosis, was also detected in thymocytes and splenocytes at 6 and 9 h, and showed a tendency to disappear by 12 h. Although the number of lymphocytes decreased in the model, the numbers of neutrophils did not. These results suggested that V. vulnificus has selective cytotoxicity for lymphocytes in peripheral blood in vivo, and the lymphocyte depletion was probably associated with apoptosis in vivo.
 ...
PMID:Depletion of lymphocytes, but not neutrophils, via apoptosis in a murine model of Vibrio vulnificus infection. 1559 Dec 50


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>