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C D Heidecke

Publications and source records attributed to C D Heidecke.

At least 19 recordsLinked to original sources
PubMed2004

Modeling of esophageal bolus flow by functional data analysis of scintigrams.

Peristaltic forces cause a topographic, time-dependent distribution of bolus mass during its esophageal transport. A two-dimensional spatial-temporal pattern (profile) of local transit times is constructed by computer-based double compression of scintigraphic images sampled from whole swallows. Reconstruction by Gaussian bands and modeling this pattern discloses transient ellipsoidal bolus structures. The structures studied in 10 healthy volunteers present highly reproducible quantitative parameters for marking a region-specificity of transit times, which is related to the known region-selectivity of esophageal functions. Correlation of bolus flow with the dynamics of peristalsis is essential for understanding the complex mechanisms of esophageal transport as well as for diagnostic discrimination of disturbances of bolus flow.

Adult↗
PubMed2003

[Receptors and signal proteins of the innate immune system as new targets in sepsis therapy. Reprogramming of the immune response].

During polymicrobial sepsis,microbial pathogens and their products activate the innate immune system through signaling receptors of the Toll-like receptor (TLR) family, resulting in hyperinflammation and organ injury. The analysis of preclinical mouse models has shown that inactivation of the common TLR signaling adaptor protein MyD88 prevents the hyperinflammatory response and improves survival.Importantly, MyD88 deficiency does not impair antibacterial defense mechanisms.Thus,TLRs and proteins involved in TLR signaling may represent interesting targets for the development of new drugs for reprogramming pathophysiological immune responses during sepsis.

Animals↗
PubMed2002

Fulminate intracardiac thrombosis associated with Budd-Chiari-syndrome and inferior vena cava thrombosis.

The most common cause of edema of the legs and dyspnea is congestive heart failure. Further differential diagnosis such as renal or hepatic failure have to be considered. We report the case of a previous healthy 65-year-old woman who developed dyspnea and massive edema of the legs followed by acute hepatic and renal failure. Imaging studies showed a thrombosis of the inferior vena cava (IVC) caused by a tumor between the right kidney and the IVC. Histological examination revealed a leiomyosarcoma of the IVC. Hepatic failure due to venous outflow obstruction (Budd-Chiari syndrome, BCS) was diagnosed. Coagulation profile showed a complex disorder due to acute hepatic failure. Factor V Leiden and prothrombin gene mutation G20210A could be excluded. The thrombosis extended from the femoral veins up to the right atrium. After 11 days of anticoagulation with heparin platelet counts decreased by more than 50%. Suspecting a heparin-induced thrombocytopenia the patient was placed on recombinant hirudin (lepirudin) for anticoagulation. Hepatic venogram showed a thrombosis of the hepatic vein orifices but not of the hepatic veins. The tumor and the thrombi were removed surgically. When the cardiopulmonary bypass was terminated new intracardiac thrombi occurred. Despite immediate surgical intervention the patient finally died due to right ventricular failure caused by the fulminate intracardiac thrombosis. In conclusion, thrombosis of the IVC may mimic congestive heart failure and may cause BCS. Neoplasms and coagulation disorders may cause thrombosis of the IVC.

Aged↗
PubMed2001

Critical role of Kupffer cell-derived IL-10 for host defense in septic peritonitis.

Intra-abdominal infection in patients following major visceral surgery is associated with high mortality. Using a macrophage depletion technique, we demonstrate that in murine septic peritonitis, Kupffer cells are a major source of systemic IL-10 levels. Kupffer cell-depleted mice were highly susceptible to the lethal effects of septic peritonitis and exhibited an increased bacterial load. Kupffer cell-depleted mice were protected by the administration of an IL-10-Fc fusion protein. Loss of Kupffer cell-derived IL-10 was associated with a weak increase in serum IL-12 levels, whereas TNF, IL-1alpha, and IL-18 levels were not significantly elevated, suggesting that the loss of Kupffer cell-derived IL-10 did not result in a toxic cytokine release syndrome. Instead, loss of Kupffer cell-derived IL-10 was associated with a reduced splenocyte production of IFN-gamma that is required for immune protection in murine septic peritonitis. Therefore, the results suggest that the protective function of IL-10 in septic peritonitis may not be restricted to the anti-inflammatory activities of IL-10.

Animals↗
PubMed2001

Inhibition of natural killer cells results in acceptance of cardiac allografts in CD28-/- mice.

Successful transplantation of allogeneic organs is an important objective in modern medicine. However, sophisticated immune defense mechanisms, primarily evolved to combat infections, often work against medical transplantation. To investigate the roles of natural and adaptive immune responses in transplant rejection, we functionally inactivated key effector systems of the innate (NK cells) and the adaptive immune system (CD28-mediated costimulation of T cells) in mice. Neither of these interventions alone led to acceptance of allogeneic vascularized cardiac grafts. In contrast, inhibition of NK-receptor-bearing cells combined with CD28-costimulation blockade established long-term graft acceptance. These results indicate a concerted interplay between innate and adaptive immune surveillance for graft rejection. Thus we suggest that inactivation of NK-receptor-bearing cells could be a new strategy for successful survival of solid-organ transplants.

Animals↗
PubMed2000

[Immune paralysis of T-lymphocytes and monocytes in postoperative abdominal sepsis. Correlation of immune function with survival].

In vitro functions of stimulated peripheral T cells and monocytes were investigate in patients experiencing sepsis following major visceral surgery. Cell culture supernatants were analyzed by ELISA for IL-2, IFN-gamma, IL-4, IL-10, TNF-alpha, IL-1 beta, and IL-12p40. In addition, monocyte HLA class II expression was determined by flow cytometry. T cell secretion of IL-2, TNF-alpha, and in part IFN-gamma (but not IL-4) was significantly diminished in non-survivors throughout the entire course of sepsis, compared to controls and sepsis survivors. Production of IL-1 beta and IL-12 p40 by monocytes was strongly reduced in both survivors and non-survivors at the onset of sepsis. Persistence of depressed monocyte cytokine secretion correlated with lethality. Thus, overall suppression of cytokine production by T cells and monocytes was already observed at the beginning of postoperative sepsis. HLA class II expression by monocytes exhibited a strong and sustained down-regulation with no significant differences between sepsis survivors and non-survivors. In summary, suppression of both T cell and monocyte functions develops early during postoperative sepsis. Recovery of immune functions and severity of immune defects are associated with outcome.

Cytokines↗
PubMed2000

Sepsis after major visceral surgery is associated with sustained and interferon-gamma-resistant defects of monocyte cytokine production.

BACKGROUND: Recent clinical trials failed to demonstrate beneficial effects of anti-inflammatory sepsis therapy. The present study therefore asked the following questions: Is there evidence for immunosuppression during postoperative sepsis? When, during the septic course, may immunosuppression develop? Can defective cellular functions be restored by in vitro treatment with interferon-gamma (IFN-gamma)? METHODS: The study included 35 patients with sepsis after major visceral surgery and 85 control patients. Monocyte secretion of interleukin (IL)-1 beta, IL-12 p40 and p70, IL-18, tumor necrosing factor, and IL-10 with or without IFN-gamma treatment and its correlation with the course and outcome of postoperative sepsis were determined. RESULTS: Postoperative sepsis was associated with an immediate defect of endotoxin-stimulated monocyte production of IL-12 p40, IL-1 beta, and IL-10 in both surviving and nonsurviving patients. During the final phase of postoperative sepsis, a significant recovery of IL-12 p40 and IL-1 beta secretion, but not of IL-10 production, correlated with survival. Despite the exposure of monocytes in vitro to IFN-gamma for 16 hours, the production of the biologically active IL-12 p70 heterodimer was severely suppressed both in survivors and nonsurvivors, although the secretion of the p40 subunit was restored. In contrast, IFN-gamma treatment resulted in a significant suppression of monocyte IL-1 beta production in all patient subgroups. Alterations of monocyte tumor necrosing factor secretion were not observed. The production of IL-18 was below the limits of detection in all samples. CONCLUSIONS: Postoperative sepsis was associated with immediate monocyte defects that affected both pro- and anti-inflammatory cytokine secretion, which suggests that immunosuppression is a primary rather than a compensatory response to a septic challenge. Sepsis survival correlated with the recovery of the proinflammatory, but not the anti-inflammatory, response. The treatment of monocytes with IFN-gamma did not reconstitute defective proinflammatory cytokine production.

Cytokines↗
PubMed2000

Massive chemokine transcription in acute renal failure due to polymicrobial sepsis.

Abdominal sepsis and septic shock are still major causes of mortality in intensive care units (ICU). Acute renal failure (ARF) is one of the hallmarks encountered in septic shock. The pathophysiological alterations leading to ARF are poorly understood. A novel murine model of polymicrobial sepsis (colon ascendens stent peritonitis [CASP]) was used to investigate functional renal parameters, renal chemokine transcription levels, and recruitment of inflammatory leukocytes in septic ARF. CASP was induced by inserting a 14-gauge stent into the colon ascendens of C57BL/6 mice, generating a septic focus resulting in polymicrobial sepsis. Mice were monitored for urine output and serum azotemia. Kidneys were harvested for analysis of leukocyte infiltration by immunohistochemistry and chemokine gene expression by RNase protection assay (3, 6, 12, and 18 h). CASP, but not sham-CASP, resulted in anuria immediately after surgery and in elevated serum creatinine and BUN detected 18 h after CASP surgery, confirming acute renal failure. Progressive induction of chemokine gene expression was observed for IP-10, MIP-2, MIP-1alpha, MIP-1beta, MCP-1, and RANTES peaking at 12 h with subsequent decrease. Immunohistochemistry revealed an accumulation of neutrophils and monocytes which had adhered to the renal vascular endothelium. Thus, acute renal failure in sepsis is accompanied by a marked upregulation of chemokines of the CC and CXC group within the kidney.

Acute Kidney Injury↗
PubMed2000

Endotoxin-induced lung inflammation is independent of the complement membrane attack complex.

Several products of the activated complement system are known to modulate endothelial cell function in vitro. It has been shown that the membrane attack complex (MAC) (C5b-C9) can enhance tumor necrosis factor alpha (TNF-alpha)-induced expression of P- and E-selectin and intercellular adhesion molecule type 1 in cell cultures of human umbilical vein endothelial cells. In the present study the potential role of this synegism for lung injury during endotoxin-mediated septic shock in vivo was examined using a model of C6-deficient PVG (C-) (RT1(C)) rats and the congenic PVG (C+) (RT1(C)) strain. Following administration of a high (5 mg/kg) or low (0.5 mg/kg) dose of lipopolysaccharide (LPS) (Escherichia coli O55:B5), we determined the expression of cytokines, chemokines, and adhesion molecules as well as the recruitment of leukocytes in the lung. Challenge with intraperitoneal i.p. injections of LPS resulted in a strong induction of TNF-alpha, interleukin-1alpha/beta, cytokine-induced neutrophil chemoattractant, interferon-inducible protein 10, macrophage inflammatory proteins 1alpha and 2, macrophage chemotactic protein 1, and P-selectin. However, there were no significant differences between PVG (C-) and PVG (C+) rats. Immunoperoxidase staining showed a similar increase of lung infiltration by CD11b/c(+) leukocytes in both rat strains. We therefore conclude that the described synergism between TNF-alpha and the MAC of the complement system on the induction of endothelial adhesion molecules is dispensable for inflammatory processes during endotoxin-mediated septic shock in vivo.

Animals↗
PubMed1999

Selective defects of T lymphocyte function in patients with lethal intraabdominal infection.

BACKGROUND: In recent models, compensatory antiinflammatory immune reactions triggered in response to systemic inflammation were considered important for the outcome of sepsis. The present study investigated T-cell functions in patients with postoperative sepsis due to intra-abdominal infection. METHODS: Peripheral T cells were purified from 32 sepsis patients and 41 healthy controls. Proliferation and production of interferon (IFN)-gamma, interleukin (IL)-2, IL-4, tumor necrosis factor (TNF), and IL-10 were stimulated by cross-linking of CD3 and CD28. RESULTS: T-cell proliferation and production of IL-2 and TNF were severely suppressed in patients with lethal intraabdominal infection as compared with survivors and healthy controls. Sepsis survivors showed normal T-cell proliferation and IL-2 release, whereas secretion of TNF was reduced. However, TNF suppression in survivors was less severe than in nonsurviving patients. Defective T-cell functions were observed at the onset of sepsis and persisted throughout the entire observation period. T-cell production of IL-4 and IL-10 was not affected by postoperative intraabdominal infection. CONCLUSIONS: Defective T-cell proliferation and secretion of IL-2 and TNF correlate with sepsis mortality, thus indicating an important role of T 'cells for the immune defense against postoperative infection. Immune defects were evident at the onset of sepsis, suggesting that immunosuppression may develop as a primary response to sepsis without preceding immune hyperactivity.

Abdomen↗
PubMed1999

Impact of experimental peritonitis on bone marrow cell function.

BACKGROUND: The effects of abdominal sepsis on the regulation of cell turnover in bone marrow and on the function of hematopoietic stem cells were investigated. METHODS: In a new mouse model of abdominal sepsis (colon ascendens stent peritonitis [CASP]) the proliferation, apoptosis, and colony-forming capacity of bone marrow cells were determined. RESULTS: Both experimental peritonitis and sham surgery increased proliferation of bone marrow cells significantly (P < .01). Incubation with granulocyte-macrophage colony-stimulating factor but not granulocyte colony-stimulating factor further augmented proliferation of bone marrow cells from septic mice. In contrast to cell proliferation, bone marrow cell apoptosis was significantly (P < .001) increased in response to CASP but not to sham surgery. CASP surgery and treatment of normal bone marrow cells with lipopolysaccharide, tumor necrosis factor-alpha, interleukin 1 beta, and interferon gamma increased the number of apoptotic cells to a similar extent. Stem cell assays revealed that during the late phase of peritonitis the colony formation by granulocytic-monocytic precursors was increased, whereas mature erythroid colony-forming cells were suppressed. Incubation of normal bone marrow cells with lipopolysaccharide and cytokines showed similar effects. CONCLUSIONS: These results reveal differential effects of experimental peritonitis on various hematopoietic lineages and suggest a potential role of inflammatory mediators for the dysregulation of bone marrow cell function during abdominal sepsis.

Animals↗
PubMed1999

Mechanisms of acute inflammatory lung injury induced by abdominal sepsis.

Sequestration of neutrophils and release of histotoxic mediators are considered important for the development of pathologic alterations of the lung defined as adult respiratory distress syndrome. Mechanisms of inflammatory lung injury caused by abdominal sepsis were investigated using the colon ascendens stent peritonitis (CASP) model that closely mimics the human disease. In the CASP model, a continuous leakage of intraluminal bacteria into the peritoneal cavity is induced by implantation of a stent in the ascending colon, generating a septic focus. In contrast to the cecal ligation and puncture model of peritonitis, survival of mice following CASP surgery is dependent on IFN-gamma, but independent of tumor necrosis factor (TNF). Here we show that the systemic inflammation induced by CASP surgery results in a rapid and profound increase of lung vascular permeability that was associated with the activation and recruitment of neutrophils to the lung. Activation of circulating granulocytes was characterized by increased production of serine proteinases and reactive oxygen metabolites, as well as elevated expression of cell surface Mac-1. Expression of MIP-2, KC, MIP-1alpha and E-selectin mRNA in lung was strongly increased within 3 h following CASP surgery, whereas up-regulation of IP-10, MCP-1 and P-selectin was delayed. In contrast, induction of RANTES, LIX, ICAM-1 and VCAM-1 mRNA was weak or not detectable after CASP surgery. Importantly, recruitment of leukocytes to the lung was normal in lipopolysaccharide-resistant mice, and was not affected by antibody neutralization of TNF or the chemokines MIP-2 and KC.

Abdomen↗
PubMed1999

Stented versus nonstented pancreaticojejunostomy after pancreatoduodenectomy: a prospective study.

OBJECTIVE: To compare morbidity and mortality rates of stented versus nonstented pancreaticojejunostomy after partial pancreatoduodenectomy. BACKGROUND DATA: Despite a marked reduction in the mortality rate after partial pancreatoduodenectomy in recent years, leakage of the pancreaticojejunostomy still occurs in 5% to 25% of patients and remains the major source of complications. METHODS: The authors compared the morbidity and mortality rates of 85 consecutive patients who had a partial pancreatoduodenectomy with (n = 44) or without (n = 41) temporary stented external drainage of the pancreatic duct between 1994 and 1997. RESULTS: A pancreatic fistula was diagnosed in 3 of the 44 patients (6.8%) with stents versus 12 of the 41 patients (29.3%) without stents. Surgical reintervention was necessary in 1 of the 3 patients with a pancreatic fistula in the stented group and 3 of the 12 patients with a pancreatic fistula in the nonstented group. There were two deaths after surgery, both in the nonstented group. The median hospital stay after surgery was 13 days in patients with stents and 29 days in patients without stents. CONCLUSION: In this nonrandomized prospective observational study, temporary external drainage of the pancreatic duct with a PVC tube significantly reduced the leakage rate of the pancreaticojejunostomy as well as the duration of hospital stay after partial pancreatoduodenectomy. Although promising, these observations require confirmation by further studies.

Adult↗
PubMed1998

Importance of T cells to accelerated rejection and acceptance of renal allografts in sensitized rat recipients.

BACKGROUND: Sensitized recipients often experience fulminant allograft loss by yet ill-defined cellular and/or humoral immune mechanisms. In this study, we analyzed the contribution of cellular elements, in particular T cells, to the accelerated rejection of renal allografts in sensitized rats. METHODS AND RESULTS: LEW rats sensitized with BN skin grafts died of uremia in 3.3+/-0.9 days after transplantation of a BN kidney, similarly to bilaterally nephrectomized animals. Adoptive transfer of 10(6) graft-infiltrating mononuclear cells as well as their CD25+ subset into otherwise normal LEW recipients accelerated rejection of BN test cardiac allografts (5.4+/-0.5 days to 6.6+/-0.4 days vs. 7.8+/-0.8 days in controls, P<0.0007), while the CD25- population was ineffective (8.0+/-0.6 days, NS). Furthermore, alpha/beta-T-cell receptor (TCR)-targeted therapy with R73 monoclonal antibody abrogated accelerated rejection, and produced long-term survival in sensitized animals treated before kidney engraftment (day -7 to day -1). Long-term survival was associated with an up-regulation of intragraft interleukin-4 and interleukin-10 expression in conjunction with depressed Th-1-type cytokines. In addition, alpha/beta-TCR-targeted therapy even in low subtherapeutic dose decreased IgM alloantibody levels, and prevented the switch from IgM to IgG alloantibody response. CONCLUSIONS: This is the first report that documents the striking efficacy of alpha/beta-TCR-targeted therapy in sensitized rat renal transplant recipients. The results provide evidence for a critical role of T cells for both accelerated rejection and long-term graft survival. Up-regulation of Th2-type cytokine profile may, at least in part, contribute to the acquisition of immune unresponsiveness after alpha/beta-TCR-targeted therapy in this well-defined rat renal transplant model.

Adoptive Transfer↗
PubMed1998

Increased susceptibility to postoperative sepsis in patients with impaired monocyte IL-12 production.

IL-12 is a potent immunoregulatory cytokine that is essential for the development of protective immunity, as demonstrated by numerous animal models of infection. Here, we provide evidence for a critical role of IL-12 in human sepsis. The results of a prospective study of 184 patients undergoing major elective surgery of the upper and lower gastrointestinal tract revealed that, in contrast to patients showing uneventful recovery, monocyte IL-12 production was severely and selectively impaired in patients developing postoperative sepsis. Moreover, the extent of monocyte IL-12 suppression correlated with the severity of postoperative sepsis. Monocyte IL-12 secretion was suppressed before surgery and remained low until the onset of sepsis. Therefore, the suppression of IL-12 secretion preceded the onset of postoperative sepsis but did not occur as a consequence of major surgery. In contrast, IL-1beta production was only reduced during the late postoperative course in patients developing postoperative sepsis, and TNF-alpha release was even increased at different time intervals before the onset of sepsis. Thus, reduced IL-12 release does not reflect a general defect in monocyte cytokine production. Consequently, these results establish a critical role for IL-12 in early resistance to postoperative infection and may allow for the development of novel therapeutic strategies designed to stimulate host defense mechanisms and to reduce the incidence and severity of septic complications.

Aged↗
PubMed1998

Bronchogenic cyst of the esophagus with high tumor marker levels--a case report and review of the literature.

Bronchogenic cysts of the esophagus are rare in comparison with the relatively common bronchogenic cyst of the lung. Only a few cases have been reported in literature since 1930. We report on a case of a 43-old-male with a bronchogenic cyst in the distal esophagus, which was misdiagnosed as a malignant esophageal tumor based on preoperative imaging and high levels of the tumor markers CA 19-9 and CA 125.

Adult↗
PubMed1998

Essential role of gamma interferon in survival of colon ascendens stent peritonitis, a novel murine model of abdominal sepsis.

Despite considerable progress, peritonitis and sepsis remain life-threatening conditions. To improve the understanding of the pathophysiology encountered in sepsis, a new standardized and highly reproducible murine model of abdominal sepsis termed colon ascendens stent peritonitis (CASP) was developed. In CASP, a stent is inserted into the ascending colon, which generates a septic focus. CASP employing a stent of 14-gauge diameter (14G stent) results in a mortality of 100% within 18 to 48 h after surgery. By inserting stents of small diameters, mortality can be exactly controlled. Thus, CASP surgery with insertion of a 22G or 18G stent (22G or 18G CASP surgery) results in 38 or 68% mortality, respectively. 14G CASP surgery leads to a rapid invasion of bacteria into the peritoneum and the blood. As a consequence, endotoxemia occurs, inflammatory cells are recruited, and a systemic inflammatory response syndrome develops. Interestingly, the most pronounced upregulation of inflammatory cytokines (gamma interferon [IFN-gamma], tumor necrosis factor alpha [TNF-alpha] and interleukin-12) is observed in spleen and lungs. CASP surgery followed by stent removal at specific time intervals revealed that all animals survived if intervention was performed after 3 h, whereas removal of the septic focus after 9 h did not prevent death, suggesting induction of autonomous mechanisms of a lethal inflammatory response syndrome. 18G CASP surgery in IFN-gamma receptor-deficient (IFNgammaR-/-) mice revealed an essential role of IFN-gamma in survival of sepsis, whereas TNF receptor p55-deficient (TNFRp55-/-) mice did not show altered survival rates. In summary, this study describes a novel animal model that closely mimics human sepsis and appears to be highly suitable for the study of the pathophysiology of abdominal sepsis. Importantly, this model demonstrates a protective role of IFN-gamma in survival of bacterial sepsis.

Abdomen↗