PubMed Health⌕ Search

Biomedical subjects

K Orth

Publications and source records attributed to K Orth.

At least 19 recordsLinked to original sources

Multifocal epithelioid hemangioendothelioma: case report of a clinical chamaeleon.

Epithelioid hemangioendothelioma is an extremely rare vascular bone tumor with a slow growth and poor prognosis. The term was designed to describe neoplasms that had an appearance in between hemangiomas and sarcomas. Various synonyms for epithelioid hemangioendothelioma are used clinically: low grade anaplastic angiosarcoma, cellular hemangioma, histiocytoid hemangioma and angioendothelioma. However, it represents 1% of all vascular neoplasms and is locally aggressive. We report the course of disease of a 47-year-old man who presented to our clinic with unspecific abdominal and back pain. Radiological findings revealed multiple lesions in the spine as well as liver and spleen involvement. Tumor histology of the bone and liver biopsies confirmed the diagnosis of epithelioid hemangioendothelioma. Although treatment was initiated with thalidomide, the patient developed multiple organ dysfunction syndrome (MODS) and succumbed to his disease. This case report may contribute to the data on clinical findings and natural history of this rare tumor.

Angiogenesis Inhibitors↗

G-CSF during large field radiotherapy reduces bone marrow recovery capacity.

OBJECTIVE: Side effects of chemo- and radiotherapy are granulo- and thrombocytopenia. However, the long-term effects of in vivo granulocyte-colony-stimulating factor (G-CSF) stimulation of the hematopoietic system during radiotherapy are not yet completely understood. In the present study, we sought to determine the bone marrow effect of G-CSF during radiotherapy. MATERIAL AND METHODS: In a prospective, randomized clinical trial 10 patients (6 m, 4 f, 30-64 yrs, mean 50.6 yrs) were assigned to large field radiotherapy (RT). 7 patients (pat.) with non-Hodgkin lymphoma, one patient with Hodgkin's disease and 2 patients with small-cell carcinoma of the lung were included. The patients were randomized to either radiotherapy alone (group A) or radiotherapy with simultaneous G-CSF (group B) treatment and assessed for acute and late toxicity. Blood samples were drawn and analyzed before and after G-CSF stimulation. The mobilization effectivity of G-CSF on CD34 superset+ progenitor cells was measured using flow cytometry and colony forming units (CFU) testing on admission and during the complete follow-up period (1, 3 and 18 months post RTx). RESULTS: Overall, 50 pat. were intended to be included to the protocol. However, the preliminary analysis revealed a significant decrease of thrombocytes and CD34 superset+ progenitor cells in the G-CSF treatment group. According to the study protocol further treatment was stopped. Peripheral leukocyte counts ranged between 2800 - 4375 /mul in 9/10 pat. In group B mean thrombocyte levels dropped below 30.000 mg/l and CD34 superset+ progenitor cells to 50% (interruption criteria, p<0.02, Student's t-test). Hemoglobin values did not vary. Differential blood smears showed differences in granulocyte counts and a higher proportion of neutrophils in group B. Lymphocyte counts of patients randomized to group A were significantly decreased when compared to group B. In group A, 3/5 pat. developed an overshooting reaction (4,7 x increase) after G-CSF-stimulation. In arm B circulating CD34 superset+ progenitor cells dropped. In arm A, 3/5 pat. had an initial overshoot reaction when compared to none in group B. CFU (> 40 cells) and cluster (4 -39 cells) showed considerable variations. CONCLUSION: Our results demonstrate that simultaneous treatment with G-CSF during radiotherapy reduces the mobilization of CD34+ progenitor cells and exhaust the bone marrow capacity while peripheral leukocyte counts remain at baseline levels.

Adult↗

ERK7 is an autoactivated member of the MAPK family.

Extracellular signal-regulated kinase 7 (ERK7) shares significant sequence homology with other members of the ERK family of signal transduction proteins, including the signature TEY activation motif. However, ERK7 has several distinguishing characteristics. Unlike other ERKs, ERK7 has been shown to have significant constitutive activity in serum-starved cells, which is not increased further by extracellular stimuli that typically activate other members of the mitogen-activated protein kinase (MAPK) family. On the other hand, ERK7's activation state and kinase activity appear to be regulated by its ability to utilize ATP and the presence of its extended C-terminal region. In this study, we investigated the mechanism of ERK7 activation. The results suggest that 1) MAPK kinase (MEK) inhibitors do not suppress ERK7 kinase activity; 2) intramolecular autophosphorylation is sufficient for activation of ERK7 in the absence of an upstream MEK; and 3) multiple regions of the C-terminal domain of ERK7 regulate its kinase activity. Taken together, these results indicate that autophosphorylation is sufficient for ERK7 activation and that the C-terminal domain regulates its kinase activity through multiple interactions.

Adenosine Triphosphate↗

Urinary endotoxin excretion and urinary tract infection following kidney transplantation.

Following kidney transplantation, urine endotoxin levels were measured among 44 patients and compared to bacterial cultures. Urine samples were collected either via transurethral catheters or - after removal of the catheter on postoperative day 4 - by midstream void. In a control group of ten healthy volunteers, urine endotoxin levels were measured daily for 10 days. Urinary endotoxin concentration was measured by means of a chromogenically modified Limulus amebocyte lysate (LAL) test. The levels among patients with positive bacteriological findings (n = 21) were always elevated ( > 0.7 EU/ml). Furthermore, there was a marked, statistically significant difference in endotoxin values between samples with bacterial growth and samples with fungal or without any growth (P < 0.001). All 21 of the 44 patients with urinary tract infection (UTI) were endotoxin-positive. Seven more patients who received antibiotics had elevated urinary endotoxin levels, but no bacterial growth in the urine culture. No bacterial infection or significant urinary endotoxin was found in the control group. In summary, the detection of urinary endotoxin in samples obtained by either suprapubic/transurethral catheters or midstream void is an early, sensitive, and specific means of diagnosis that can be carried out even during antibiotic treatment.

Bacteria↗

Endotoxin release and endotoxin neutralizing capacity during colonoscopy.

In 38 patients who underwent elective colonoscopy, endotoxin and endotoxin neutralizing capacity (ENC) were determined by use of the limulus--amebocyte--lysate test. A control group of 10 patients, prepared for colonoscopy, were sampled in the same manner as the study group prior to endoscopy. Elevated endotoxin plasma levels were only found when comparing the plasma levels before endoscopy with the highest levels available during endoscopy. The timed endotoxin plasma levels did not change significantly by use of the conventional limulus amebocyte test. However, ENC was found to decrease significantly 5 min after the onset of endoscopy. Maximal values were reached at the end of colonoscopy which recovered completely 24 h later. These results, obtained in a population which did not receive any infusions, demonstrate that the half life of endotoxin in the circulation seems to be very short and therefore endotoxin cannot itself be detected. On the other hand, small amounts of endotoxin reaching the blood stream are able to reduce ENC which can be analyzed by a modified limulus--amebocyte--lysate test. With the use of ENC and plasma endotoxin determinations, we are able to show significant endotoxemia during a minimal invasive procedure such as colonoscopy.

Adult↗

Endovascular stent-graft placement versus conventional open surgery in infrarenal aortic aneurysm: a prospective study on acute phase response and clinical outcome.

BACKGROUND: For the treatment of aortic aneurysm, stent-graft implantation is an alternative method to open surgery. There is no study comparing both methods with regard to endotoxaemia, the acute phase cascade, and clinical outcome. METHODS: In this prospective study, we enrolled 40 patients (34 males, 6 females; mean age 72.1+/-7.5 [58-92] years) with infrarenal abdominal aortic aneurysm who underwent aortic surgery. Comparable groups of patients were treated with open (n=20) or endovascular (n=20) stent-graft implantation. To characterize the inflammatory response, plasma levels of endotoxin, endotoxin-neutralizing capacity (ENC), interleukin-6 (IL-6), C-reactive protein (CRP), and white blood cell count were determined. In all patients, measurements were performed on admission, skin suture, 4 h and from the first to fifth postoperative day. As parameters for the clinical outcome, we assessed daily temperature, lung function, pain, duration of postoperative hospital stay, and morbidity. Wilcoxon rank test was used for statistical analysis. RESULTS: In both groups, a significant increase of endotoxin plasma levels and a decrease of ENC was found already after skin incision. IL-6 levels peaked 4 h postoperatively in both groups, whereas CRP rose at the first postoperative day, reaching a maximum at day 2. Conventionally operated patients had significantly higher plasma levels of endotoxin, IL-6, and CRP and lower ENC during and after surgery than patients with stent-graft implantation. Moreover, patients with endovascular stent grafting had significant less postoperative pain, less restriction of total vital capacity, a shorter hospital stay, and a lower morbidity. CONCLUSIONS: Endovascular stent grafting of infrarenal aortic aneurysm seems to be superior not only in terms of the inflammatory response but also in overall clinical outcome.

Acute-Phase Reaction↗

Inflammatory response during abdominal and thyroid surgery: a prospective clinical trial on mediator release.

Several studies have been demonstrated that endotoxin is a potent stimulus of the acute inflammatory response following traumatic injury. Although numerous studies have indicated that the extent of surgical intervention correlates well with the inflammatory response, the potential role of endotoxin as a trigger under those conditions still remains unknown. Therefore, the aim of this study was to elucidate whether or not the up-regulated inflammatory mediators are paralleled by increased endotoxin plasma levels during and following surgery, and whether the extent of surgical intervention represents a crucial factor under those conditions. To study this, plasma was collected at various time points during and after surgery from 52 patients subjected to abdominal surgery (i.e., major surgery) and 25 patients subjected to thyroid surgery (i.e., minor surgery). Plasma was assessed for endotoxin, endotoxin neutralizing capacity (ENC), and inflammatory mediators (leucotriene-C4 [LTC4]-, 6-keto-prostaglandin-F-1-alpha [PGF]-, thromboxane-B2 [TxB2], interleukin-6 [IL-6], and C-reactive protein [CRP]). Furthermore, splanchnic blood circulation was measured by determination of the intraluminal pH of the stomach and sigma (pHi) by intraluminal tonometry. Mesenteric lymph nodes were also collected at the time point of organ mobilization in the major surgery group and were assessed for bacterial translocation. Among all parameters investigated, endotoxin showed the most rapid changes. A significant increase in plasma levels of endotoxin and a decrease of ENC were found in the major surgery groups following induction of anesthesia and in the minor surgery groups after skin incision. Moreover, the incidence of elevated endotoxin levels was significantly higher (89% with elevated endotoxin levels) than the incidence of bacterial translocation (35% with gram-negative bacteria) in mesenterial lymph nodes of the major surgery group. pHi decreased significantly in both groups after skin incision, but no difference was observed between the major and minor surgery groups. Plasma mediators of the arachidonic acid cascade (LTC4, PGF, and TxB2) were only elevated in individual patients during and following surgery in both groups. Conversely, the post-operative increase in the acute phase mediators was significantly different in the major and minor surgery groups. IL-6 plasma levels peaked higher and earlier after major surgery than after minor surgery and the delayed increase of CRP was significantly greater in the major surgery group. In conclusion, the results indicate that plasma levels of endotoxin significantly correlate with the severity of the surgical intervention and may play an important role in inducing mediators of the acute phase reaction under such conditions.

6-Ketoprostaglandin F1 alpha↗

Changes of gut barrier function during anesthesia and cardiac surgery.

The aim of this clinical study was to investigate the time sequence between intraoperative and postoperative endotoxemia, changes in intramucosal pH(I), mediator release, and acute phase proteins and their relationship to postoperative infections. In 60 patients (median age 61 [33-72] years, male/female: 50/10) plasma levels of endotoxin, endotoxin neutralizing capacity (ENC), leukotriene-C4 (LTC4), 6-ketoprostaglandin-F-1alpha (PGF), thromboxane-B2 (TxB2), interleukin-6 (IL-6), and C-reactive protein (CRP) were measured before, during, and after cardiac surgery. The intraluminal pH(I) of the stomach was assessed as a marker of splanchnic blood circulation. Patients were divided in one group with postoperative infections (group A, n = 8) and another groups without infections (group B, n = 52). Among all measured parameters, endotoxin plasma levels showed the most rapid changes. A significant increase of endotoxin plasma levels and a decrease in ENC appeared after the induction of anesthesia, culminating in a peak after reperfusion. Endotoxin showed a significantly higher increase in group A (14fold) compared to group B (sixfold, p<0.001), whereas ENC decreased by eightfold in both groups. The parameters of the arachidonic cascade increased and pH(I) decreased, however, there were no significant differences between both groups. The latest increase was observed for the acute phase proteins IL-6 and CRP. IL-6 levels peaked 6 hours postoperatively with a 20fold (group B) and 30fold (group A) increase (p < 0.001 vs baseline; no differences between groups), whereas CRP rose at the first postoperative day with a 21 fold (group B) and 25fold (group A) increase at day 2 (p<0.001 vs baseline, no difference between groups). Differences between both groups appeared at the second postoperative day for IL-6 (median values group A/B: 421/219 pg/mL; p <0.05) and at the fifth postoperative day for CRP (median values group A/B: 321/81 mg/L; p < 0.05). In conclusion, endotoxin seems to be the earliest trigger of the mediator cascade in acute phase response and may indicate infections in the postoperative course.

Acute-Phase Proteins↗

Disruption of signaling by Yersinia effector YopJ, a ubiquitin-like protein protease.

Homologs of the Yersinia virulence effector YopJ are found in both plant and animal bacterial pathogens, as well as plant symbionts. These YopJ family members were shown to act as cysteine proteases. The catalytic triad of the protease was required for inhibition of the mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF-kappaB) signaling in animal cells and for induction of localized cell death in plants. The substrates for YopJ were shown to be highly conserved ubiquitin-like molecules, which are covalently added to numerous regulatory proteins. YopJ family members exert their pathogenic effect on cells by disrupting this posttranslational modification.

Amino Acid Sequence↗

A distinctive role for the Yersinia protein kinase: actin binding, kinase activation, and cytoskeleton disruption.

The bacterial pathogens of the genus Yersinia deliver several virulence factors into target cells using a type III secretion system. We demonstrate that Yersinia protein kinase A (YpkA), an essential bacterial virulence factor, is produced as an inactive serine/threonine kinase. The inactive kinase is activated within the host cell by a cytosolic eukaryotic activator. Using biochemical purification techniques, we demonstrate that actin is a cellular activator of YpkA. This stimulation of YpkA kinase activity by actin depends on the presence of the C-terminal twenty amino acids of YpkA, because deletion of these 20 aa not only obliterates YpkA activity, but it also destroys the interaction between YpkA and actin. Activated YpkA functions within cultured epithelial cells to disrupt the actin cytoskeleton. The disruption of the actin cytoskeleton by YpkA would be expected to inhibit macrophage function and phagocytosis of Yersinia.

Actins↗

Fluorescence detection of small gastrointestinal tumours: principles, technique, first clinical experience.

Photodynamic therapy (PDT) is a form of cancer treatment based on the selective accumulation of a photosensitizer in neoplastic tissue. The fluorescent properties of a photosensitizer permit diagnostic localization of primary tumours and/or metastasis. Occult lesions are hard to detect and can easily be missed during routine laparoscopy. Fluorescence observation offers additional optical information and the ability to detect these occult tumours. Clinically, we used 5-aminolevulinic acid for peritoneal staining and tumour demarcation via tumour-specific fluorescence induced by protoporphyrin IX. For laparoscopic observations, a "D-Light" system was used; the conventional white light source was equipped with an optical blocking filter that transmits at the excitation wavelength (380-450 nm) and blocks all other parts of the spectrum. With the aid of a suitable observation filter, the relevant fluorescence was detectable. With the help of this fluorescence we increased the capacity to detect occult tumours, that were missed with white-light observation (9/26). In the gastrointestinal tract, we used a krypton laser at 405 nm for PP IX fluorescence induction. Although there were high sensitivity rates for neoplasms (81% peritoneal carcinomas, 60% gastric cancer), no exact histopathological statement could be achieved at because of false-positive fluorescence, mainly caused by inflammation (6/32). Current clinical goals and the future perspectives of photodynamic diagnostic are discussed.

Aminolevulinic Acid↗

Gallbladder carcinoma and surgical treatment.

Gallbladder carcinoma shows an unusual geographic and demographic distribution. It is relatively uncommon in Europe, but more frequent in Israel, Chile, Bolivia and in Southwestern Native Americans in the United States. Chronic cholecystitis, choledochal cysts, high body mass index, female gender, age, nicotine and industrial exposure to carcinogens are associated risk factors. The frequency of gallbladder cancer in all operations of the biliary tract is about 1-3%, reflecting the commonest biliary tract malignancy. Preoperative imaging, including ultrasound and computed tomography (CT), may reveal signs indicative of the presence of malignancy. However, most patients are not diagnosed prior to surgical intervention. Survival depends on the ability to achieve a curative resection, including hepatectomy and lymph node dissection in patients with local extended tumour according to the stage of the disease. Overall, the curative resection rates for gallbladder carcinoma range from 10% to 30%. Regional and para-aortic lymphadenectomy provides no survival benefit for patients with para-aortic disease, which has a negative influence on prognosis equivalent to that of distant metastases. A survival benefit is seen only in selected patients with metastases limited to the regional nodes. Taking a sample biopsy of the para-aortic nodes before starting surgery is recommended because these nodes are involved more frequently than expected. For those patients with unresectable cancer, palliative surgical, endoscopic or radiological bypass procedures can improve quality of life. Other approaches to the management of advanced tumours include systemic chemotherapy or combined chemo-radiotherapy and need further evaluation. Early-stage tumours are often discovered as an incidental finding during (laparoscopic) cholecystectomy or on histological examination of the gallbladder, mostly necessitating relaparotomy and extensive resection. In the following, management of patients with gallbladder cancer at different stages and situations is discussed.

Carcinoma↗

Methylene blue mediated photodynamic therapy in experimental colorectal tumors in mice.

Methylene blue (MB+) is a well-known dye in medicine and has been discussed as an easily applicable drug for the topical treatment during photodynamic therapy (PDT). The therapeutic response of MB+ was investigated in vivo by local injection of MB+ in a xenotransplanted subcutanous tumor (adeno-carcinoma, G-3) in female nude mice. MB+ in a concentration of 1% was applied both undiluted and diluted to 0.1 and 0.01% with isotonic sodium chloride. Treatment with 1% MB+ and subsequent irradiation at 662 nm with 100 J/cm2 led to complete tumor destruction in 79% of the treated animals. A decrease of the fluence rate from 100 to 50 mW/cm2 increased the phototoxic response as well as fractionated light application. Small sensitizer concentrations reduced the PDT effect significantly. It seems that the light induced reaction of MB+ could be correlated with the rapid production of reactive oxygen species. Below a threshold dose of MB+ oxidative damage of the tissue is prevented. However, above this dose, as a point of no return, MB+ acts as an extremely potent oxidant.

Adenocarcinoma↗

Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector.

The bacterial pathogen Yersinia uses a type III secretion system to inject several virulence factors into target cells. One of the Yersinia virulence factors, YopJ, was shown to bind directly to the superfamily of MAPK (mitogen-activated protein kinase) kinases (MKKs) blocking both phosphorylation and subsequent activation of the MKKs. These results explain the diverse activities of YopJ in inhibiting the extracellular signal-regulated kinase, c-Jun amino-terminal kinase, p38, and nuclear factor kappa B signaling pathways, preventing cytokine synthesis and promoting apoptosis. YopJ-related proteins that are found in a number of bacterial pathogens of animals and plants may function to block MKKs so that host signaling responses can be modulated upon infection.

Bacterial Proteins↗

Identification of the human YVH1 protein-tyrosine phosphatase orthologue reveals a novel zinc binding domain essential for in vivo function.

A human orthologue of the Saccharomyces cerevisiae YVH1 protein-tyrosine phosphatase is able to rescue the slow growth defect caused by the disruption of the S. cerevisiae YVH1 gene. The human YVH1 gene is located on chromosome 1q21-q22, which falls in a region amplified in human liposarcomas. The evolutionary conserved COOH-terminal noncatalytic domain of human YVH1 is essential for in vivo function. The cysteine-rich COOH-terminal domain is capable of coordinating 2 mol of zinc/mol of protein, defining it as a novel zinc finger domain. Human YVH1 is the first protein-tyrosine phosphatase that contains and is regulated by a zinc finger domain.

Alleles↗

[Photodynamic ablation and argon-plasma coagulation of premalignant and early-stage malignant lesions of the oesophagus--an alternative to surgery?].

Eleven patients with high-grade mucosal dysplasia in a columnar-lined oesophagus and 2 patients with a squamous carcinoma (uT1) underwent photodynamic therapy (PDT) and argon-plasma coagulation (APC). For PDT, 5-aminolevulinic acid (5-ALA) was given orally (60 mg/kg) and treated endoscopically with a light dose of 150 J/cm2 (100 mW/cm2) at 635 nm 4-6 h later. A second PDT was performed under the same conditions 2-3 weeks later. Patients who received APC were treated 4 times on average to reach radical Barrett mucosa eradication. All patients were consistently given medication to suppress acid production. No complications occurred in either group. Follow-up endoscopies and multiple biopsies for 3-42 months showed squamous regeneration in the dysplastic columnar-lined oesophagus in all 11 patients. Two patients with squamous carcinoma were found to have a recurrence 9 and 12 months later. PDT with 5-ALA-induced endogenous prophyrins, as well as APC combined with omeprazole protection, can eradicate superficial high-grade dysplastic mucosa in Barrett's oesophagus. However, we did not succeed in destroying a manifest carcinoma.

Aged↗

Signaling network of paclitaxel-induced apoptosis in the LNCaP prostate cancer cell line.

OBJECTIVES: To attempt to identify the relationship of the key regulator molecules in paclitaxel-induced apoptosis using two metastatic cell lines: the human prostate carcinoma LNCaP line and the cervical carcinoma HeLa cell line. METHODS: Both LNCaP and HeLa cells were continuously exposed to clinically achievable concentrations of paclitaxel and observed for activation of programmed cell death as measured by cytotoxic dose-response curves, poly(adenosine diphosphate-ribose) polymerase cleavage, bcl-2 phosphorylation, and the activation of caspase-7 (interleukin-1 beta converting enzyme (ICE)-LAP3). RESULTS: Initially, we asked whether paclitaxel-induced bcl-2 phosphorylation is triggered by the spindle assembly checkpoint via an active cdc2 kinase-dependent pathway and whether phosphorylation of endogenous bcl-2 is the signal that activates cell death machinery. Paclitaxel-induced G2/M cell cycle arrest correlated with cdc2 kinase activity and bcl-2 phosphorylation. Olomoucin, a specific inhibitor of cyclin-dependent kinases, inhibited bcl-2 phosphorylation. On the basis of these studies, we then investigated whether bcl-2 was phosphorylated in a cell cycle-dependent fashion. Analysis of synchronized HeLa cells demonstrated that endogenous bcl-2 is phosphorylated in a G2/M cell cycle-dependent manner without apoptosis. CONCLUSIONS: Our results indicate that the events associated with paclitaxel-induced cytotoxicity are connected to each other and represent the signaling network of paclitaxel-induced mitotic arrest and cell death. In addition, we confirmed that the death-decision of paclitaxel-induced apoptosis is not mediated by bcl-2 phosphorylation and believe that this decision may be mediated by the activated spindle assembly checkpoint.

Antineoplastic Agents, Phytogenic↗

Paclitaxel-associated multimininucleation is permitted by the inhibition of caspase activation: a potential early step in drug resistance.

The chemotherapeutic agent paclitaxel disrupts microtubule dynamics causing mitotic arrest, which leads to cell death. However, in paclitaxel-resistant tumor cells, treatment with paclitaxel induces abnormal progression through prophase resulting in a multimininucleated phenotype. Multimininucleation and subsequent polyploidization have been correlated with paclitaxel resistance. Paclitaxel treatment of HeLa cells resulted in cell death via typical activation of the apoptotic machinery, whereas treatment of the relative paclitaxel-resistant prostate cancer cell line PC-3 induced an attenuated caspase activation and multimininucleation. The multimininucleated phenotype could be mimicked in HeLa cells treated with paclitaxel and benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), a peptide caspase inhibitor. Interestingly, we observed no discernible difference in the pattern of cdc-2 kinase activation or phosphorylation of bcl-2-like proteins in PC-3 and HeLa cells treated with paclitaxel, which demonstrated that these molecules could not be used as indicators for the degree of caspase activation. In this study, we establish a connection between relative paclitaxel resistance, caspase attenuation/inhibition, and the multimininucleated phenotype.

Antineoplastic Agents, Phytogenic↗