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Osteoclast-like giant cell tumors (OLGT) are rare neoplasms of the pancreas and mostly associated with ductal adenocarcinomas. In this report, we present the rare case of OLGT associated with mucinous cystadenocarcinoma (MCC). We investigated the expression profile of both tumors by methods of molecular biology and immunohistochemistry. The panel of markers included osteopontin, her2/neu, mismatch repair genes, K-ras, p53, E-cadherin, VEGF-C, and podoplanin. Osteopontin was expressed by the osteoclast-like giant cells but not by the mononuclear tumor cells of the OLGT. We detected an amplification and overexpression of her2/neu in the MCC but not in the OLGT. Although we observed an immunohistochemical expression of hMSH2 and hMLH1 in the OLGT, we were not able to confirm this result by western blot analysis. We also did not find any microsatellite instability (D2S123, BAT26). While mutation of K-ras codon 12 was found in both tumor components, there was wild-type DNA of p53. E-cadherin was expressed in MCC but not in OLGT. VEGF-C was only positive in osteoclast-like giant cells and some of the mononuclear cells of OLGT. The vessel-rich stroma of OLGT did not present any podoplanin-positive lymphatic vessel. The observation of our case and others in the published literature may indicate separating OLGT with undifferentiated carcinoma from OLGT with MCC for the better clinical outcome of the latter.

The bicentenary of the birth of Rokitansky, the first true descriptive pathologist, was celebrated in February 2004. Rokitansky gathered many and important specimens that are now displayed in the Federal Museum of Pathological Anatomy in Vienna. On examining Rokitansky's collection we found a myxoma of the pulmonary valve of a 70-year-old woman who died in 1833. Cardiac myxomas are rare but are the most frequent primary heart tumors, appearing even less frequently on cardiac valves. Modern histology has confirmed Rokitansky's diagnosis on gross pathology. The good condition of this 171-year-old specimen was surprising. Thus, Rokitansky described the myxoma 75 years before Ribbert's first description of a myxoma in this rare localization.

Resistance to anticancer drugs such as the widely used antimetabolite 5-fluorouracil (FU) is one of the most important obstacles to cancer chemotherapy. Using GeneChip arrays, we compared the expression profile of different stages of FU resistance in colon cancer cells after in vitro selection of low-, intermediate- and high-resistance phenotypes. Drug resistance was associated with significant changes in expression of 330 genes, mainly during early or intermediate stage. Functional annotation revealed a majority of genes involved in signal transduction, cell adhesion and cytoskeleton with subsequent alterations in apoptotic response, cell cycle control, drug transport, fluoropyrimidine metabolism and DNA repair. A set of 33 genes distinguished all resistant subclones from sensitive progenitor cells. In the early stage, downregulation of collagens and keratins, together with upregulation of profilin 2 and ICAM-2, suggested cytoskeletal changes and cell adhesion remodeling. Interestingly, 6 members of the S100 calcium-binding protein family were suppressed. Acquisition of the intermediate-resistance phenotype included upregulation of the well-known drug resistance gene ABCC6 (ATP-binding cassette subfamily C member 6). The very small number of genes affected during transition to high resistance included the primary FU target thymidylate synthase. Although limited to an in vitro model, our data suggest that resistance to FU cannot be explained by known mechanisms alone and substantially involves a wide molecular repertoire. This study emphasizes the understanding of resistance as a time-depending process: the cell is particularly challenged at the beginning of this process, while acquisition of the high-resistance phenotype seems to be less demanding., (Copyright 2004 Wiley-Liss, Inc.)

On February 19th 2004 we celebrated the 200th anniversary of Carl Rokitansky's birth. Together with Morgagni and Virchow, Rokitansky paved the way for the development of modern pathology. In addition, he was the co-founder of the so-called Second Vienna Medical School. Rokitansky represents a personality on the threshold of the change in medicine from a phenomenological-dominated philosophy to an evidence-based science. This jubilee essay aims at outlining this development particularly with regard to the Vienna Medical School before and after Rokitansky.

The bicentenary of Carl Rokitansky's birth prompted us to evaluate his less well-known work related to osteopathology. Of various articles containing humoropathological interpretations of osseous diseases, one work should be highlighted. It is, to the best of our knowledge, the first description of a spondylocostal dysplasia, re-discovered many years later, precisely described and accompanied by an excellent illustration.

Since tumor cells are known to express heat shock proteins (HSPs) as a response to cellular stress, such as heat, our goal was to determine the expression of HSPs in human hepatocellular carcinoma (HCC) before and after percutaneous radiofrequency (RF) ablation using a rat model. In 12 nude rats, human HCC cells (SK-HEP-1) were inoculated subcutaneously. A total of 21 tumors were grown in the bilateral flanks of the rats. Of those, 19 were treated with percutaneous RF ablation (diameter of RF electrode, 18 gauge; RF ablation energy, 60-600 W; duration, 20-100 sec). To determine the extent of necrosis, and the cellular expression of HSP 70 and HSP 90, the tumors were excised within 6, 12 and 24 h after RF ablation, respectively. The extent of the coagulation necrosis and the expression of HSP 70 and 90 were evaluated. Linear regression analysis showed a significant correlation between the volume of coagulation necrosis and the RF energy applied. Before RF ablation, expression of HSP 70 and 90 was 0% and 0-30%, respectively. Following RF ablation, the maximum level of HSP 70 expression was 60%, and the maximum level of HSP 90 expression was 100%. The expression of HSP 70 and 90 in HCC is significantly increased by RF ablation. These findings are of particular importance in the host-tumor immune response and might be useful in forthcoming immunotherapeutical strategies.

The transmembrane component of the dystroglycan complex, a heterodimer of alpha- and beta-dystroglycan, was recently localized at the basal cell membrane domain of podocytes, and it was speculated that it serves as a device of the podocyte for maintaining the complex podocyte foot process architecture, and for regulating the exact position of its ligands, the matrix proteins laminin and agrin, in the glomerular basement membrane (GBM). The redistribution of dystroglycan in two experimental rat models of foot process flattening and proteinuria-i.e., podocyte damage induced by polycationic protamine sulfate perfusion, and reactive oxygen species (ROS)-associated puromycin aminonucleoside nephrosis-was examined. In both experimental diseases, aggregation and reduced density of alpha-dystroglycan by endocytosis by podocytes was observed. In in vitro solid-phase binding assays, protamine and ROS competed with the binding of alpha-dystroglycan with purified laminin and a recombinant C-terminal fragment of agrin that contains the dystroglycan-binding domain. These changes were associated with disorder of the fibrillar components of the lamina rara externa of the GBM, as confirmed quantitatively by fractal analysis. These results indicate that both polycation and ROS induce similar changes in the distribution of podocyte alpha-dystroglycan that involve competitive disruption of alpha-dystroglycan/matrix protein complexes, endocytosis of the liberated receptor by podocytes, and disorganization of the matrix protein arrangement in the lamina rara externa. This links functional damage of the dystroglycan complex with structural changes in the GBM.

Heat shock proteins (HSPs) are known to be of crucial importance in host-tumor interactions. The goal of this study was to determine whether there was an increase in HSP expression in a patient suffering from unresectable hepatocellular carcinoma treated with percutaneous radiofrequency (RF) ablation. Immediately before RF ablation, a computed tomography (CT)-guided core needle biopsy (diameter, 18 gauge) was obtained from the tumor. The RF ablation was then performed using a saline-perfused RF ablation system (diameter of RF electrode, 15 gauge; ablation time, 10 min). Twenty-four hours after tumor ablation, core needle biopsy was repeated, and biopsy specimens were obtained from the residual tumor margin visible on contrast-enhanced CT. For both procedures, no side effects or clinically relevant complications were observed. The specimens were mapped by immunohistochemistry, determining the cellular expression of HSP 70 and HSP 90. After RF ablation, in the cytoplasm and at the tumor cell surface, an 8-fold increase in HSP 70 and a 1.2-fold increase in HSP 90 was observed, respectively. In the cell nucleus, the HSP 90 expression before RF ablation was 10%, and decreased to 0% after RF ablation. We have demonstrated that, following RF ablation, cellular expression of HSP 70 and HSP 90 in hepatocellular carcinoma is increased. We further suggest that routing of HSP 90 from the nucleus to the cell surface occurred after RF ablation. This may be of relevance in further therapeutic anti-tumor strategies.

Objective: To evaluate the frequency, presentation and outcome of non-traumatic aortic dissection/rupture as a cause of cardiac arrest., Design: Retrospective analysis of a cardiac arrest registry in a tertiary care hospital emergency department., Results: Over 11.5 years, aortic dissection/rupture was identified as the immediate cause of cardiac arrest in 46 (2,3%) out of 1990 patients with sudden cardiac arrest, primarily affecting the abdominal aorta in 25 and the thoracic aorta in 21 cases. The characteristics of the 46 patients were as follows: male gender (74%), median age 71 years (IQR 59-76), high co-morbidity (89%), previously known aortic aneurysm (33%), pulseless electric activity (70%) as initial cardiac rhythm. When performed, bedside abdominal sonography or echocardiography was almost always diagnostic. Patients with abdominal aortic dissection/rupture had abdominal (52%) and/or flank pain (32%). Patients with thoracic aortic dissection/rupture complained of chest pain (48%) or dyspnoea (19%). Return of spontaneous circulation occurred in 12 (26%) of 46 patients, emergency surgery was performed in eight of these patients, 2 (4%) survived to discharge in good neurological condition., Conclusions: Cardiac arrest caused by aortic dissection/rupture is rare, and mortality remains very high, even when circulation can be restored initially. Common features such as previously known aortic aneurysm, old age, male gender and pulseless electrical activity as initial cardiac rhythm should increase suspicion of the condition.

The anti Her-2/neu monoclonal antibody Trastuzumab has strong inhibiting effects on tumor growth in vitro and in vivo and is therefore used for immunotherapy in breast cancer patients. Due to necessity of frequent applications, however, cost intensiveness of Trastuzumab treatment and its limited duration of affectivity, an active immunization inducing a perhaps preventive and long-term immunity to Her-2/neu remains a desirable goal. We attempted to induce anti Her-2/neu antibodies by peptide vaccination and to test their efficacy in inhibiting tumor cell growth in vitro. By computer aided analyses, 7 putative B cell epitopes of Her-2/neu were defined and synthesized. These peptide epitopes were coupled to tetanus toxoid and used for immunization in BALB/c mice. Among these peptides, immunizations with 2 single peptides or a combination of 2 peptides induced anti-peptide antibody levels, primarily of the IgG1 isotype. These antibodies were also directed against the native Her-2/neu antigen, as shown in precipitation assays and ELISA with cell lysates of the Her-2/neu overexpressing breast cancer cell line SK-BR-3. Isolated IgG fractions from immune sera incubated with SK-BR-3 cells led to a moderate inhibition of the tumor cell growth in vitro, as well as to complement dependent cell lyses comparable to that achieved by incubation with Trastuzumab. Moreover, peptide immunization in rabbits generated anti-Her 2-neu IgG that, in contrast to mouse sera, were able to mediate a 31-46% lysis of SK-BR-3 cells in ADCC experiments. We conclude from our data that immunization with Her-2/neu peptides successfully induced humoral immune response with anti-tumor activity in an animal model., (Copyright 2003 Wiley-Liss, Inc.)

To assess a potential common pattern of genetic alterations in chemotherapy-resistant tumors we analyzed four tumors from breast cancer patients (patients 1-4) after neoadjuvant chemotherapy, by comparative genome hybridization (CGH) and conventional chromosome banding analysis. All patients showed structural aberrations involving chromosomes 1, 5, 11, 16, and 17. In CGH analysis, the patients showed typical imbalances for ductal breast cancer: gains of 1q (3 patients), 5q (2 patients), 8q (3 patients), and X (4 patients) and losses of 1p33 approximately p36 (3 patients), 16q (3 patients), 17p (3 patients), 19 (4 patients), and 22q (4 patients). Other recurrent imbalances of atypical pattern for ductal breast cancer were gain of 4q21 approximately q32 (2 patients), 20q21 approximately q22 (2 patients), and 21 (2 patients) and loss of 20p (3 patients). Three patients showed involvement of several regions bearing genes of drug resistance (MDR1 [HUGO symbol: ABCB1], BCRP [HUGO symbol: ABCG2], MRP1 [HUGO symbol: ABCC1], RFC1); the fourth patient displayed an amplification in the region of MYC (alias c-myc), thus providing--at the level of the light microscope--an explanatory background for the ability of their tumors to survive anthracycline-, taxane- and cyclophosphamide-based chemotherapy. Conventional cytogenetic analysis and CGH displayed highly coincidental findings in the tumors of four patients after neoadjuvant chemotherapy for breast cancer.

Serous papillary adenocarcinomas of the ovary are often associated with microcalcifications, namely psammoma bodies. Archebacteria such as nanobacteria are, for example, involved in kidney stone formation. Nanobacteria deserve close scrutiny as their cytotoxicity and ability to cross the placenta present a potential clinical risk. In this study we investigated whether nanobacteria are associated with psammoma bodies in ovarian cancer. We identified in all seven carcinomas with multiple psammoma body nanobacterial antigens in histological specimens and in the ascitic fluid. Control cases of adenocarcinomas without such calcifications did not present nanobacterial antigens. This finding indicates that apart from non-malignant conditions, nanobacteria could also be found in cancer. Hence, nanobacterial infection may be of clinical importance as these bacteria are related to microcalifications in ovarian cancer.

Background: The cause of preferential metastatic spreading to cervical lymph nodes in oral squamous cell cancer (SCC) is not quite clear. As the density of microvessels may influence the metastatic behaviour, we were interested in how the density of blood/lymphatic microvessels are related to primary SCC and the clinical course of the disease., Methods: Lymphatic and blood microvessels of 28 patients with oral SCC were identified immunohistochemically by antibodies against podoplanin and CD34, respectively. Lymphatic microvessel density (LVD) and blood microvessel density (MVD), and the expression of VEGF-C were determined. These findings were compared with the long-term clinicopathological data of the patients., Results: LVD and MVD were significantly higher than in control tissues. The amount of lymphatic microvessels correlated positively with the expression of VEGF-C, the tumour grade, the nodal status and with later appearing metastasis. The latter three parameters, however, did not influence the clinical course of the disease., Conclusions: VEGF-C expression in oral SCC triggers lymphatic angiogenesis, which may result in a higher risk for cervical lymph node metastasis. The angiogenetic effect of VEGF-C may also favour the onset of late lymphatic and haematogenous metastases.

When a new hypothesis about the etiology and pathogenesis of a disease is developed, there is always the danger that it will be presented as the only acceptable explanation for the occurrence of a given pathologic condition. In view of the well-proven multifactoral pathogenesis of atherosclerosis, we would like to emphasize that we are not postulating that immunity to HSP60 is the only cause of atherogenesis, especially in the later stages where there are clinically-apparent sequelae, such as myocardial infarction, stroke, and other atherosclerosis-dependent symptoms. In this article, we summarized some of the experimental and clinical data that we and others have collected in support of the concept that atherosclerosis is a good example of pleotropic antagonism, and postulated that age-dependent diseases are the price we pay for genetic traits established by natural selection to assure maximum survival until the age of reproduction, the effects of which may, however, become deleterious later in life. In the present case, the cost we pay for protective immunity to microbial and altered autologous HSP60 is the risk of cross-reactivity with HSP60 expressed by arterial endothelial cells that are subjected to stress factors already known as classical atherosclerosis risk factors. We showed that the first inflammatory stage of atherosclerosis starts early in life, long before it becomes clinically apparent. More severe lesions that lead to atherosclerosis-dependent organ-specific or systemic symptoms will only occur if classical atherosclerosis risk factors, especially those involving the cholesterol metabolism, remain present.

Epithelial cells of the mammary gland possess the inherent capacity to form epithelial monolayers in vitro. This requires coordination of cell migration, cell-cell contact formation, and cell proliferation. Using time-lapse phase contrast videomicroscopy we have observed mammary gland epithelial cells over different time scales. We show the generation of a complete polarized epithelial monolayer in real-time, starting from a few cells. We subsequently concentrated on the early stages of this process by tracking epithelial cells during phases of polarized migration. We performed migration analysis using fractal measures. With this technology the structure of seemingly random processes not accessible to the usual methods of linear analysis can be measured. As a control and proof of principle approach we applied infection of cells with an adenoviral vector, which is used as a gene targeting vector for many applications. Infection markedly influenced the patterns of migratory behavior. We, therefore, believe that time-lapse videomicroscopy in combination with fractal analysis can contribute to differential characterization of distinct cellular migration patterns. This will be useful in situations of long-term alterations in cell culture systems.

Objective: Lipoprotein (a) is an independent risk factor for atherosclerosis. Atherosclerotic degeneration is usually found in abdominal aortic aneurysms (AAAs), whereas thoracic aortic aneurysms (TAAs) caused by aortic dissection are not suggested to be linked pathogenetically to atherosclerosis. Lipoprotein (a) was analyzed in patients with AAA and TAA and in healthy individuals in relation to the extent of atherosclerosis., Methods: Included in the case control study were patients with AAA (n = 75) and TAA with dissection (n = 39) and healthy control subjects (n = 43), for a total of 157 participants. Serum lipoprotein (a) was measured with nephelometry. Lipoprotein (a) levels were compared between age-matched and gender-matched paired samples of the three groups, and an association of lipoprotein (a), aortic aneurysm, and the extent of atherosclerosis was determined in multivariate analysis., Results: Median lipoprotein (a) levels of patients with AAA and TAA and of control subjects were 18.9 mg/dL (interquartile range [IQR], <9.6 to 40.5), less than 9.6 mg/dL (IQR, <9.6 to 16.7), and less than 9.6 mg/dL (IQR, <9.6 to 16.3), respectively. Lipoprotein (a) was positively associated with the extent of atherosclerosis in patients and control subjects (P <.0001). Lipoprotein (a) levels of patients with AAA were significantly higher compared with patients with TAA (P <.0001) and control subjects (P <.0001). Multivariate analysis confirmed an independent association between lipoprotein (a) and AAA (P =.009). No significant differences of lipoprotein (a) were found between patients with TAA and control subjects (P =.3)., Conclusion: The lipoprotein (a) serum level, an indicator of atherosclerosis, is significantly elevated in patients with abdominal aneurysms independently of cardiovascular risk factors and the extent of atherosclerosis. Patients with TAAs caused by dissection have lipoprotein (a) levels comparable with healthy individuals.

Kinetic studies of cell proliferation rates shed light on the growth dynamics of cancer. Most such studies are based on measurements of cell numbers that were evaluated in time intervals of about 12 h. Studies of the initial tumour growth with short measuring intervals are rare. This study was therefore designed with 1 h measuring intervals over a 24 h period. Human breast cancer cell lines (ZR-75-1, SK-BR-3, MCF-7) and a benign cell line (HBL-100) were used to study the hourly thymidine uptake as a measure of cells in synthesis. In parallel experiments, the same cell lines were also exposed to tumour necrosis factor alpha (TNF-alpha) to explore the effect of an apoptosis-inducing substance on initial tumour growth kinetics. In time-evolution plots, there was an oscillation of the labelling index of thymidine uptake for all investigated cell lines, with and without TNF-alpha. Based on the results obtained, a mathematical model was developed mimicking the real experiment. To describe the system dynamically a cellular automaton model was studied. The growth kinetics revealed by the simulation were in accordance with our experimental data. Two- and three-dimensional growth simulations of this computer model yielded objects morphologically similar to real images of human breast cancer. Almost identical fractal dimensions of the virtual and real tumours further supported this visual similarity. The cellular automata models could, therefore, be seen as a bridge towards realistic in vivo scenarios. From a clinical point of view, the results obtained may be applicable not only to primary tumours, but even to tumour cell microfoci and small metastases, which are a major concern in early metastasizing tumours such as breast cancer., (Copyright 2002 John Wiley & Sons, Ltd.)

Seventy-six pituitary adenomas of akromegalic patients were investigated to find out the prognostic relevance of the intracytoplasmic distribution of cytokeratins (CK), immunohistochemically defined hormone production profile, proliferative activity and clinical presentation. CK distribution, growth fraction (MIB1 index) and hormone production profile were analyzed by means of immunohistochemistry. Apoptotic activity was investigated by the TUNEL method. Two different CK distribution patterns were seen: a dot-like pattern in 29 cases (type 1 adenomas), and a perinuclear fibrillary pattern in 47 cases (type 2 adenomas). Type 2 adenomas showed more prominent coexpression of prolactin (p < 0.0001), luteotrophic hormone (p < 0.002), follicle-stimulating hormone (p < 0.005), thyroid-stimulating hormone (p < 0.0001), and alpha-subunit (p < 0.005), as compared to type 1 adenomas. The mean MIB1 index was significantly higher in type 1 vs. type 2 tumors (4.23%, range: 1.93% - 9.83% vs. 2.07%, range: 0.67% - 4.87%, p < 0.0001). Apoptotic activity was too low in both examined groups to be used for balancing of tumor cell turnover. Clinical analysis of patients with type 1 adenomas revealed female predominance, younger age, larger tumor size, and more frequently aggressive growth with higher incidence of suprasellar extension (p < 0.0001) and cavernous sinus infiltration (p < 0.0001), as well as larger proportions of re-operations and incomplete resections (34.5% vs. 8.51%). Additionally, the interval until re-operation was shorter in type 1 adenomas (mean: 16 months, range: 9 - 21 months vs. mean: 57 months, range: 18- 158 months). We conclude that classification of adenomas of akromegalic patients based on intracytoplasmic CK distribution, combined with examination of proliferative activity, and immunohistochemically defined hormone production profile, provides important prognostic information for the management of akromegalic patients.

Objectives: The spatial distribution of cancer foci of prostate carcinomas with negative initial biopsies was compared to that of prostate carcinomas with positive initial biopsies to detect areas in which carcinomas were more frequently located when the initial biopsy was negative., Methods: Twenty patients with prostate cancer and a negative initial biopsy trial were detected among 218 patients with preceding systematic biopsies (9.2%) in our hospital. Analysis of the prostatectomy specimens regarding cancer distribution, multifocality, tumour size, Gleason score, and stage was performed using pathohistological techniques and three-dimensional computer reconstruction., Results: Prostatectomy specimens with negative initial biopsies showed more frequently cancer foci in apical (p<0.0001) and dorsal (p<0.02) prostatic compartments, higher incidence of multifocality (p<0.01), and smaller size of carcinoma foci (p<0.00003) compared to carcinomas in 81 stage-matched prostatectomy specimens with positive initial biopsies. Comparing both groups, no significant differences were noted in Gleason score of preoperative biopsies and prostatectomies, prostate weight, prostate-specific antigen (PSA) level, digital rectal examination, and patients age., Conclusions: Missing the cancer in clinically significant prostate carcinomas by current systematic biopsy techniques may also be due to an apico-dorsal cancer location, particularly in combination with multifocality and small size of carcinoma foci in large prostates. In case of reasonable clinical suspicion of prostate cancer and negative initial biopsy, an early repeat biopsy with special emphasis on the apico-dorsal peripheral zone should be envisaged.

Using reverse transcriptase-polymerase chain reaction (RT-PCR), we have recently described a bona fide deletion within the coding sequence of the large subunit of ribonucleotide reductase (R1) mRNA in colon cancer. Consecutive studies have raised questions about the nature of this phenomenon, because the corresponding genomic alteration at the DNA level or an aberrant protein could not be detected. Thus we considered an in vitro artifact during RT-PCR as a possible explanation for this observation. In contrast to reverse transcriptase, Taq DNA polymerase or C. therm DNA polymerase did not generate the aberrant product, suggesting the demand for the template switching activity intrinsic to retroviral reverse transcriptases. In fact, virtually the same deletion was observed in RT-PCR experiments when in vitro transcribed R1 mRNA was used. Considering structural prerequisites for template switching within R1 mRNA, we show that two direct repeats adjacent to a strong stem-loop secondary structure flank the deleted region of 1851 base pairs. Because several mRNAs encoding proteins of clinical and diagnostic importance fulfill these criteria, template switching enhances the potential risk of observing artifacts when interpreting results from RT-PCR studies. As shown in the present example, this may involve the artificial generation and the misinterpretation of PCR fragments amplified from targets relevant to tumor biology or cancer pharmacology. As a possible solution, one-step PCR with C. therm polymerase should be considered. This polymerase eliminates the artificial generation of aberrant mRNA signals observed during cDNA synthesis.

Over the past years, techniques of nonlinear dynamics have gained increasing attention in cardiology. This kind of partly interdisciplinary research is supposed to provide a better understanding of cardiac disease, especially in the field of tachyarrhythmia. This article intends to introduce the principles of diagnostic procedures in terms of nonlinear dynamics, chaos theory and stochastic processes related to cardiology. An introduction to a new technique of wavelet analysis is given, and possible applications in the quantitative classification of high-risk patients for sudden cardiac death are discussed.

Objective: To determine the early effects of therapy of endotoxin (ET) shock with epinephrine, norepinephrine, or dopexamine on splanchnic circulation, oxygen metabolism, sigmoid mucosal pHi, bacterial translocation, and morphologic integrity of the ileal, colonic, and sigmoid mucosa., Summary Background Data: Conflicting concepts exist concerning the catecholamine therapy of septic shock, but little is known about the effects of catecholamine treatment on splanchnic circulation and mucosal integrity., Methods: ET shock was induced in pigs by ET infusion over 30 minutes, and animals were studied for 4 hours. All animals were resuscitated with fluid. To mimic the treatment of septic shock in humans, mean arterial pressure was maintained in two groups at >70 mm Hg with the administration of epinephrine or norepinephrine. A third group of animals received dopexamine at 7 microg/kg per minute. Systemic and splanchnic blood flow and oxygen metabolism were studied, sigmoid colon mucosal pHi was obtained tonometrically, and bacterial translocation was determined by culture of portal venous blood, mesenteric lymph nodes, liver, spleen, and lung specimens. Histologic sections of ileal, colonic, and sigmoid mucosa were morphometrically examined for therapy effects., Results: All investigated catecholamines increased cardiac output and systemic oxygen delivery, whereas intestinal blood flow and oxygen delivery remained unchanged. Sigmoid mucosal pHi decreased in all study animals, but the decrease was most pronounced in the epinephrine group. Pigs receiving epinephrine also showed >40% damage of the mucosa of the ileum and colon, whereas animals receiving ET alone, norepinephrine, or dopexamine showed only moderate lesions with signs of restitution. No animal showed bacterial translocation., Conclusions: Systemic hemodynamics and oxygen metabolism data do not reflect intestinal perfusion. Norepinephrine or dopexamine administration in ET shock causes no additional impairment of intestinal integrity. Epinephrine therapy, in contrast, is associated with a significant reduction of mucosal pHi and considerable early mucosal damage. Its application in septic shock is hazardous.

Radiation-induced brachial plexus lesions are progressive and irreversible complications. Until now, there is no way to successful prevention and treatment of this problem. In our series, relief of pain could be achieved by neurolysis in some cases, but there was no recovery of sensory and motor function. In order to improve the vascularity and nerve tissue regeneration, we performed muscle or gliding tissue flaps after neurolysis in our department. Since 1975, 25 patients who developed radiation-induced plexopathy were treated in our department. We followed 18 patients to evaluate the benefits of our surgical intervention. None of the patients had improvement of their sensory or motor impairment. Relief of severe pain was achieved in 83% either by neurolysis only with or without muscle or gliding tissue flap. In some cases, paresis worsened postoperatively. We also observed a return of severe pain after the operation.

Apoptotic cell death in human tumours has been demonstrated by electron and light microscopy. In adenomas, fragmented and apoptotic nuclei and signs of phagocytosis have been observed close to the basement membrane. In carcinomas the characteristic structures were apoptotic bodies with small fragments of chromatin. DNA fragmentation was shown by in situ end-labelling. Quantitative assessment of apoptosis and proliferation revealed a high apoptotic index (AI) in all types of adenoma (tubular: 1.77+/-0.35%, tubulovillous: 2.38+/-0.41%; villous: 3.3+/-0.39%) as well as loss of compartmentalization of proliferating and dying cells. In carcinomas a shift towards proliferation was evident, as shown by lower AIs than in adenomas (0.9+/-0.68% and 1.1+/-0.12% for moderately and poorly differentiated tumours), higher Ki67 indices (38.32+/-2.23% and 57+/-3.89%, respectively) and higher mitosis (0.9+/-0.56% and 1.21+/-0.17%, respectively). However, apoptosis was observed in all tumours and is available as a target for therapeutic intervention. Expression of the apoptosis related proteins bcl-2 and bak also reflected loss of compartmentalization. While bcl-2 did not show a consistent relationship to AI in tumour specimens, bak was positively correlated with apoptosis in 4 of 8 adenomas and 4 of 7 carcinomas, suggesting a role for this protein in the induction of apoptosis in a subset of tumours.

Since few years a new vacuum-assisted biopsy is used in addition to the common gun-needle biopsy in suspicious lesions of the mamma. Aim of our study was to compare these two techniques in regard to their histological outcome. Retrospectively, 149 of the 1997 performed biopsies and the corresponding operation specimens were evaluated. The biopsied lesions were divided in star-like densities, roundish opacities and different forms of microcalcifications. We found both stereotactical methods very accurate. In vacuum-assisted biopsies more representative material could be obtained in cases of microcalcifications. The better quality of the tissues made the histological result more reliable. In concern to other lesions in the mammogram there was no difference between the two techniques at all. In summary, both stereotactical methods revealed comparable and valuable results whereas in any form of microcalcifications we suggest to apply the vacuum-assisted method.

Fractal analysis techniques are common tools in physics and image processing. In the past few years they have gained increasing attention in medical sciences, e.g., cardiology, pathology and radiology, respectively. This article intends to describe this new technique by applying fractal analysis to the instant of a breast carcinoma. One of the advantages of fractal analysis is the ability to describe an irregular and complex object by a measureable value, called the fractal dimension. The fractal dimension can be determined by using the box-counting method. We applied this technique to the mammography as well as to the histologic section of a breast carcinoma. The application of fractal analysis provides a specific measureable value of the growth pattern of a tumor. Thus, the fractal dimension serves in addition to the common used metric diameter.

Epidermal growth factor (EGF) exhibits a cytoprotective effect on gastrointestinal epithelia via a receptor-mediated mechanism. We investigated the effect of EGF on Clostridium difficile toxin A (TxA)- and toxin B (TxB)-induced damage of human colon. Ussing-chambered colonic mucosa was exposed serosally to EGF before and during luminal exposure to TxA and TxB. Resistance was calculated from potential difference and short-circuit current. Epithelial damage was assessed by light microscopy and alteration of F-actin by fluoresceinated phalloidin. Luminal exposure of colonic strips to TxA and TxB caused a time- and dose-dependent decrease in electrical resistance, necrosis and dehiscence of colonocytes, and disruption and condensation of enterocyte F-actin. These effects were inhibited by prior, but not simultaneous, serosal application of EGF (20 nM). Administration of the tyrosine kinase inhibitor genistein (10(-6) M) inhibited the protective effects of EGF. We conclude that EGF protects against TxA and TxB probably by stabilizing the cytoskeleton, the main target of these toxins.

Deaths of young athletes are mainly caused by cardiac problems. Noncardiac deaths are infrequent and related to heat stress, drugs, sickle cell trait, and asthma. Herein, we report the case of a 28-year-old man, who collapsed during a marathon race, within sight of the finish line. Despite immediate resuscitation, he died shortly after hospitalization. Autopsy findings revealed neither unambiguous cardiac nor previously published noncardiac causes. Traumatic or drug-related death was excluded as well. We did find, however, focally hyperinflated pulmonary areas adjacent to atelectasis, interstitial emphysema, and mucosal infoldings of several bronchi. Histologically, two-thirds of medium-sized bronchi presented paucity of cartilages. Hence, the resulting flaccidity of the bronchial wall might cause bronchial obstruction, which we related to the genesis of this sudden and unexpected death.

Autoimmune cholangitis is clinically characterized by cholestasis and serologically by the presence of antinuclear antibodies (ANA) and a lack of antimitochondrial antibodies (AMA). Morphologic characteristics are non suppurative bile duct destruction (NSBDD), ductopenia and occasionally granulomas. The aim of the study was to characterize the inflammatory infiltrate to find about the possible mechanism of bile duct destruction in AIC. Liver biopsy material of ten patients (9 female/1 male, mean age of 45,5 a) with the clinical and serologic features of AIC were evaluated morphologically for the presence of NSBDD, ductopenia and granulomas. The inflammatory infiltrate was characterized immunohistochemically using Ab against CD3 (pan T lymphocytes), OPD 4 (helper T lymphocytes and memory T lymphocytes), CD8 (cytotoxic T lymphocytes), GB4 (activated cytotoxic T lymphocytes), L26 (pan B lymphocytes), CD56 and CD57 (NK/K cells). Lymphocyte subsets were investigated with regard to quantity and distribution within liver tissue. For control ten cases of PBC were also investigated simultaneously. NSBDD was found in five, granulomas in three cases. Portal inflammation was seen in all cases. In 9 cases T cells outweighed B cells. GB4 positive activated cytotoxic T lymphocytes were found within bile duct epithelium in five cases. All these cases showed associated NSBDD. NK/K cells were seen infrequently. Similar findings were observed in the ten cases of PBC. We therefore conclude that bile duct destruction in AIC is mediated by activated cytotoxic T lymphocytes. AIC cannot be differentiated from PBC histologically or by immunomorphology.

Autonomous and uncoordinated proliferation of epithelia leads to various well-known growth patterns such as expansive (cauliflower-like), radiating infiltrative, polycyclic, and roundish-ovoid figures. All attempts to describe such natural growth patterns graphically by Euclidean geometry have failed and remain no more than works of art. However, fractal geometry is a new tool for the characterization of irregularly-shaped and complex figures. Moreover, behind a fractal structure there is a basic power-law which provides the opportunity to simulate these forms artificially. A prerequisite for achieving this goal of simulating tumour growth by computer is to establish whether typical tumour growth patterns are fractal. Hence, an investigation was undertaken of 20 tumours (malignant, metastases or benign) exhibiting the above-mentioned typical patterns. If tumour outlines are fractal they have to possess a fractal non-integer dimension which significantly exceeds the integer Euclidean dimension. The fractal dimension of tumour outlines was determined using the box-counting method. Almost all tumours presented a fractal dimension and virtual tumour images were created by utilizing available fractal software. In conclusion, the determination of the fractal dimension of solid neoplasms may be an additional morphometric parameter for growth assessment and it probably provides further opportunity to simulate cancer growth and infiltration by computer animation.

Hemangiomas of the head and neck region can represent a therapeutic challenge depending on their size, location and symptoms. We report a case of a 40-year-old woman who presented with a 2-cm encapsulated cavernous hemangioma in the infratemporal fossa (ITF). Extensive workup included CT, MRI and angiography. A transoral/transpalatine approach avoiding osteotomy was used for surgical excision. After an unremarkable postoperative course the patient has remained disease-free after a 2-year follow-up period. We suggest this surgical approach as an alternative in carefully selected cases of circumscribed small, benign lesions of the ITF.

Cell death by apoptosis is a major determinant of growth of normal tissues and tumours. The present study aimed to elucidate signal factors involved in its regulation. Epithelial cells in control liver, during regression of cyproterone acetate induced liver hyperplasia, in liver (pre)neoplasia and in uterus undergoing apoptosis in vivo show immunostaining for transforming growth factor beta 1 (TGF-beta 1) as detected by anti-pre(266-278) TGF-beta 1 antibodies. Positive immunostaining is also seen in a few intact cells of hyperplastic, regressing liver apparently preparing for apoptosis, but is virtually not found in hepatocytes of normal or growing liver nor in cells undergoing death by necrosis. Recombinant latency associated protein (rLAP, dimer of the pro-region non-covalently associated with the mature region) complex and mature TGF-beta 1 induce apoptosis in isolated hepatocytes cultured in vitro. These findings suggest an involvement of TGF-beta 1 in the induction of apoptosis in certain epithelia in vivo.

Parenchymal liver cells were isolated from human liver pieces of surgical waste as well as from rat livers. DNA synthetic activity was measured after different times in primary culture by [3H]thymidine incorporation and autoradiography. Labeling of control cultures of human hepatocytes at densities between 8,000 and 15,000 cells/cm2 was very low (0.4 to 1.3%). Human recombinant epidermal growth factor increased labeling 2- to 4-fold (P less than 0.01). Treatment with known inducers of liver growth in rats, namely, cyproterone acetate, alpha-hexachlorocyclohexane, nafenopin, phenobarbital, and rifampicin did not increase the number of labeled human liver cells. In some of the experiments, a 24-h exposure to the chemicals of rat or human hepatocytes was followed by a 24-h treatment with epidermal growth factor (EGF). In rat hepatocytes, incorporation rates were significantly increased. Cyproterone acetate and EGF acted in an additive manner, alpha-hexachlorocyclohexane and EGF were clearly overadditive, and phenobarbital had little effect. In human hepatocytes, little alteration in labeling indices was found; in some cases labeling was, rather, found to be lower than in cultures treated with EGF alone. These results show that human hepatocytes cultured in vitro are sensitive to stimulation of DNA synthesis by EGF; they differ from rat hepatocytes in their response to some drugs which show liver growth-promoting activity in rodents.