Bruton's tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination.

Bruton's tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates myeloid cell activation and inflammatory responses. Here we demonstrate efficacy of BTK inhibition in a model of secondary progressive autoimmune demyelination in Biozzi mice with experimental autoimmune encephalomyelitis (EAE). We show that late in the course of disease, EAE severity could not be reduced with a potent relapse inhibitor, FTY720 (fingolimod), indicating that disease was relapse-independent. During this same phase of disease, treatment with a BTK inhibitor reduced both EAE severity and demyelination compared to vehicle treatment. Compared to vehicle treatment, late therapeutic BTK inhibition resulted in fewer spinal cord-infiltrating myeloid cells, with lower expression of CD86, pro-IL-1ß, CD206, and Iba1, and higher expression of Arg1, in both tissue-resident and infiltrating myeloid cells, suggesting a less inflammatory myeloid cell milieu. These changes were accompanied by decreased spinal cord axonal damage. We show similar efficacy with two small molecule inhibitors, including a novel, highly selective, central nervous system-penetrant BTK inhibitor, GB7208. These results suggest that through lymphoid and myeloid cell regulation, BTK inhibition reduced neurodegeneration and disease progression during secondary progressive EAE.

Gender Difference in Distribution of Estrogen and Androgen Receptors in Intestinal-type Gastric Cancer.

BACKGROUND: Gender difference in survival of patients with gastric cancer is not well investigated. The aim of this study was to analyze the gender-related distribution of estrogen receptor alpha (ERα) and androgen receptor (AR) in the epithelium and stroma of intestinal-type gastric cancer. MATERIALS AND METHODS: Immunohistochemical analysis was performed in 60 patients (42% females). RESULTS: In gastric cancer patients, frequency of ERα-positive cells was lower in epithelium than in healthy individuals, but not significantly. In stroma and epithelium, AR-positive cells were absent from samples of women with T1 and T2 stage disease, while in men, their frequency was significantly increased in stroma of those with T3 and T4 stages and was significantly higher compared to women. AR-positive cells in stroma were fibroblasts, myofibroblasts and mast cells. CONCLUSION: To our knowledge, this study is the first to show gender differences in the distribution and frequency of AR-positive cells in neoplastic stroma of gastric cancer.

Successful Treatment of Autoimmune Pulmonary Alveolar Proteinosis in a Pediatric Patient.

BACKGROUND Pulmonary alveolar proteinosis (PAP) is a rare condition characterized by the intra-alveolar accumulation of surfactant-derived material, which impairs gas exchange and results in respiratory insufficiency. Two major subtypes of PAP are autoimmune and non-autoimmune PAP. The diagnosis relies on clinical presentation, ground glass opacities on CT scan, bronchoscopy with PAS stain of BAL fluid (BALF), lung biopsy with PAS-positive material in the alveoli, and the presence of anti GM-CSF antibodies in serum or BALF for an autoimmune subtype. The therapeutic approach to pediatric cases varies according to age and the general clinical state of the child; however, whole lung lavage (WLL) and inhaled or subcutaneous GM-CSF are generally first-line therapy. CASE REPORT We report a unique case of an autoimmune type of PAP in a 12-year-old boy, who underwent successful bilateral lung transplantation after inefficacious treatment with GM-CSF, and who developed post-transplant lymphoproliferative disease (PTLD) and was successfully treated with a chemotherapeutic protocol. CONCLUSIONS Although lung transplantation is a rarely used therapeutic approach for patients with an autoimmune subtype of PAP, in cases of inefficacious treatment with other modalities, lung transplantation should be considered.

Relative potencies of three glucocorticoids to induce hypoplasia of the physis and concomitant biochemical alterations in the rat.

Although inhaled glucocorticoids are known to have systemic effects on bone metabolism, there is little comparative information on their relative potencies. The effects of three standard glucocorticoids in causing changes in bone metabolism and growth, therefore, were investigated in relation to other systemic effects in the rat. Given to male Sprague-Dawley rats, 4.5-5.5 weeks old, subcutaneously (s.c.), at doses of 0.3-10 mg/kg daily for 7 days, beclomethasone dipropionate, prednisolone and ciclesonide all dose-dependently inhibited thymus body mass index (BMI) (by 57%, 44% and 76% at 3 mg/kg). Ciclesonide, potently and prednisolone, less effectively, also repressed femoral bone growth (by 41% and 18% at 10 mg/kg), significantly reducing body weight gain (both by 100% at 10 mg/kg), and serum concentrations of acid phosphatase (ACP) and tartarate resistant acid phosphatase (TRACP) (by >30% at 10 mg/kg); both increased serum glucose and triglycerides levels. Serum alkaline phosphatase (ALP) was not affected. Beclomethasone dipropionate had little or no effect on these additional variables. In conclusion, ciclesonide showed pronounced bone growth inhibiting activity after s.c. administration to the rat while other two glucocorticoids showed differences in activity on bone metabolism. However, this model is sufficiently sensitive and specific for testing the effect of glucocorticoids on bone metabolism.

Estrogen and androgen receptors in inflammatory fibroid polyp (Vanek's tumor): case report.

BACKGROUND/AIM: Vanek's tumor is an inflammatory fibroid polyp (IFP) of very low incidence, which originates in the submucosa of the stomach, duodenum, jejunum and ileum. The etiology of this tumor is still unknown. Histologically, IFP is characterized by submucosal spindle cell proliferation in fibromyxoid stroma with inflammatory infiltrate. The aim of the present study was to investigate the presence of estrogen and androgen receptors in IFP and compare it with its proliferative loci. PATIENTS AND METHODS: The study analyzed a 79-year-old patient suffering from IFP. Analyses were performed by immunohistochemistry. RESULTS: Androgen-positive spindle cells were detected at the periphery of onion skin-like formations. Estrogen receptor-positive cells were not detected and Ki67 showed low proliferative activity. CONCLUSION: This case report shows for the first time the presence of androgen receptor-positive cells whose location corresponds with the distribution of Ki67-positive cells in IFP.

Environmental exposure to xenoestrogens and oestrogen related cancers: reproductive system, breast, lung, kidney, pancreas, and brain.

The role of steroids in carcinogenesis has become a major concern in environmental protection, biomonitoring, and clinical research. Although historically oestrogen has been related to development of reproductive system, research over the last decade has confirmed its crucial role in the development and homeostasis of other organ systems. As a number of anthropogenic agents are xenoestrogens, environmental health research has focused on oestrogen receptor level disturbances and of aromatase polymorphisms. Oestrogen and xenoestrogens mediate critical points in carcinogenesis by binding to oestrogen receptors, whose distribution is age-, gender-, and tissue-specific. This review brings data about cancer types whose eatiology may be found in environmental exposure to xenoestrogens. Cancer types that have been well documented in literature to be related with environmental exposure include the reproductive system, breast, lung, kidney, pancreas, and brain. The results of our data mining show (a) a significant correlation between exposure to xenoestrogens and increased, gender-related, cancer risk and (b) a need to re-evaluate agents so far defined as endocrine disruptors, as they are also key molecules in carcinogenesis. This revision may be used to further research of cancer aetiology and to improvement of related legislation. Investigation of cancers caused by xenoestrogens may elucidate yet unknown mechanisms also valuable for oncology and the development of new therapies.

Cancer risk and the complexity of the interactions between environmental and host factors: HENVINET interactive diagrams as simple tools for exploring and understanding the scientific evidence.

BACKGROUND: Development of graphical/visual presentations of cancer etiology caused by environmental stressors is a process that requires combining the complex biological interactions between xenobiotics in living and occupational environment with genes (gene-environment interaction) and genomic and non-genomic based disease specific mechanisms in living organisms. Traditionally, presentation of causal relationships includes the statistical association between exposure to one xenobiotic and the disease corrected for the effect of potential confounders. METHODS: Within the FP6 project HENVINET, we aimed at considering together all known agents and mechanisms involved in development of selected cancer types. Selection of cancer types for causal diagrams was based on the corpus of available data and reported relative risk (RR). In constructing causal diagrams the complexity of the interactions between xenobiotics was considered a priority in the interpretation of cancer risk. Additionally, gene-environment interactions were incorporated such as polymorphisms in genes for repair and for phase I and II enzymes involved in metabolism of xenobiotics and their elimination. Information on possible age or gender susceptibility is also included. Diagrams are user friendly thanks to multistep access to information packages and the possibility of referring to related literature and a glossary of terms. Diagrams cover both chemical and physical agents (ionizing and non-ionizing radiation) and provide basic information on the strength of the association between type of exposure and cancer risk reported by human studies and supported by mechanistic studies. Causal diagrams developed within HENVINET project represent a valuable source of information for professionals working in the field of environmental health and epidemiology, and as educational material for students. INTRODUCTION: Cancer risk results from a complex interaction of environmental exposures with inherited gene polymorphisms, genetic burden collected during development and non genomic capacity of response to environmental insults. In order to adopt effective preventive measures and the associated regulatory actions, a comprehensive investigation of cancer etiology is crucial. Variations and fluctuations of cancer incidence in human populations do not necessarily reflect environmental pollution policies or population distribution of polymorphisms of genes known to be associated with increased cancer risk. Tools which may be used in such a comprehensive research, including molecular biology applied to field studies, require a methodological shift from the reductionism that has been used until recently as a basic axiom in interpretation of data. The complexity of the interactions between cells, genes and the environment, i.e. the resonance of the living matter with the environment, can be synthesized by systems biology. Within the HENVINET project such philosophy was followed in order to develop interactive causal diagrams for the investigation of cancers with possible etiology in environmental exposure. RESULTS: Causal diagrams represent integrated knowledge and seed tool for their future development and development of similar diagrams for other environmentally related diseases such as asthma or sterility. In this paper development and application of causal diagrams for cancer are presented and discussed.

Claudin-3 and Clara cell 10 kDa protein as early signals of cigarette smoke-induced epithelial injury along alveolar ducts.

Smoking-associated chronic obstructive pulmonary disease is characterized by inflammation, changes affecting small airways, and development of emphysema. Various short- and long-term models have been introduced to investigate these processes. The aim of the present study was to identify markers of early epithelial injury/adaptation in a short-term animal model of cigarette smoke exposure. Initially, male BALB/c mice were exposed to smoke from one to five cigarettes and lung changes were assessed 4 and 24 hr after smoking cessation. Subsequently, animals were exposed to smoke from five cigarettes for 2 consecutive days and lungs investigated daily until the seventh postexposure day. Lung homogenates cytokines were determined, bronchioloalveolar fluid cells were counted, and lung tissue was analyzed by immunohistochemistry. Exposure to smoke from a single cigarette induced slight pulmonary neutrophilia. Smoke from two cigarettes additionally induced de novo expression of tight junction protein, claudin-3, by alveolar duct (AD) epithelial cells. Further increases in smoke exposure induced epithelial changes in airway progenitor regions. During the recovery period, the severity/frequency of epithelial reactions slowly decreased, coinciding with the switch from acute to a chronic inflammatory reaction. Claudin-3 and Clara cell 10 kDa protein were identified as possible markers of early tobacco smoke-induced epithelial injury along ADs.

Lung cancer and environmental chemical exposure: a review of our current state of knowledge with reference to the role of hormones and hormone receptors as an increased risk factor for developing lung cancer in man.

Lung cancer is a dominant cause of cancer mortality. The etiology of lung cancer is mainly related to cigarette smoking, airborne genotoxic carcinogens, and arsenic, but its sex-specific incidence suggests that other mechanisms, such as hormones, may also be involved in the process of carcinogenesis. A number of agents commonly present in the living environment can have dual biological effects: not only are they genotoxic / carcinogenic, but they are also hormonally active as xenoestrogens. This dualism may explain sex-specific differences reported in both types and incidence of lung cancer. In a novel approach to investigate the complexity of lung cancer, etiology, including systems biology, will be used as a tool for a simultaneous interpretation of measurable environmental and biological parameters. Using this approach, the etiology of human lung cancer can be more thoroughly investigated using the available data from oncology and environmental health. The information gained could be applied in the introduction of preventive measures, in personalized medicine, and in more relevant legislation, which should be adjusted to reflect the current knowledge on the complex environmental interactions underlying this life-threatening disease.

[Apoptosis in toxicologic pathology]. / Apoptoza u toksikoloskoj patologiji.

Toxicologic pathology provides expertise to the interpretation of the toxicity and safety of pharmaceuticals, biological agents, human and animal food aditives, environmental and industrial chemicals, and medical devices in animal studies. The histopathology findings are integrated with other study data (clinical and biochemistry data, autopsy) providing a comprehensive report on efficacy and safety of a chemical, device or material and the relationship of toxicity to exposure. Since its discovery, apoptosis emerged as a molecular control point in the regulation of physiological processes, toxic insults and diseases by means of a programmed cell death. Numerous factors include chemicals, oxidative stress, anoxia, and irradiation. Suppression, overexpression or mutation of a number of genes which orchestrate the apoptotic process are associated with disease. Also, the disbalance in apoptosis processes is documented in viral, autoimmune and neurodegenerative diseases, as well as in tumors. Research in the pharmacologic industry is driven toward developing new drugs for treatment schedules for these and other diseases. Toxicologic pathology findings of apoptosis should assist regulatory agencies in understanding the potential hazard or benefit of the tested substance (is the finding of apoptosis normal variation, spontaneous event or provoked by tested drug). Since the great majority of initial histopathological examinations made on toxicity studies and animal disease models are done on routine hematoxylin and eosin-stained slides, the morphology alone is sufficient for accurate and adequate identification of apoptosis.

Clarithromycin suppresses airway hyperresponsiveness and inflammation in mouse models of asthma.

Macrolide antibiotics, a class of potent antimicrobials, also possess immunomodulatory/anti-inflammatory properties. These properties are considered fundamental for the efficacy of macrolide antibiotics in the treatment of diffuse panbronchiolitis and cystic fibrosis. In patients with asthma, macrolide antibiotics have been reported to reduce airway hyperresponsiveness and improve pulmonary function. However, their beneficial actions in asthmatics possibly could be attributed to antimicrobial activity against atypical pathogens (e.g. Chlamydia pneumoniae), corticosteroid-sparing effect (inhibition of exogenous corticosteroid metabolism), and/or their anti-inflammatory/immunomodulatory effects. In order to investigate whether efficacy of macrolide antibiotics in asthma results from their immunomodulatory/anti-inflammatory activity, the influence of clarithromycin pretreatment (2 h before challenge) was examined on ovalbumin-induced airway hyperresponsiveness and airway inflammation in the mouse. Clarithromycin treatment (200 mg/kg intraperitoneally) decreased IL-4, IL-5, IL-13, CXCL2 and CCL2 concentrations in bronchoalveolar lavage fluid and markedly reduced inflammatory cell accumulation in bronchoalveolar lavage fluid and into the lungs, as revealed by histopathological examination. Furthermore, clarithromycin-induced reduction in inflammation was accompanied by normalization of airway hyperresponsiveness. In summary, in ovalbumin-induced mouse models, clarithromycin efficiently inhibited two important pathological characteristics of asthma, airway hyperresponsiveness and inflammation. These data suggest that the efficacy of clarithromycin, as well as of other macrolide antibiotics, in asthmatic patients could be attributed to their anti-inflammatory/immunomodulatory properties, and not only to their antimicrobial activity or exogenous corticosteroid-sparing effects.

Intranasal challenge with increasing ovalbumin doses differently affects airway hyperresponsiveness and inflammatory cell accumulation in mouse model of asthma.

OBJECTIVE: To investigate whether challenge with increasing allergen doses could differently affect allergen-induced airway hyperresponsiveness (AHR) and inflammatory cell accumulation in mouse model of asthma, providing an experimental model to investigate their relationship. MATERIAL AND METHODS: AHR and accumulation of inflammatory cells in bronchoalveolar lavage fluid (BALF) and into the lungs were compared in ovalbumin-sensitized mice that were challenged intranasally with 2.5, 10, 25 or 100 microg of ovalbumin/mouse. RESULTS: Both AHR and inflammatory cell accumulation were proportional to the ovalbumin dose used for challenge. However, in group challenged with 10 microg of ovalbumin airway inflammation was present, although allergen-induced AHR was not detected. Additional analysis indicated that neither mucous hyperproduction nor eosinophil degranulation could be correlated to presence of AHR in this model, whereas concentration of interleukin (IL)-13 in BALF was increased only in those groups in which AHR was present. CONCLUSIONS: Altogether, intranasal challenge of mice with increasing allergen doses could serve as a suitable experimental system for investigation of mechanisms by which airway inflammation leads to allergen-induced AHR. Our initial findings are in line with previous reports that dissociate AHR from amount of eosinophil accumulation and imply the role of IL-13 in this process.

Developmental and transplacental genotoxicology: fluconazole.

Over the last 40 years mankind has been facing new types of radiochemical environmental settings with every decade. During the last decade, biomonitoring was additionally focused on assessing associations between environmental exposure(s) and both early and late biological effects in children. Despite efforts to control and avoid child exposure to genotoxic agents the incidence of childhood cancers is increasing. Some cancers in adulthood may be the consequence of a multi-step process which starts with intrauterine and childhood exposure. This highlights the importance of a comprehensive interpretation of multiple health effects, especially considering recent studies suggesting that most health disorders are related to DNA changes. When exposed to genotoxic agents, a developing organism (fetus or child) is constantly being forced to reorganize into new equilibriums in order to adjust to a xenobiotic environment. In addition, the influence of sex hormones on radiochemical sensitivity is still unknown. For this reason special attention should be paid to puberty. The results of recent studies on animal models and follow up studies on children after nuclear accidents show long-lasting cytogenetic damage even after low dose exposures and their transgenerational persistance. To evaluate age-related difference and transplacental genotoxic potency fluconazole (FC) was investigated by in vivo micronucleus (MN) assay in adult mice, young mice and in transplacentally exposed newborn pups. Compared to the baseline values, FC caused no detectable genome damage in adult animals, but there was a significant increase in MN frequency in young animals and in newborn pups. Our study thus exemplifies an age-related chemosensitivity, and argues that cancer-promoting disturbances of complex prenatal developmental mechanisms and maturation during childhood require a new approach using systems biology.

Local IgE and inflammation in chronic rhinosinusitis of asthmatics and non-asthmatics.

The aim of the study was to show the difference in the pattern of inflammation, and Th1/Th2 polarization between asthmatic and non-asthmatic patients with CRS, specifically eosinophil activation, local IgE levels in the sinus fluid and tissue, and the severity of inflammation were measured. The maxillary sinus lavages, mucosal biopsies and bacteriological swabs were taken in 17 asthmatic and 36 non-asthmatic adult patients with CRS. The concentrations of IgE, eosinophil cationic protein (ECP), myeloperoxidase (MPO), and tryptase were analyzed and IgE+ cells, eosinophils, lymphocytes and plasma cells were counted. The granulocyte activation markers and IgE in sinus lavages, and the inflammatory and IgE+ cells counts were significantly higher in the asthmatics with the greatest difference in ECP and IgE concentrations. The tryptase concentrations did not differ, but only in the asthmatics they correlated significantly with the IgE concentrations and IgE+ cells count. Asthmatic patients present a distinct subgroup among the patients with chronic rhinosinusitis (CRS). The levels of the cellular markers and IgE in the sinus fluid differ from those of non-asthmatic patients with CRS. The activation of granulocytes (especially eosinophils), local IgE concentrations and the inflammatory cells infiltration are significantly higher in the asthmatics.

Influence of Helicobacter pylori infection persistence on bcl-2 expression in gastric mucosa inflammatory cells.

Chronic Helicobacter (H.) pylori infection is an etiological factor related to gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The expression of bcl-2 protein significantly decreases as the grade of MALT lymphoma advances. The aim of this study was to evaluate bcl-2 expression in inflammatory cells in lamina propria in gastric biopsy samples collected from two groups of patients with chronic gastritis divided on the basis of the success or failure of H. pylori eradication. Sixty-five patients with chronic gastritis were divided into two groups of 45 and 20 patients according to their therapeutic response. The gastric mucosa samples were analyzed histologically in both groups of patients before and after standard therapy (for eradicated, after one therapeutic cycle; and for non-eradicated, after three therapeutic cycles) for H. pylori density, urease activity and bcl-2 expression. In the eradicated group of patients, H. pylori eradication was accompanied by significantly lower grades of bacterial colonization and lower urease activity in the corpus and antrum. Bcl-2 expression in inflammatory cells showed no statistically significant changes in either patient group at either location. There was no between-group difference in bcl-2 expression either. In conclusion, persistent long-lasting H. pylori infection is associated with higher grades of bacterial colonization and higher urease activity but not with bcl-2 expression in inflammatory cells.

Influence of H. pylori infection and eradication on p53, c-erbB-2 and Ki-67 in gastric mucosa.

BACKGROUND/AIMS: To evaluate the expression of antigens c-erbB-2, p53, and Ki-67 in gastric biopsy, bacteria density and urease activity in two groups of patients with chronic gastritis separated on the basis of the success or failure of H. pylori eradication. METHODOLOGY: Sixty-five patients with chronic gastritis were split in two groups (n=45/20) related to response to the therapy. The gastric mucosa samples (Sydney system) were analyzed histologically in both groups of patients before and after standard therapy (for eradicated, E group after one cycle; for non-eradicated, NE group after three cycles) for H. pylori infection, urease activity, c-erbB-2, p53 and Ki-67 expression. Sera samples taken before and after treatment were also analyzed for specific antibody against H. pylori. RESULTS: The eradication of H. pylori in patients of the E group was accompanied with significant lower colonization grades of bacteria, urease activity, proliferating rate, p53, and Ki-67 expression while c-erbB-2 expression was unchanged. In the NE group, all parameters were the same before and after therapy with exception of p53, which was slightly higher on both locations. Strong expression of c-erbB-2 in corpus of the NE group was determinate. Serum activity of specific antibodies against H. pylori was lower after the therapy in both groups of patients, but in the eradicated group this change was much stronger that in the non-eradicated. CONCLUSIONS: Long persisting infection is related with higher colonization grades of bacteria, urease activity, p53, c-erbB-2 and Ki-67 expression. Changes of those markers are connected with duration of infection and location where these changes were obtained.

Anti-inflammatory activity of azithromycin attenuates the effects of lipopolysaccharide administration in mice.

Macrolide antibacterials inhibit the production of various cytokines and the migration of inflammatory cells. These anti-inflammatory actions of macrolides may be beneficial in attenuating inflammatory processes involved in bacterial sepsis. Therefore, we investigated the ability of azithromycin to attenuate the deleterious effects of lipopolysaccharide (LPS), in three different LPS-induced inflammatory models. Our results show that azithromycin (10 and 100 mg/kg) significantly attenuated the intraperitoneal LPS-induced increase in plasma TNF-alpha concentration. It also increased survival rate in a septic shock model in mice challenged with intravenous LPS. Oral treatment with azithromycin (up to 300 mg/kg) was less effective in suppressing neutrophil infiltration into the lungs 24 h after intranasal LPS challenge, possibly because of a slower onset of action or inadequate dosing. In the same model, azithromycin given intraperitoneally significantly improved inflammatory markers (total cell number, neutrophil percentage and MIP-2 concentration) in bronchoalveolar lavage fluid. In conclusion, azithromycin exhibits significant anti-inflammatory properties but the potency of such effects varies depending on the experimental model and route of administration.

Comparison of genomic damage caused by 5-nitrofurantoin in young and adult mice using the in vivo micronucleus assay.

The antibiotic 5-nitrofurantoin (5-NF) has been used widely for the treatment of urosepsis in children during the last 20 years. Recent experimentation suggests the need for reevaluating its genotoxic potential. Because of possible differences in the metabolism and clearance of 5-NF in young and adult animals, we conducted a study to determine whether micronuclei caused by 5-NF were age-related. The in vivo micronucleus (MN) assay was performed on 3- and 8-week-old mice given single intraperitoneal injections of 5, 10, and 50 mg/kg 5-NF. Blood samples from the tail vein were taken before injection (baseline) and at 48, 96, 168, and 336 hr (2 weeks) after the treatment. One thousand reticulocytes were analyzed for micronuclei from each animal. Compared to similar baseline values for young and adult mice, 5-NF caused a significant increase in MN frequency in both age groups. The mean MN frequency in the young animals was higher than in the adult animals for each dose and sampling time. MN frequencies remained significantly elevated in young animals even 2 weeks after exposure to 5-NF. The results of the study confirm the genotoxic potential of 5-NF in young and adult animals, and indicate that young animals are more sensitive to the genotoxic effects of 5-NF than adult mice and that the response in young mice persists for a significantly longer time. These findings may be related to poorly developed mechanisms of xenobiotic detoxification and renal elimination in young animals.

Basaloid squamous cell carcinoma of the esophagus: a case report.

Basaloid squamous cell carcinoma (BSCC) of the esophagus is an extremely rare tumor which should be differentiated from adenoid cystic and small cell undifferentiated carcinoma. We present the case of a 48-year-old male patient with esophageal BSCC. This tumor has specific histological features which may be difficult to recognize by small endoscopic biopsy examination. In our patient the surgical specimen revealed BSCC with an aggressive pattern (invasion of the whole esophageal wall thickness, lymph node metastases and intraneural spread). We proposed chemotherapy and radiotherapy after surgery, which resulted in a survival of 17 months.

Ochratoxin A-induced apoptosis in rat kidney tissue.

The aim of our study was to find whether ochratoxin A (OTA) induces the apoptosis and/or necrosis of kidney tissue in rats. In the first experiment, the highest number of apoptotic cells was found in rats sacrificed one day after OTA administration (1.00 mg/kg b.w., i.p.). The number of apoptotic cells reduced gradually and they were not seen nine days after OTA administration. A possible dose-dependence of histological changes was checked in kidney tissue of rats given 0.25, 0.50 or 1.00 mg of OTA/kg b.w., i.p. three times a week for four weeks. The number of apoptotic cells showed a clear dose-dependence, but necrosis was absent even at the highest doses. The time-dependent appearance of lesions related to OTA administration was checked by administering 0.50 mg OTA/kg body weight to rats, and sacrificing them one day after 1, 3, 6, and 9 doses/administrations, or 6 and 21 day after 12 doses/administrations. Long-term administration is associated with continued and increased apoptosis without necrosis, suggestive of OTA's role in the pathogenesis of progressive renal atrophy.