Influence of cigarette smoking on the level of mRNA of somatostatin receptor 3 (SSTR3) in the gastric mucosa of patients with functional dyspepsia.

PURPOSE: Helicobacter pylori (H. pylori) infection and smoking of cigarettes increase individual risk to gastric carcinoma. In stomach tumors, an expression of somatostatin receptor 3 (SSTR3) is diminished or completely lost. The purpose of these studies was to determine the influence of smoking cigarettes and H. pylori infection on the expression of SSTR3 in patients with functional dyspepsia. MATERIALS AND METHODS: The study comprised 109 patients with functional dyspepsia in the age range 28-61 years. The total 218 biopsies used for analysis were divided into two groups: group I - 176 biopsies from non-smokers (72 from H. pylori positive ones), and group II - 42 biopsies from cigarette smokers (28 from H. pylori positive patients). The SSTR3 mRNA amount in the gastric mucosa (1 biopsy from the antrum and 1 biopsy from the corpus) was determined by real time RT-PCR. The presence of H. pylori colonization in the stomach tissue was evaluated by multiplex PCR. RESULTS: In the H. pylori negative samples the amount of the SSTR3 mRNA was significantly lower for smokers than for non-smokers (by 40%, p < 0.010). Infection with H. pylori caused reduction of the level of SSTR3 mRNA in non-smoking patients by ca. 30% (p < 0.01), while in samples from smokers the SSTR3 mRNA level was similar regardless of H. pylori infection. CONCLUSIONS: The cigarettes smoking and H. pylori infection are independent factors leading to decreasing of the SSTR3 mRNA level in gastric mucosa of patients with functional dyspepsia.

NT-3 modulates BDNF and proBDNF levels in naïve and kindled rat hippocampus.

Both mature and precursor forms of neurotrophins regulate nerve development, survival and plasticity. Brain-derived neurotrophic factor (BDNF) synthesis and secretion in turn are regulated by neuronal activity, such as epilepsy. Further, neurotrophins themselves are regulated by neurotrophin levels. Neurotrophin-3 (NT-3) and BDNF in particular can be co-expressed and each can regulate the levels of the other. This regulation is thought to be mediated through receptor tyrosine kinase (Trk) activity. It is not known whether this neurotrophin-neurotrophin interaction occurs in hippocampal tissue in vivo, or how it is influenced by neuronal activation. In this study, we explored the reciprocal influences of intraventricular infusions of NT-3 and BDNF in naïve and kindled hippocampi of rats using Western blotting. We confirm that hippocampal kindling resulted in a significant increase in levels of BDNF both in cytochrome C (control) infused and NT-3 infused kindled rats. However, NT-3 infusion significantly reduced BDNF levels in both kindled and non-kindled hippocampi compared to their cytochrome C infused counterparts. These results are consistent with our earlier studies demonstrating lowered levels of TrkA and TrkC (NGF modulates BDNF levels via TrkA) following chronic NT-3 infusion. Although kindling led to an increase in BDNF, this was not accompanied by any detectable change in the levels of proBDNF. However, there was a significant increase in proBDNF following NT-3 infusions, suggesting NT-3 may reduce proBDNF processing. In contrast, neither NT-3 nor proNT-3 levels were affected by kindling or chronic BDNF infusions, consistent with down-regulation of TrkB by chronic BDNF infusion. Thus, modulation of BDNF by NT-3, likely mediated by Trk receptors, occurs in naïve and kindled adult rat hippocampus.

The effects of brain-derived neurotrophic factor (BDNF) administration on kindling induction, Trk expression and seizure-related morphological changes.

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that mediates synaptic plasticity and excitability in the CNS. Recent evidence has shown that increased BDNF levels can lead to hyperexcitability and epileptiform activities, while suppression of BDNF function in transgenic mice or by antagonist administration retards the development of seizures. However, several groups, including our own, have reported that increasing BDNF levels by continuous intrahippocampal infusion inhibits epileptogenesis. It is possible that the continuous administration of BDNF produces a down-regulation of its high-affinity TrkB receptor, leading to a decrease of neuronal responsiveness to BDNF. If so, then animals should respond differently to bolus injections of BDNF, which presumably do not alter Trk expression, compared with continuous infusion. To test this hypothesis, we compared the effects of intrahippocampal BDNF continuous infusion and bolus injections on kindling induction. We showed that continuous infusion of BDNF inhibited the development of behavioral seizures and decreased the level of phosphorylated Trks or TrkB receptors. In contrast, multiple bolus microinjections of BDNF accelerated kindling development and did not affect the level of phosphorylated Trks or TrkB receptors. Our results indicate that different administration protocols yield opposite effects of BDNF on neuronal excitability, epileptogenesis and Trk expression. Unlike nerve growth factor and neurotrophin-3, which affect mossy fiber sprouting, we found that BDNF administration had no effect on the mossy fiber system in naive or kindled rats. Such results suggest that the effects of BDNF on epileptogenesis are not modulated by its effect on sprouting, but rather by its effects on excitability.

Continuous infusion of neurotrophin-3 triggers sprouting, decreases the levels of TrkA and TrkC, and inhibits epileptogenesis and activity-dependent axonal growth in adult rats.

Neurotrophin-3 (NT-3), a member of the neurotrophin family of neurotrophic factors, is important for cell survival, axonal growth and neuronal plasticity. Epileptiform activation can regulate the expression of neurotrophins, and increases or decreases in neurotrophins can affect both epileptogenesis and seizure-related axonal growth. Interestingly, the expression of nerve growth factor and brain-derived neurotrophic factor is rapidly up-regulated following seizures, while NT-3 mRNA remains unchanged or undergoes a delayed down-regulation, suggesting that NT-3 might have a different function in epileptogenesis. In the present study, we demonstrate that continuous intraventricular infusion of NT-3 in the absence of kindling triggers mossy fiber sprouting in the inner molecular layer of the dentate gyrus and the stratum oriens of the CA3 region. Furthermore, despite this NT-3-related sprouting effect, continuous infusion of NT-3 retards the development of behavioral seizures and inhibits kindling-induced mossy fiber sprouting in the inner molecular layer of the dentate gyrus. We also show that prolonged infusion of NT-3 leads to a decrease in kindling-induced Trk phosphorylation and a down-regulation of the high-affinity Trk receptors, TrkA and TrkC, suggesting an involvement of both cholinergic nerve growth factor receptors and hippocampal NT-3 receptors in these effects. Our results demonstrate an important inhibitory role for NT-3 in seizure development and seizure-related synaptic reorganization.

[Vascular endothelial growth factor (VEGF) and its role in neoplastic processes]. / Naczyniowo-sródblonkowy czynnik wzrostu (VEGF) i jego rola w procesie nowotworowym.

This review concerns structural and functional properties of human vascular endothelial growth factor as well as the process of alternative splicing of its transcript. Regulation of VEGF gene transcription and participation of the protein in the angiogenesis of tumours are also broadly discussed.

Quantitative RT-PCR assay for mRNA of VEGF and histone H4 in the determination of proliferative and angiogenic activity in vulvar pathology.

Proliferative and angiogenic activity of tissue specimens taken from women with various vulvar pathologies were evaluated by determining the number of mRNA VEGF molecules and H4 histone mRNA molecules, by means of the QRT-PCR (TaqMan) technique. Following a cluster analysis the results, where normalised. Euclidean distances were used, all the cases were classified into three groups of pathologies. Group I included low degree vulvar pathologies, group II included high degree vulvar pathologies and group III included vulvar pathologies with high proliferative and angiogenic activity. Significant differences were found in the proliferative and angiogenic activity between groups I and III, and between groups II and III, while no statistically significant differences were found between groups I and II.

[Expression of VEGF, KDR, p53, E6 HPV16 and HPV18 in vulvar and cervix cancer]. / Ekspresja genów angiogenezy--VEGF i jego receptora KDR, genu supresorowego P53 oraz E6 HPV16 i HPV18 w raku sromu i szyjki macicy.

The aim of the study was a comparison of expression of angiogenesis genes: vascular endothelial growth factor (VEGF), KDR, suppressor gene p53, E6-HPV16 and HPV18, in tissue samples of normal, dystrophic, lymph nodes and malignant cancers of vulva and uterine cervix. The results demonstrate that molecular diagnostics of cancers using gene expression profiling indicates the definitive difference in expression profiles of aforementioned genes in tissues of the same malignancy.

[Profiles of expression of genes coding kininogen and kinin receptors as a marker of tissue pathology in cervical cancer coexisting with HPV infection]. / Ekspresja genów receptorów dla kinin i kininogenu w raku szyjki macicy wspólistniejacym z infekcja HPV.

Kinins are peptides involved in inflammatory processes, vascular permeability, proliferation and mitogenesis of tumor cells. The majority of kinins actions are mediated through an interaction with cell surface bradykinin receptors BR1 and BR2. Kinins precursor is kininogen (kng). The changes in proteins are initiated by changes in the expression of genes coding these proteins, thus can be a valuable diagnostic markers of malignant processes including cervical carcinoma. The paper presents an analysis of kininogen-kinins receptor genes expression in women treated surgically because of a carcinoma of uterine cervix. Among the studied women in 5 cases previously brachyHDR therapy was applied. In all studied cases HPV 18 infection and in 2 cases a co-infection HPV 16/18 by use of Consensus Primers MY09, MY 11 and type specific primers for HPV 16, 18 was ascertained. In RNA extracts the number of the mRNA copies for kiningen, BR1 and BR2 was assessed using QRT-PCR Taq Man. The higher expression of BR1 than BR2 was marked in the tissue with cancer cells. In the patients after brachytherapy higher expression of BR2 than BR1 mRNA was found. The higher BR1 expression was also shown in iliac lymph nodes in patients with active neoplastic process, opposite to the patients after brachytherapy in whom higher BR2 expression was ascertained. The lack of expression of kng mRNA was found only in 3 specimens. The high expression of kinin receptors especially BR1 in infiltrating carcinoma margin can be a marker of pathology intensity: proliferative potential of neoplasms cells or chronic inflammatory state in the presence of invasive carcinoma.

Experimental bone marrow alterations following single and multiple high-dose steroids in rabbits.

Nineteen New Zealand white rabbits received one (n = 5), two (n = 5), or three (n = 9) injections of 60 mg methylprednisolone and were sacrificed 10, 20, 30, and 60 days following the last treatment. They were compared to 15 controls for histological examination of femoral and humeral epiphyses and femoral condyles. Treated animals had a significant rise in serum triglycerides (p less than 0.01) 10 days following treatment. 15 treated animals and 6 controls had grade I lesions of bone marrow (p less than 0.05). Lesions of grades II and III were only observed in 5 treated animals. The severity of histological lesions were not correlated with steroid doses. Tetracycline fixation was suppressed in treated rabbits.

[Rheumatoid polyarthritis, Gougerot-Sjögren syndrome and chronic myeloid leukemia. Apropos of 2 cases]. / Polyarthrite rhumatoïde, Syndrome de gougerot-sjögren et leucémie myéloïde chronique. A propos de 2 cas.

Two cases of rheumatoid arthritis with Sjögren's syndrome are reported which developed chronic myelocytic leukemia. The relationships between these illnesses, rheumatoid arthritis and Sjögren's syndrome on the one hand, and a myeloproliferative disorder on the other hand, are discussed, as well as the possible role of the treatment regimens (synoviorthesis with radio-isotopes in case number 1). The possibility that this association came about by pure coincidence can not be excluded due to the exceptional character of these illnesses.

[Treatment of acute myeloid leukemia with a protocol combining intensive induction chemotherapy, early consolidation treatment, splenectomy and long-term maintenance chemotherapy. Preliminary study]. / Traitement des leucémies aiguës myéloïdes par un protocole associant une chimiothérapie d'induction intensive, un traitement précoce de consolidation, une splénectomie et une chimiothérapie de maintien au long cours. Etude préliminaire.

Twenty-seven patients aged from 10 to 60 years (mean 34.4 +/- 13 years) in the first perceptible phase of acute myeloid leukemia were subjected to intensive induction chemotherapy consisting of adriamycin (ADM), vincristin (VCR) and cytosine arabinoside (ARA-C). Twenty-four patients (89%) attained complete remission (CR) after 1 to 3 cycles and were then given an early consolidation treatment with one of the previous cycles. This was followed by long-term continuous maintenance chemotherapy with 6-mercaptopurine (6-MP) and methotrexate (MTX) alternatively and 3-monthly reinforcement courses of donaurubicin (DNR) and VCR. Twenty of these 24 patients were splenectomized soon after the consolidation treatment. None of the spleens were enlarged, and histological sections of the spleens, liver biopsies and mesenteric lymph-nodes stained with routine dyes and by the naphthol AS-D chloroacetate esterase method revealed mature granulocytes but no demonstrable leukaemic cells. In the group of splenectomized patients, the probabilities of staying in complete remission at 27 and 44 months were 70 +/- 12.6% and 52 +/- 18.5% respectively, and the probabilities of remaining alive at 32 and 55 months were 79 +/- 11% and 57 +/- 19% respectively. Age over 40 and evidence of extramedullary infiltration at presentation appeared to leave little hope of disease-free survival. The rationale for the present therapeutic study is discussed.

[Treatment of rectocolic and gastric adenocarcinomas with 5-fluorouracil associated with high doses of folinic acid. Results of an experimental study]. / Traitement des adénocarcinomes recto-coliques et gastriques par le 5-fluorouracile associé a des fortes doses d'acide folinique. Résultats d'une étude pilote.

We report the results of a therapeutic trial in patients with rectocolic and gastric metastatic adenocarcinomas. This trial is based on experimental evidence that an excess of reduced intracellular folic acid increases the cytotoxicity of fluoropyrimidines. The treatment consists of 5-fluorouracile (5-FU) (370 to 400 mg/m2/24 h) and folinic acid in high doses (200 mg/m2: 24 h) given simultaneously for 5 consecutive days; the interval between courses is 21 days. Thirty patients with measurable rectocolic adenocarcinomas were evaluated. They were divided into two groups: 16 patients had had no previous chemotherapy and 14 had not responded to chemotherapy with 5-FU alone or associated with other cytostatic drugs. Response rates were 56% in the first group and 21% in the second. Five patients with measurable gastric adenocarcinomas were also evaluated; none had received previous chemotherapy. A partial response was recorded in three of these patients. Toxicity of the therapeutic regimen was acceptable. Stomatitis was the most common toxic side-effect. In patients with severe adverse side-effects recurrence was efficiently prevented by decreasing the daily dose of 5-FU to 30 mg/m2 during subsequent courses. We conclude that in the tumors studied folinic acid in high doses can improve the antitumoral effect of 5-FU and induce a response to this agent in some rectocolic tumors which were previously resistant.