Helicobacter pylori and gastric cancer.
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Helicobacter Infections↗
Biomedical subjects
M Valentini
Publications and source records attributed to M Valentini.
Overweight and hypertension : a 2-way street?
Cross-sectionally, higher weight is associated with higher blood pressure levels; prospectively, baseline weight and weight gain predict higher blood pressure. The loss of weight is frequently associated with a decrease in blood pressure. These findings suggest that weight gain may pathophysiologically contribute to blood pressure elevation. In this review, we present data to indicate that the reverse is also true; persons of equal weight who had higher initial blood pressures gain more weight in the future. We also propose a plausible hypothesis to explain this reverse relationship. Both the blood pressure elevation and the gain of weight may reflect a primary increase in sympathetic tone. It is well known that in a milieu of increased sympathetic tone, the beta-adrenergic responsiveness decreases. Sympathetic overactivity and decreased cardiovascular beta-adrenergic responsiveness have been described in hypertension. beta-Adrenergic receptors mediate increases in energy expenditure. If these metabolic receptors were downregulated in hypertension, the ability of hypertensive patients to dissipate calories would decrease and they would gain more weight. The possible relationship of decreased beta-adrenergic responsiveness to weight in hypertension can be experimentally tested. Such research may contribute to an explanation of why patients with hypertension can rarely lose weight. An understanding of this pathophysiological relationship may open new avenues for therapeutic interventions.
Adult↗
Determination of a redox compensation index and its relationships to glycaemic control in type 2 diabetes mellitus.
The measurement of single parameters of oxidative stress in biological fluids can often give results difficult to interpret as to the real involvement of oxidative processes in a given disease condition. In the present study we propose a novel integrated parameter, called "redox compensation index", obtained by combining the results of two established and convenient procedures, i.e. the Fox-2 assay for plasma lipid hydroperoxides and the ferric reducing/antioxidant power (FRAP) assay for total antioxidant potential of plasma. These procedures were employed for the evaluation of oxidative stress in a group of patients with type 2 diabetes mellitus, a condition in which oxidative processes are implicated in the development of complications. In type 2 diabetic patients, plasma lipid hydroperoxides were directly correlated with levels of glycated hemoglobin. On the other hand, a significant inverse correlation was observed between levels of glycated hemoglobin and redox compensation values. The data reported suggest that the redox compensation index could represent a convenient parameter for the direct appraisal of oxidative status in clinical subjects, and are in support of the proposed role of protein glycation in production of oxidative alterations during type 2 diabetes mellitus.
Aged↗
[The physiopathological aspects of chronic gastritis, Helicobacter pylori and precancerous gastric changes].
Chronic gastritis represents the paradigmatic histological condition by means of which the various clinical displays develop. Among the several etiologic factors, Helicobacter pylori (Hp) certainly represents a determining element for the promotion of such condition. Several morpho-functional evaluations (parietal cells, peptic cells, acid secretion, peptic secretion, gastrinemia) point out how Hp has on the mucosa a mainly direct action, without any substantial modifications of the gastric milieu. Certainly, the bacteria help the bodyfundic atrophic gastritis, but seldom this condition contributes to the modification of the gastric pH in such a relevant way so as to prime the fall of events which lead to the preneoplastic/neoplastic modifications. Metaplastic, dysplastic and neoplastic clones may arise, in the course of Hp infection, even in conditions of normochloridria. Such bacterium behaves as a cofactor of various other damaging or predisposing agents, contributing to modulate the risk by acting on host genetic susceptibility.
Chronic Disease↗
Gastric high-grade dysplasia.
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Anti-Ulcer Agents↗
Redox modulation of cell surface protein thiols in U937 lymphoma cells: the role of gamma-glutamyl transpeptidase-dependent H2O2 production and S-thiolation.
The expression of gamma-glutamyl transpeptidase (GGT), a plasma membrane ectoenzyme involved in the metabolism of extracellular reduced glutathione (GSH), is a marker of neoplastic progression in several experimental models, and occurs in a number of human malignant neoplasms and their metastases. Because it favors the supply of precursors for the synthesis of GSH, GGT expression has been interpreted as a member in cellular antioxidant defense systems. However, thiol metabolites generated at the cell surface during GGT activity can induce prooxidant reactions, leading to production of free radical oxidant species. The present study was designed to characterize the prooxidant reactions occurring during GGT ectoactivity, and their possible effects on the thiol redox status of proteins of the cell surface. Results indicate that: (i) in U937 cells, expressing significant amounts of membrane-bound GGT, GGT-mediated metabolism of GSH is coupled with the extracellular production of hydrogen peroxide; (ii) GGT activity also results in decreased levels of protein thiols at the cell surface; (iii) GGT-dependent decrease in protein thiols is due to sulfhydryl oxidation and protein S-thiolation reactions; and (iv) GGT irreversible inhibition by acivicin is sufficient to produce an increase of protein thiols at the cell surface. Membrane receptors and transcription factors have been shown to possess critical thiols involved in the transduction of proliferative signals. Furthermore, it was suggested that S-thiolation of cellular proteins may represent a mechanism for protection of vulnerable thiols against irreversible damage by prooxidant agents. Thus, the findings reported here provide additional explanations for the envisaged role played by membrane-bound GGT activity in the proliferative attitude of malignant cells and their resistance to prooxidant drugs and radiation therapy.
Fluorescent Dyes↗
Is adjuvant tamoxifen used optimally in the treatment of breast cancer? Results of an Italian survey.
BACKGROUND: Institutional and physician-related factors can influence the way in which physicians interpret research results. The aim of this study was to determine what physicians know about, and their opinions of, hormone treatment in breast cancer patients, and the factors comprising their medical decision-making. MATERIALS AND METHODS: A questionnaire was mailed to a random sample of physicians inquiring as to their preferences with respect to adjuvant tamoxifen, and the usual duration of the treatment applied in various clinical scenarios (according to a woman's menopausal status, the oestrogen receptor status and the stage of disease). RESULTS: Of 500 physicians identified, 38% returned the questionnaire. Of the non-responders, a random sample of 60 physicians was interviewed by phone. The total number of available questionnaires was 250 (50%). About 3/4 of the doctors would prescribe tamoxifen in older ER+ women and 30%-40% in post-menopausal ER-patients, but only 2/5 would do so in younger ER+ women. The vast majority of physicians considered five years as standard for ER+ patients. Nevertheless, about 1/4 of the doctors chose a shorter treatment duration for node-negative, pre-menopausal patients. A minority of physicians used tamoxifen for longer than five years. Older clinicians were less likely to prescribe tamoxifen, particularly for low-risk patients. CONCLUSIONS: According to the data of the recent EBCTG overview, an additional 20,000 lives could be saved worldwide each year if tamoxifen were given to all early breast cancer patients with hormone-sensitive disease, irrespective of age and disease stage, and for a minimum of five years. Our study, involving a representative sample of physicians practicing in Italy, shows that tamoxifen is not used optimally, with a substantial under-use in younger women and women with node-negative disease.
Age Factors↗
Helicobacter pylori, pre-neoplastic changes, gastric cancer: a point of view.
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Cell Division↗
Parental hyperdynamic circulation predicts insulin resistance in offspring: The Tecumseh Offspring Study.
Controversy surrounds the pathogenetic mechanisms of the relationship between hyperdynamic circulation and insulin resistance. Two hundred eight children and young adults (mean age, 17.2+/-3.0 years; range, 11 to 26 years) from the Tecumseh Offspring Study whose parents had been assessed with Doppler echocardiography at the age of 34 years during the previous Tecumseh Blood Pressure Study were considered for this analysis. Offspring data were stratified according to tertiles of parental cardiac index. Parents in the top cardiac index tertile had increased heart rate (P=0.001), stroke volume (P=0.0001), left ventricular fractional shortening (P=0.02), and plasma epinephrine (P=0.02) compared with parents in the other tertiles. Body mass index (BMI) and blood pressure were similar in all groups. Offspring of parents with a high cardiac index had greater BMI (P=0.001), skinfold thickness (P=0.008), and waist/hip ratio (P=0.02), higher diastolic blood pressure (P=0.02) and plasma insulin level (P=0.001), and higher heart rate during Stroop's color test (P=0.02) than offspring of parents with a lower cardiac index. In a multivariate regression analysis, offspring BMI was predicted by parental BMI and cardiac index (P=0.0001 and 0.003, respectively). The mother-child relationship explained most of the cardiac index-BMI association. In summary, parental hyperdynamic circulation was an important predictor of overweight, abnormal fat distribution, increased blood pressure, and hyperinsulinemia in offspring. Our results illustrate the complexity of interaction between a genetic tendency and its phenotypic expression. We speculate that the degree of beta-adrenergic responsiveness may be a major determinant of the phenotypic differences between the parents and offspring found in this study.
Adolescent↗
What is the current role of endoscopic ultrasonography in oesophageal cancer?
Endoscopic ultrasonography is, probably, the most significant progress in gastrointestinal endoscopy of the last few years, and it is on the way to becoming the gold standard for pre-treatment staging of oesophageal carcinoma. Once computed tomography scan has ruled out distant metastases or evident local invasion, endoscopic ultrasonography plays a key role in an adjunctive evaluation and planning of treatment. The diagnostic accuracy of endoscopic ultrasonography in oesophageal cancer is excellent. Its main limitations are: poor differentiation between early mucosal and submucosal cancer, insufficient accuracy in detecting early lymph node invasion, and lack of complete tumour evaluation in cases of high-grade strictures. The role of endoscopic ultrasonography in post-treatment assessment is still limited by some artifacts. However, all these limitations will soon be overcome by some technical improvements.
Algorithms↗
Morphometric prognostic index in breast cancer.
OBJECTIVE: To assess the ability of the morphometric prognostic index (MPI) in predicting clinical outcome in a group of breast cancer patients with short-term follow-up and to assess the relationship between MPI and other prognosticators. STUDY DESIGN: The study group consisted of 63 cases of breast cancer. Follow-up data were available for 48 patients. MPI values were calculated, and degree of nuclear and tubular differentiation was investigated in each tumor. S-phase fraction (SPF), estrogen and progesterone receptors were also studied. RESULTS: The group of patients with MPI values < 0.60 had percent values of disease-free survival significantly higher than did those with MPI values > or = 0.60. Furthermore, significant direct correlations were found between MPI and degree of nuclear atypia and between MPI and SPF. Significant inverse relationships were found between MPI and tumor progesterone receptor levels and between MPI and degree of histologic tubular differentiation. CONCLUSION: The validity of MPI as a prognosticator in breast cancer was confirmed, even in a limited number of patients observed in short-term follow-up. MPI seems to be a reliable and economical prognosticator in selecting breast cancer patients for adjuvant chemotherapy.
Adenocarcinoma↗
Mesalazine foam (Salofalk foam) in the treatment of active distal ulcerative colitis. A comparative trial vs Salofalk enema. The SAF-3 study group.
BACKGROUND: Mesalazine enemas are of well proven efficacy for the topical treatment of distal ulcerative colitis. Although new rectal formulations of mesalazine are not expected to be superior in efficacy and tolerability to standard formulations, they may offer secondary advantages in terms of overall acceptability. AIM: To compare the efficacy, tolerability and overall acceptability of a new mesalazine rectal foam (Salofalk foam) with mesalazine enema in the treatment of active distal ulcerative colitis. PATIENTS AND METHODS: A multicentre study was carried out in patients with active proctitis, proctosigmoiditis and left-sided ulcerative colitis as evaluated by the Clinical Activity Index (CAI > or =4) and Endoscopic Index (EI > or =6). Patients were randomly assigned to receive, in open-label fashion, either mesalazine foam 2 g twice a day or mesalazine enema (2 g/60 ml twice a day) for 3 weeks. Patients who did not achieve remission (defined as CAI <4 and EI <6) after 3 weeks continued the study receiving the alternative galenic formulation for a further 3 weeks. RESULTS: A total of 195 patients were enrolled. Characteristics at baseline were similar except for concomitant therapy with oral 5-ASA products: during the 1st treatment phase, 41% of patients on enema received such treatment vs only 29% of those on foam. Patients with at least one post-treatment efficacy evaluation were included in the intent-to-treat analysis (n=89 foam, n=96 enema). After 3 weeks of treatment, 112 patients were in remission and only 59 patients entered the 2nd treatment phase thus providing data on acceptability. Remission was achieved after 3 weeks in 54% of patients treated with foam and in 67% of those treated with enema. The 90% confidence interval for the difference in remission rates was 0 to 24 and thus within the clinically acceptable range of therapeutic equivalence. At the end of the 2nd phase, 70% of patients switched to foam were in remission vs 65% to the enema. Two patients discontinued treatment with foam prematurely due to anal burning. No clinically important changes were seen in the laboratory tests. CONCLUSIONS: Salofalk foam and enema are equally effective for the treatment of proctitis, proctosigmoiditis and left-sided ulcerative colitis. The new foam preparation is as well tolerated and accepted as enemas and can be used as a therapeutic alternative to conventional mesalazine enema formulations.
Administration, Topical↗
S-phase fraction can predict event free survival in patients with pT2-T3N0M0 colorectal carcinoma: implications for adjuvant chemotherapy.
BACKGROUND: Adjuvant chemotherapy for colorectal carcinoma was found to improve survival of patients with American Joint Committee on Cancer/International Union Against Cancer Stage III disease. The usefulness of chemotherapy in patients with Stage II disease continues to be debated, and it is likely that only those patients with a poor prognosis should receive adjuvant chemotherapy. Biologic prognostic factors may allow further insight into the optimal treatment strategy for patients with Stage II or earlier disease. In this study the prognostic role of S-phase fraction (SPF) determined by flow cytometry was assessed in patients with Stage I-II colorectal carcinoma. METHODS: Specimens of surgically resected colorectal carcinoma were examined for SPF by flow cytometric DNA analysis. Consecutive patients referred to the study institution were considered eligible for this study. The main inclusion criteria were a Stage I-II tumor together with sufficient tumor material and adequate follow-up information. For each stage of disease, SPF data were associated with the recurrence rate and the disease free survival (DFS). RESULTS: Analysis was performed on 167 patients (65 with Stage I disease and 102 with Stage II disease). Among Stage I patients, SPF was high in 20 patients and low in 45 patients. In Stage II patients, there were 36 patients with low SPF and 66 patients with high SPF. In both stages, the recurrence rate and DFS were significantly worse for the subgroups of patients with high SPF. CONCLUSIONS: SPF has revealed prognostic differences among patients with surgically resected Stage I-II colorectal carcinoma. These data should be considered for planning future trials in the adjuvant setting because patients with high SPF may benefit from adjuvant chemotherapy.
Adult↗
Risk factors for endometrial cancer according to familial susceptibility.
Endometrial cancer (EC) shares some environmental or genetic risk factors with colorectal cancer (CRC). It represents a risk factor for CRC. Furthermore, EC is the most frequent extracolonic neoplasm in HNPCC (hereditary nonpolyposis colorectal cancer) and, in this syndrome, it has the same inheritance pattern as CRC. Neoplastic family history and clinical features were evaluated in women with EC in a health care district (Pordenone Province) in Northeastern Italy from 1990 to 1995, to examine the proportion of patients with hereditary cancer and the relation with clinical characteristics of EC. We interviewed 215 patients with EC (average age 61 years, range 35-88) in relation with some risk factors (age, weight, diabetes, menstrual and reproductive pattern, synchronous and metachronous neoplasms) and we obtained their family pedigree. Twenty-nine patients (13.5%) had a CRC family history, 66 (30.7%) showed an aspecific cancer aggregation in their families and more than half (120, 55.8%) had a negative cancer family history. Family pedigrees were consistent with a dominant inherited cancer pattern in 8 patients (3.7%) belonging to the CRC-related family history group. A different pattern of family history distribution emerged in relation with age (< 55 vs. > or = 55, p < 0.001) and body mass index (BMI) (< 26 vs. > or = 26, p = 0.002). Patients with a CRC pedigree were more numerous in the younger group, in the group with lower BMI and in pre-menopausal women.
Adolescent↗
Lymphocyte proliferative response in brown bears: cytokine role and glucocorticoid effect.
Lymphocyte stimulation and proliferation play a pivotal role in the immune response to soluble as well as to cellular, bacterial, and viral antigens. In this study, peripheral blood mononuclear cells (PBMC), mainly composed of lymphocytes, were separated by Ficoll-Hypaque density gradient centrifugation from 50-ml jugular vein blood samples drawn from six captive and five wild-caught brown bears (Ursus arctos) (eight Apennine brown bears from the Italian population; three of undetermined origin). Stimulation of cultured bear PBMC with the two classical T lymphocyte mitogens phytohemagglutinin (PHA) and Concanavalin A (ConA) was followed by a significantly greater proliferative response than that shown by human PBMC (n = 11) (PHA: T = 4.03, d.f. = 20, P = 0.001; ConA: T = 4.25, d.f. = 20, P < 0.0005; Student's t-test, oneway ANOVA). As in humans, the PBMC proliferative response in bears was markedly (> 50%) inhibited by addition of transforming growth factor beta (TGF beta) human recombinant cytokine to the culture. Further fractionation provided a cell preparation extremely rich in peripheral blood lymphocytes (PBL) (mean +/- SD = 96.1 +/- 1.7%). Addition of interleukin 1 (IL1) or interleukin 2 (IL2) human recombinant cytokines to cultured PBL stimulated with a suboptimal concentration of mitogens resulted in a ninefold increase in the lymphocyte proliferative response. Dexamethasone (DEX, a synthetic analog of hydrocortisone) inhibited the bear PBMC proliferative response by 22.2 +/- 4.3% (mean +/- SD), compared with 46.2 +/- 6.9% and 91.8 +/- 8.1% (mean +/- SD) in humans and mice (n = 11) (Mus domesticus), respectively. Inhibition of the brown bear and human PBMC responses was markedly (> 60%) reduced by the addition of IL2. The finding that IL1 and IL2 augment and that DEX inhibits bear lymphocyte proliferative response suggests that these cytokines can be used to increase the immune response in vaccinations, and that DEX may hamper several immunologically mediated diseases.
Animals↗
MLH1 and MSH2 constitutional mutations in colorectal cancer families not meeting the standard criteria for hereditary nonpolyposis colorectal cancer.
Genetic diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) may have a significant impact on the clinical management of patients and their at-risk relatives. At present, clinical criteria represent the simplest and most useful method for the identification of HNPCC families and for the selection of candidates for genetic testing. However, reports of mismatch repair (MMR) gene mutations in families not fulfilling the minimal diagnostic criteria point out the necessity to identify additional clinical parameters suggestive of genetic predisposition to colorectal cancer (CRC) related to MMR defects. We thus investigated a series of 32 Italian putative HNPCC individuals selected on the basis of one of the following criteria: 1) family history of CRC and/or other extracolonic tumors; 2) early-onset CRC; and 3) presence of multiple primary malignancies in the same individual. These patients were investigated for the presence of MLH1 and MSH2 mutations by single-strand conformation polymorphism analysis. Pathogenetic truncating mutations were identified in 4 (12.5%) cases, 3 of them involving MSH2 and 1 MLH1. In addition, 2 missense MLH1 variants of uncertain significance were observed. All pathogenetic mutations were associated with early age (<40 years) at onset and proximal CRC location. Our results support the contention that constitutional MMR mutations can also occur in individuals without the classical HNPCC pattern. Moreover, evaluation of the clinical parameters associated with MMR mutations indicates that early onset combined with CRC location in the proximal colon can be definitely considered suggestive of MMR-related hereditary CRC and should be included among the guidelines for referring patients for genetic testing.
Adaptor Proteins, Signal Transducing↗
Consequences of the increased autonomic nervous drive in hypertension, heart failure and diabetes.
It is estimated that 40 million people in the USA have hypertension, 14 million are diabetic and 4 million suffer congestive heart failure. Since all three conditions are age-related, as the longevity in industrialized societies continues to improve, the overall burden of congestive heart failure, hypertension and diabetes will increase. These major diseases of civilization are characteristically associated with an increased autonomic cardiovascular drive. In our terminology the output that emanates from the central nervous system via sympathetic and parasympathetic efferents is referred to as "tone". The overall "drive" depends on the balance between inhibitory (parasympathetic) and excitatory (sympathetic) tone and the organ's responsiveness to that tone. The responsiveness, in turn, depends on the receptors' properties as well as on the intrinsic functional or anatomic properties of the responding organs. These components can change independently. For example, in the course of hypertension the alpha-adrenergic responsiveness increases whereas the beta-adrenergic responses are down-regulated. Another example is: plasma noradrenaline and sympathetic tone are increased in elderly subjects but their circulation does not show any tell-tale response of increased sympathetic tone, presumably because the responses to sympathetic tone decrease with aging. These complex interactions between the autonomic tone and organ responsiveness determine to a great extent the overall clinical impact of the autonomic abnormality in hypertension, non-insulin-dependent diabetes mellitus and in congestive heart failure. The major thesis of this review is that, whether primary or secondary, whether easily discerned or hidden, an enhanced autonomic drive, independent of the underlying condition, greatly increases the risk of poor cardiovascular outcomes. It follows that targeting the underlying autonomic imbalance in congestive heart failure, hypertension and diabetes may not only be pathophysiologically sound but such an approach may also lead to better outcomes.
Animals↗
Atrophic gastritis and intestinal metaplasia in Helicobacter pylori infection: the role of CagA status.
OBJECTIVE: Helicobacter pylori (H. pylori) is a major factor in determining the risk for development of gastric adenocarcinoma through the intermediate steps of atrophic gastritis and intestinal metaplasia. Because H. pylori infection is highly prevalent in asymptomatic populations and only a few people develop cancer, additional factors may influence the risk for development of cancer, once infection is established. Some factors may pertain to differences among bacterial strains. Because infection by H. pylori strains possessing cagA (cytotoxin-associated gene A), a gene encoding a high-molecular-weight immunodominant antigen (CagA), is associated with enhanced induction of gastritis, the aim of our study was to evaluate potential differences in the prevalence and intensity of atrophy and intestinal metaplasia between CagA-positive and CagA-negative H. pylori-infected patients. METHODS: Eighty H. pylori-infected patients among 120 consecutive dyspeptic patients referred for upper gastrointestinal endoscopy were studied. Six bioptic specimens were taken from the gastric antrum: five for histological examination, and one for urease test. The H. pylori status was determined by histology, CLO test, and serology (in a standardized ELISA) for serum IgG and IgA directed to H. pylori. The CagA status was determined by Western blotting to detect serum IgG antibodies to CagA. Gastritis was classified according to the Sydney System. A score from 0 to 3 was assigned to each of the following morphological variables: atrophy, intestinal metaplasia, and mononuclear and neutrophilic cell infiltration. The association between CagA status and histological features was assessed by means of the chi2 test for trend. RESULTS: Among the 80 H. pylori-infected patients 53 (66%) were CagA seropositive and 27 (34%) were CagA seronegative. The mean age of the two groups was similar. CagA-positive patients had significantly higher scores for atrophy (p = 0.006), intestinal metaplasia (p = 0.01), and mononuclear (p < 0.001) and polymorphonuclear (p = 0.002) cell infiltration than did CagA-negative patients. No differences in contrast, were found for H. pylori density. CONCLUSION: Infection with CagA-positive H. pylori strains is associated with an increased prevalence and intensity of antral atrophy and intestinal metaplasia, in addition to higher degrees of gastritis. Our results seem to suggest that the CagA status could be a helpful parameter to define a subgroup of H. pylori-infected patients at increased risk of developing gastric adenocarcinoma.
Adult↗