Platelet function and coagulation abnormalities in type 1 Gaucher disease patients: effects of enzyme replacement therapy (ERT).
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Adolescent↗
Biomedical subjects
G Palumbo
Publications and source records attributed to G Palumbo.
Long-term oral plus topical mesalazine in frequently relapsing ulcerative colitis.
BACKGROUND: In cross-sectional studies, it was demonstrated that the therapeutic effect of mesalazine is closely related to its mucosal concentration. AIM: This study was carried out to verify in a longitudinal study if it was possible to improve the clinical course of ulcerative colitis at high risk of recurrence by increasing mucosal mesalazine concentration. METHODS: Eighteen consecutive ulcerative colitis patients on continuous oral 5-ASA treatment (2.4-3.2 g/day) in clinical remission who had had at least four moderate to severe relapses in the preceding 2 years (referred period) were assigned to assume oral (3.2-4.8 g/day) and topical (4 g/day) mesalazine in order to increase mucosal drug concentration and were followed up for 2 years (study period). The localisation of disease was 12 pancolitis, six left colitis. The number and severity of recurrences, number of visits and endoscopies, courses of steroids and days of hospitalisation were compared with those of the previous 2 years. Rank signed test for paired data was used for statistical analysis. RESULTS: The total number of recurrences was significantly lower during the study period in comparison with that of referred period (8 versus 80, respectively, p < 0.0001). No courses of steroids or hospitalisation were necessary during study period in comparison with those of referred period (0 versus 33, p < 0.0001; 0 versus 93, p = 0.03, respectively). A total number of 249 visits were done during the referred period and 116 during the study period (p < 0.0001) with a total of 87 endoscopies during referred period and 44 during study period (p < 0.0001). CONCLUSIONS: The continuous use of topical mesalazine associated with a high oral dosage significantly improves the clinical course of ulcerative colitis patients at high risk of relapse.
Administration, Oral↗
Assessment of the QoL in Italian menopausal women: comparison between HRT users and non-users.
OBJECTIVES: The aim of this cross-sectional study was to describe QoL in a large sample of women attending menopause centres and compare untreated postmenopausal women and matched HRT users by employing the Women's Health Questionnaire (WHQ) and two generic instruments, the SF-36 and the EQ-5D. METHODS: Overall, 2906 women were recruited by 64 menopause centres throughout Italy, of whom 2160 filled in the questionnaire (1093 on HRT and 1067 not on HRT; response rate: 74%). RESULTS: HRT users tended to be younger, healthier and with shorter menopause duration as opposed to non users, while no major socio-economic differences were present. At multivariate analysis, the presence of chronic diseases, low socio-economic status and living in Southern Italy represented the most important predictors of poor QoL. Furthermore, HRT users showed a lower probability of reporting problems in usual activities and pain/discomfort (EQ-5D), role limitations due to emotional problems (SF-36) and anxiety/fears (WHQ). HRT users also showed highly significant better outcomes in those areas that are more directly attributable to hormonal changes of mid age, namely vasomotor symptoms and sexual problems. CONCLUSIONS: Although QoL is mainly influenced by socio-economic and cultural factors, HRT has the potential for improving not only symptoms, but also more general aspects of physical and psychological well-being of symptomatic postmenopausal women.
Estrogen Replacement Therapy↗
Compliance to hypertension guidelines in clinical practice: a multicentre pilot study in Italy.
The aim of this study was to investigate the diagnostic approach to recently diagnosed hypertensive patients by primary care physicians in Italy and to find out whether general practitioners manage these patients according to 1999 WHO/ISH guideline recommendations. In total, 228 consecutive patients (117 men and 111 women, mean age 51+/-12 years) with recently diagnosed hypertension (<2 years) referred for the first time to six outpatient hypertension centres throughout Italy were included in the study. The primary care physicians' approach was evaluated during the specialist visit by a specific questionnaire containing detailed questions about diagnostic work-up and treatment made at the time of the first diagnosis of hypertension. At the study visit, 71% of the patients were on treatment with antihypertensive drugs and 18.7% of them had blood pressure (BP) values lower than 140/90 mmHg. A complete clinical and laboratory evaluation according to the minimum work-up suggested by the guidelines had been carried out in only 10% of the patients. A full physical examination had been performed in 60% of the patients, electrocardiogram in 54%, serum total cholesterol in 53%, glucose in 49%, creatinine in 49%, urine analysis in 46%, potassium in 42%, and fundus oculi in 19%. Additional investigations such as ambulatory BP monitoring, echocardiogram, carotid ultrasonogram, and microalbuminuria had been carried out in a minority of patients (21, 18, 9, and 3%, respectively). The impact on hypertension guidelines on patients' management in everyday primary care practice appears marginal. Thus, our findings indicate that the majority of general practitioners manage hypertensive patients according to a simple BP-based approach rather than a more integrated approach based on global risk stratification.
Chi-Square Distribution↗
Validation of Italian version of the Women's Health Questionnaire: assessment of quality of life of women from the general population and those attending menopause centers.
OBJECTIVES: The Women's Health Questionnaire has been developed and validated in Anglo-Saxon and Swedish populations. The purpose of this study was to evaluate the Italian version of the questionnaire to determine whether cross-cultural differences exist in the perception of quality of life, and to use it to compare the quality of life in women attending menopause centers with that of women in the general population. METHODS: An Italian version of the Women's Health Questionnaire (WHQ) was produced, using the forward-backward translation method to ensure conceptual equivalence, and approved by the originator. Women were recruited by random selection from the general population and from menopause centers, those taking hormone replacement therapy being ineligible. The questionnaire was completed anonymously at home and mailed to the co-ordinating center. Psychometric evaluation included tests of item convergent and discriminant validity, internal-consistency reliability, test-retest reliability, construct validity and the discriminative properties of the questionnaire. RESULTS: The completeness of the data was good, with missing-value rates consistently low for most items. Item-scale correlations, used to evaluate internal consistency, were also good and the scaling success rate, used to measure item discriminant validity, was high for all scales. Scale scores were reliable for seven out of nine scales and test-retest reliability was excellent. There were few significant differences between the two populations of women in most of the WHQ areas. A comparison of Italian data with published data on English women showed great similarity. CONCLUSION: The Italian version of the WHO is valid and reproducible. The subjective perception of the menopause and its related problems is similar in geographically and culturally different populations.
Affect↗
Involvement of oxygen radicals in cytarabine-induced apoptosis in human polymorphonuclear cells.
We investigated apoptosis in polymorphonuclear neutrophils (PMNs) induced by cytarabine (Ara-C). This drug increased apoptosis by 100% with respect to the controls after 3 hr of incubation. This increase was inhibited by N-acetyl-L-cysteine (NAC) or diphenyleneiodonium chloride (DPI). Ara-C alone caused an early increase (after a 30-min incubation) in intracellular oxidant generation (inhibitable by rotenone, fumonisin b1, and DPI) and in protein tyrosine phosphorylations (inhibitable by NAC). The drug also affected the observed reduction of dimethylthiazol diphenyltetrazolium bromide (MTT). No extracellular release of reactive oxygen species (ROS) was elicited by the addition of Ara-C, while the drug increased the release of ROS by N-formyl-leucyl-phenylalanine-(f-MLP) but not phorbol 12-myristate 13-acetate-stimulated PMNs. This phenomenon was abolished by the addition of genistein, whereas such an effect was not observed following the addition of 1-(5-isoquinolynilsulfonyl)-2-methylpiperazine (H7). Ara-C induced ROS release from PMNs in the presence of subthreshold concentrations of f-MLP (priming effect). These results indicate that intracellular ROS production from mitochondria promotes Ara-C-induced apoptosis. Ara-C primes plasma membranes by a mechanism involving protein tyrosine phosphorylations and may also contribute to ROS generation from the granules.
Antimetabolites, Antineoplastic↗
As compared to kaolin clotting time, silica clotting time is a specific and sensitive automated method for detecting lupus anticoagulant.
Lupus anticoagulants (LAs) are antiphospholipid antibodies capable of interfering with the coagulation system and modifying in vitro the phospholipid-dependent clotting tests. Colloidal silica was used as activator to perform an activated partial thromboplastin time (aPTT) in 73 plasma samples with pathologically elevated kaolin clotting time (KCT) values using a photooptical automated coagulometer. Samples were incubated for 5 min with micronized silica, and after recalcification, the clotting times were measured. Pathologically prolonged results were confirmed by a confirmation and a neutralization test adding platelet-poor normal plasma (PPNP) and natural phospholipids, respectively. Silica clotting time (SCT) was abnormally elevated in 72/73 (98.6%) (mean ratio 1.71 +/- 0.28) KCT positive samples and normalized (mean ratio 1.03 +/- 0.16) after adding natural phospholipids to test plasma. The values expressed as SCT and KCT ratios were significantly correlated (r = .92; P < .001). SCT was normal in 40 healthy subjects utilised as controls (mean ratio 0.99 +/- 12). Sensitivity, specificity and diagnostic accuracy of SCT were 98.6%, 100% and 97.6%, respectively. Our data suggest that SCT is a sensitive test for detecting LA with a prolonged KCT in automated photooptical coagulometers. This peculiarity makes it particularly useful, in combination with diluted Russel viper venom time (dRVVT), for large-scale screening tests on LA.
Adult↗
Hypoxic pelvic perfusion with mitomycin C using a simplified balloon-occlusion technique in the treatment of patients with unresectable locally recurrent rectal cancer.
HYPOTHESIS: To evaluate the role of hypoxic pelvic perfusion in providing therapeutic options for palliation without relevant complications in a homogeneous group of patients with unresectable locally recurrent rectal cancer who are nonresponders or have disease progression after the standard treatments. DESIGN: Nonrandomized and noncontrolled phase II experimental study. SETTING: University hospital, L'Aquila, and the National Cancer Institute, Naples and Milan, Italy. PATIENTS: Eleven patients had symptomatic unresectable pelvic recurrent rectal cancer. The mean +/- SD product of the 2 maximum perpendicular diameters of the recurrent cancer was 24.2 +/- 11.0 cm(2) (range, 10-48 cm(2)). Tumor fixation to the pelvic side walls or proximal sacrum were the main criteria for unresectability. All patients were free from extrapelvic disease and had a life expectancy longer than 3 months. INTERVENTION: Patients were submitted to one course of pelvic perfusion with mitomycin C (MMC) (25 mg/m(2)) by means of a simplified balloon occlusion technique. A pharmacokinetic evaluation of the procedure was also performed. MAIN OUTCOME MEASURES: Response rate and time to disease progression were the primary endpoints; overall survival was the secondary endpoint. RESULTS: Mean +/- SD value of the ratios of pelvic MMC area under the plasma concentration curve (0 to 20 minutes) (AUC(0-20)) to systemic MMC AUC(0-20) was 13.30 +/- 6.52. During the procedures there were no technical, hemodynamic, or vascular complications, and no deaths occurred during surgery or in the postoperative period. The response rate was 36.3% (95% confidence interval [CI], 6.5%-66.1%). Pain response rate was 45.4% (95% CI, 16.6%-76.2%). Median survival was 12.2 months (range, 5.7-19.5 months). Median time to disease progression was 6 months (range, 3-8 months). Two-year overall survival was 9.1%. CONCLUSIONS: Hypoxic pelvic perfusion with MMC is a safe and good palliative treatment for patients with unresectable locally recurrent rectal cancer. Further studies are necessary to establish if a different sequence in the multimodular treatment of these patients could be more useful.
Antibiotics, Antineoplastic↗
Bcl-2 exerts a pRb-mediated cell cycle inhibitory function in HEC1B endometrial carcinoma cells.
OBJECTIVE: In various human tumors the expression of Bcl-2 appears to vary significantly during the transformation process. Indeed, in several glandular systems, Bcl-2 levels appear to be sustained in premalignant lesions and rather low after the malignant change. Since we recently reported that transformed human endometrial cells display constitutively low levels of Bcl-2, we set out to investigate the biological meaning of this down-regulation. To this end we analyzed the effects of Bcl-2 forced overexpression in a moderately differentiated endometrial cell line of human origin. METHODS: Bcl-2 overexpression was obtained by transfecting HEC1B human endometrial adenocarcinoma cells with a suitable bcl-2 vector. The effects of Bcl-2 overepression were evaluated in several transfectants (cell clones and mixed populations) by FACS, growth rates, cloning efficiencies, and modification of the phosphorylation status of the pRb protein. Accompanying changes in the expression of the CDK inhibitor p21(WAF1/CIP1) were evaluated as well. RESULTS: Bcl-2 overexpression resulted in a reduced cell proliferation rate, decreased cloning efficiency, appreciable cell morphology changes, G2/M cell cycle arrest, remarkable accumulation of the dephosphorylated form of retinoblastoma protein, and a significant rise in p21(WAF1/CIP1). CONCLUSIONS: From these observation it may be deduced that the observed loss and down-regulation of the antiapoptotic protein in endometrial glandular human tumors is not random but possibly related to the cellular transformation process. It may be also inferred that the coincidence of a progressive fading of both Bcl-2 and cyclin inhibitor p21(WAF1/CIP1) expressions, together with accumulation of the hyperphosphorylated form of the retinoblastoma protein, may be seen as a potential indicator of ongoing malignant changes.
Adenocarcinoma↗
Photo-activation of hypericin with low doses of light promotes apparent photo-resistance in human histiocytic lymphoma U937 cells.
We have observed that exposure of U937 cells, pre-incubated for 18 h with 0.2 microM hypericin, to 599 nm laser radiation with a fluence of 2.5 J/cm(2) renders them insensitive to higher light doses. In fact, pre-sensitized cells appear to be fully resistant to light doses that normally determine massive cellular apoptosis in experimental photo-dynamic therapy. The appearance of the photo-resistance, as measured by evaluating the changes in levels of expression of pro and anti apoptotic proteins, PARP fragmentation and cell viability is exclusively observed with exposure to light doses not exceeding 5-6 J/cm(2). Above this energy, necrosis replaces apoptosis upon photo-stimulation of U937 cells. Here, we describe the appearance of photo-resistance in hypericin-loaded U937 cells, but could not fully unravel the molecular mechanism underlying this process. However, the observed stimulation of the expression of the HSP-70 protein upon photo-induced stress may suggest its involvement in this process.
Anthracenes↗
Neurochemical and behavioural effects of chronic aldicarb administration in rats.
Changes in neurochemical parameters, behavioural and memory performances due to aldicarb (a carbamate pesticide) treatment was investigated after chronic oral administration in rats. Rats received water, or aldicarb 1 ppb (= 0.12 g/kg/day), aldicarb 10 ppb (= 1.2 g/kg/day) and aldicarb 100 ppb (= 12 g/kg/day) for 4 months. The locomotor and explorative activities were reduced, and aldicarb significantly decreased brain AChE activity while an increase was found in the passive avoidance and water-maze performance. In the striatum, aldicarb 10 ppb and 100 ppb, significantly reduced DOPA but not DOPAC concentrations, while the 10 ppb and 100 ppb doses significant increased DA levels. Aldicarb did not affect DA, DOPA and DOPAC levels in the accumbens. The neuropharmacologic effects of chronic dosing with aldicarb, AChE inhibition and dopaminergic modulation could be useful for treatment of memory deficits related to CNS disorders.
3,4-Dihydroxyphenylacetic Acid↗
Cloning and molecular characterization of three ubiquitin fusion degradation 1 (Ufd1) ortholog genes from Xenopus laevis, Gallus gallus and Drosophila melanogaster.
The yeast ubiquitin fusion degradation 1 (Ufd1) protein is involved in a degradation pathway for ubiquitin fused products. The human ortholog gene (UFD1-like, UFD1L) is deleted in patients affected by the DiGeorge/velocardiofacial syndromes. We report the cloning of UFD1L orthologs from Drosophila melanogaster (dufd1l), Xenopus laevis and Gallus gallus. The 1,125-bp Drosophila cDNA encodes a protein of 316 amino acids, showing 60% identity with the human and murine proteins. The identity to the G. gallus, X. laevis, C. elegans and S. cerevisiae proteins is 95%, 83%, 32%, and 36%, respectively. Northern expression data in Drosophila indicate that dufd1l is expressed through embryonic, larval and pupal development, as well as in the adult fly.
Adaptor Proteins, Vesicular Transport↗
Effect of space radiation on expression of apoptosis-related genes in endometrial cells: a preliminary study.
In this paper we present some preliminary results on alteration of gene expression caused by radiation on human endometrial cells. To this purpose, we have studied the modulation of the expression of the bcl-2 gene family in two cell lines following irradiations with low energy protons and gamma-rays from a 60Co. The two epithelial cell strains, namely AN3Ca and HEC1B cells, both obtained from human neoplastic endometrial tissues, grow in culture and continue to maintain some differentiated functions typical of the original tissue. Indeed, these cells, that can be considered as representative of different stages of cellular transformation of endometrium. Because their epithelial nature and rapid growth, the expression of genes related to the maintenance of the cellular homeostasis (correction of omeostasis), as the pro and anti-apoptotic ones, is expected to be susceptible to changes in environment, including radiation. The effects have been evaluated in terms of both cell survival and changes in the expression of pro- and anti apoptotic proteins. Even though the data reported above can not be considered complete and/or definitive, nevertheless, in whole, they confirm that these cells may constitute a suitable model system to study, at molecular level, the effects of cosmic radiation on endometrium. Further observation, ensuing from these preliminary data, is that endometrial cells present different sensitivity to radiation in regard to its 'quality' and 'dosage', in accord to the original stage of differentiation.
Apoptosis↗
Simultaneous determination of losartan and hydrochlorothiazide in tablets by high-performance liquid chromatography.
A method for the simultaneous determination of losartan potassium and hydrochlorothiazide in tablets is described. The procedure, based on the use of reversed-phase high-performance liquid chromatography, is linear in the concentration range 3.0-7.0 microg ml(-1) for losartan and 0.5-2.0 microg ml(-1) for hydrochlorothiazide, is simple and rapid and allows accurate and precise results. The limit of detection was 0.08 microg ml(-1) for losartan and 0.05 microg ml(-1) for hydrochlorothiazide.
Antihypertensive Agents↗
Modulation by alpha- and gamma-tocopherol and oxidized low-density lipoprotein of apoptotic signaling in human coronary smooth muscle cells.
Apoptosis may play an important role in atherogenesis. Oxidized low-density lipoprotein (oxLDL) promotes apoptosis in the arterial wall in addition to several other proatherogenic effects. Tocopherol supplements have been suggested to protect against coronary heart disease (CHD) in epidemiological studies. The effects of oxLDL and alpha- and gamma-tocopherol on apoptotic signaling pathways are poorly understood. Thus, the goal of the study was to investigate these pathways in the presence of copper-oxidized LDL and tocopherols in human coronary smooth muscle cells (SMC). We showed that oxLDL-mediated apoptosis, assessed by DNA fragmentation, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay, and caspase activation stimulated several transcription factors and proapoptotic dynamic movements of the Bcl-2 family proteins through the mitogen-activated protein kinase (MAPK) and Jun kinase pathways. alpha-Tocopherol and gamma-tocopherol significantly reduced these molecular events and cell death effectors caspase-3 and -8. Under our experimental conditions, alpha-tocopherol was significantly more effective than gamma-tocopherol, and oxLDL-mediated apoptosis increased c-Jun, cyclic AMP-responsive element-binding, Ets-like element kinase-dependent 7, and activating transcription factor-2 proteins as well as nuclear activity of the activated protein-1 complex in human coronary SMC. Moreover, our results demonstrate that tocopherols may exert their antiatherogenic effects at least in part via reduction of the MAPK and JunK cascade together with a protective profile of apoptotic genes of the Bcl-2 family. These data are consistent with the beneficial effects of tocopherols on atherogenesis seen in experimental studies and on CHD in epidemiological surveys.
Adult↗
Unexpected products via singlet oxygen oxygenation of functionalized 5,6-dihydro-1,4-oxathiins
[formula: see text] Single oxygen oxygenation of 5,6-dihydro-1,4-oxathiins substituted at C-3 with an electron-withdrawing group leads stereoselectively to ketosulfoxides 5 and 6, instead of the expected dicarbonyl compounds 3. A mechanism involving an unprecedented intramolecular rearrangement of the corresponding dioxetanes 2 is proposed.
Journal Article↗
Differential expression of antiapoptotic genes in human endometrial carcinoma: bcl-XL succeeds bcl-2 function in neoplastic cells.
OBJECTIVES: Previous histochemical observations have suggested a possible involvement of the bcl-2 family genes in the acquisition of neoplastic phenotype of the endometrium. Since knowledge of the type and function of genes controlling the transformed cell may result in new diagnostic, prognostic, and therapeutic approaches, we have investigated at the molecular level the biological role of bcl-2 family genes in endometrial neoplastic cells. METHODS: To investigate the relationship between the sensitivity to apoptosis and the expression of the bcl-2 family genes, we set up a model system consisting of four human endometrial carcinoma cell lines. This system constitutes an array of two cell pairs presenting, respectively, endometrioid and adenosquamous phenotypes. G2 and G3 gradings are represented within each pair; in addition, each set contains one cell line that is apoptosis-sensitive and one that is resistant. Transfection of bcl-2 and bcl-XL into apoptosis-sensitive cells was used to monitor the biological function of protective genes. RESULTS: A differential pattern of expression of bcl-2 family genes was observed in apoptosis-sensitive versus resistant cells, independent from the histological subtype. Resistant lines exhibited high amounts of Bcl-XL and low amounts of Bcl-2. Bax expression clearly correlates with cellular susceptibility to apoptosis. Transfection of bcl-XL resulted in a dose-dependent enhancement in resistance toward apoptosis. In contrast, the main effect of bcl-2 constitutive overexpression was to drastically abate the proliferative potential of transfected cells. CONCLUSIONS: These data demonstrate, at the molecular level, that bcl-XL is selected as an apoptosis-protective gene in place of bcl-2 while bax retains its dominant proapototic role.
Apoptosis↗
Surface reactions of a plasma-sprayed CaO-P2O5-SiO2-based glass with albumin, fibroblasts and granulocytes studied by XPS, fluorescence and chemiluminescence.
X-ray photoelectron spectroscopy (XPS) was used to define the chemical composition of the outermost surface layer and the surface modification of a plasma-coated phospho-silicate glass (identified as BVA) when immersed in K-phosphate buffer or in phosphate buffered human albumin solution. Its behavior was compared with that of a soda-lime-based glass (identified as BVH) treated in the same way. The surface % composition of plasma-sprayed glass was consistent with bulk composition. After incubation with buffer, a Ca-P-rich layer developed only on the surface of BVA glass. Human serum albumin was bound reversibly to both glasses maintaining its native state. However, the protein completely covered the BVA glass surface within 24 h, with the formation of a mixed albumin-Ca-P layer, while 4 days incubation was necessary for complete coverage of BVH glass surface. Murine fibroblasts seeded on plasma-coated BVA glass showed a proliferation pattern similar to that of control cells grown on Petri dish, while cells seeded on BVH had more restricted growth. A limited response was induced in polymorphonuclear granulocytes by both bulk glasses powder. In conclusion, the glass identified as BVA has the suitable characteristics of its surface layers to be considered biologically active from both a chemical and a cellular point of view.
3T3 Cells↗