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Biomedical subjects

A Giannetti

Publications and source records attributed to A Giannetti.

At least 19 recordsLinked to original sources
PubMed2007

Transcriptional profiles in melanocytes from clinically unaffected skin distinguish the neoplastic growth pattern in patients with melanoma.

BACKGROUND: It is generally accepted that sunlight may contribute to the development of melanoma. OBJECTIVES: To analyse gene expression of melanocytes obtained from clinically unaffected skin of patients with melanoma and healthy controls before and after exposure to ultraviolet B radiation. METHODS: Using GeneChip array technology, the gene expression of melanocytes obtained from the two donor groups was profiled, in order to identify transcriptional differences affecting susceptibility to melanoma. RESULTS: The data collected did not show any difference between the expression profiles of melanocytes purified from normal donors and from patients with melanoma that was able to give a statistically significant class separation. However, by means of unsupervised clustering our data could be divided into two main classes. The first class included the transcriptome profiles of melanocytes obtained from skin samples of patients with a vertical growth phase (VGP) melanoma, while the second class included the transcriptome profiles of melanocytes obtained from skin samples of patients with a radial growth phase (RGP) melanoma. CONCLUSIONS: These data suggest that melanocytes in patients with VGP and RGP melanomas show significant differences in gene expression profiles, which allow us to classify patients with melanoma also from clinically unaffected skin.

Adult↗
PubMed2006

New thymidylate synthase inhibitors induce apoptosis in melanoma cell lines.

Malignant melanoma is particularly resistant to conventional chemotherapy and radiotherapy. For this reason in the past years a huge variety of new compounds has been developed with potential chemotherapeutic activity which needs to be tested in vitro and in vivo. We investigated the in vitro action of three new experimental antifolate substances (MR7, MR21 and MR36) with a critical target for thymidylate synthase (TS), an essential enzyme for DNA synthesis. The response of two melanoma cell lines (SK-MEL-2 derived from malignant melanoma metastasis and SK-MEL-28 derived from primary malignant melanoma) was examined after treatment with these substances. The antifolate agents induced apoptosis in SK-MEL-2 and SK-MEL-28 cells as confirmed by the TUNEL technique and Comet Assay. Western-blot analysis showed a down-regulation of Bcl-2 protein level and PARP cleavage, otherwise p53 and Bax expressions were not modulated. Moreover, these antifolate-induced apoptosis was accompanied by both pro-caspase-9 and -8 activations. These results were supported by the use of the pan-caspases inhibitor Z-VAD-FMK that almost completely decreased the amount of apoptosis in both the melanoma cell lines treated with antifolate. In conclusion our results show that TS inhibitors are able to induce apoptosis through a caspase-mediated pathway, but without the involvement of the p53/Bax signalling.

Amino Acid Chloromethyl Ketones↗
PubMed2006

Recommendations for the use of etanercept in psoriasis: a European dermatology expert group consensus.

BACKGROUND: Psoriasis is a chronic, inflammatory skin disorder that has a significant impact on quality of life and, particularly in moderate to severe cases, adversely affects the patient's overall health and well-being. Biological treatments, such as etanercept, are being widely adopted across Europe for treatment of moderate to severe psoriasis due to favourable safety and efficacy profiles. The increase in usage, combined with a growing body of clinical evidence, has identified a need to clarify the best use of etanercept within its current treatment label. OBJECTIVE: To prepare a series of recommendations agreed by an expert group of dermatologists, relating to the most effective use of etanercept for psoriasis in Europe, within the product license. METHODS: An expert panel of dermatologists from across Europe completed a Delphi survey to address the current use of etanercept in psoriasis in Europe. In June 2005 the results were presented to the expert panel at their nominal group meeting, and a consensus was agreed. RESULTS: It was recommended that, where possible, patients are initiated on the 50 mg twice-weekly (BIW) dose. Etanercept should be given until remission is achieved (maximum 24 weeks) and retreatment should be initiated according to the physician's judgement. Before commencing treatment, contraindications, such as infection or previous malignancy (within 5 years), should be ruled out. CONCLUSIONS: The consensus presented herein provides valuable clarification of use of etanercept according to the label, which may have wider implications relating to the use of all biological therapies in psoriasis.

Adolescent↗
PubMed2005

Review of the potential photo-cocarcinogenicity of topical calcineurin inhibitors: position statement of the European Dermatology Forum.

Topical Calcineurin Inhibitors (TCIs) used for the treatment of atopic eczema modify the immune regulatory function of the skin and may have the potential to enhance immunosuppressive ultraviolet (UV) effects. Current recommendations on UV protection in eczema patients treated with PCIs are inconsistent and have given rise to uncertainty and anxiety in patients. Therefore, the European Dermatology Forum (EDF) developed a position statement which reviews critically the available data with regard to the problem, especially analysing and commenting the limitations of rodent models for the human situation. There is no conclusive evidence from rodent trials to indicate that long-term application of TCIs is photococarcinogenic. There is a need for further studies to investigate the validity of mouse models as well as long-term cohort studies in patients using TCIs. Available data suggest that long-term application of TCIs is safe, that there is no evidence of increased skin cancer risk and that it is ethical to treat patients with TCIs when indicated.

Administration, Topical↗
PubMed2004

The role of topical calcineurin inhibitors in atopic dermatitis.

For more than five decades, topical corticosteroids and emollients have been the mainstay of therapy for atopic dermatitis. However, the potential for side-effects limits the clinical utility of corticosteroids in providing long-term disease control. With a unique mode of action that differs from that of corticosteroids, the steroid-free topical calcineurin inhibitors (TCIs), tacrolimus ointment and pimecrolimus cream, provide skin-selective treatment that targets key factors involved in the pathogenesis of this chronic disease. An extensive series of clinical trials involving more than 16,000 patients with predominantly moderate to severe atopic dermatitis in tacrolimus studies and over 2000 patients with primarily mild to moderate disease in pimecrolimus studies has shown that both TCIs provide effective and well-tolerated treatment for atopic dermatitis. Randomized controlled trials have demonstrated that tacrolimus is superior to conventional hydrocortisone-based regimens and does not cause skin atrophy or other steroidal side-effects. Both tacrolimus and pimecrolimus prevent disease flares and provide progressive and sustained disease improvement with long-term therapy. These and other clinical benefits of TCIs are discussed, together with the safety profiles of tacrolimus and pimecrolimus and their use in clinical practice. In addition, this review summarizes findings from the many trials carried out with these agents and outlines how TCIs can provide long-term treatment and control of a chronic skin disease that may persist for years.

Administration, Topical↗
PubMed2003

The epidemiology of atopic dermatitis in Italian schoolchildren.

BACKGROUND: Atopic dermatitis (AD) is common in children in industrialized countries. Only one large population study on its prevalence has been conducted in Italy, based on self-report questionnaire. The present study was designed to estimate the prevalence of AD in schoolchildren in Italy by dermatologists' assessment and by UK Working Party criteria, and to investigate associated symptoms and factors. METHODS: Cross-sectional survey on a random sample of 9-year-old schoolchildren from seven Italian cities. Children were examined by experienced dermatologists. Parents and teachers answered standardized questionnaires. RESULTS: Of the 1369 children examined, 88 had a diagnosis of AD, with an estimated point prevalence of 5.8% (95% CI 4.5-7.1) in the reference population. The reported lifetime prevalence was 15.2 (95% CI 12.2-18.2) for AD, 11.9% (95% CI 9.0-14.8) for asthma, and 17.6% (95% CI 14.6-20.7) for rhino-conjunctivitis. The strongest associated factor was the presence of AD in at least one parent. No association of AD with maternal smoking during pregnancy, birth weight, maternal age at the time of the child birth and breast-feeding was observed. The environmental characteristics of the house and the school did not correlate with the prevalence of AD. Episodes of lower respiratory tract infections were associated with asthma, and to a lower extent also with AD and rhinitis. CONCLUSIONS: The prevalence of doctor-diagnosed AD in Italian schoolchildren is comparable to those reported for other developed countries. Family history of atopy was the single most important associated factor, while the complex interplay of environmental factors remains to be elucidated.

Asthma↗
PubMed2003

Efficacy of betamethasone valerate mousse in comparison with standard therapies on scalp psoriasis: an open, multicentre, randomized, controlled, cross-over study on 241 patients.

BACKGROUND: The scalp is a common area for plaque psoriasis. Corticosteroid-based lotions are the most widely used therapy in this clinical setting. A new formulation of betamethasone valerate 0.12% in a thermophobic, low-residue foam vehicle (Bettamousse trade mark, Mipharm, Italy; BVM) is available for the treatment of scalp dermatoses. OBJECTIVES: In an open, investigator-blinded, multicentre (28 dermatology clinics), randomized, cross-over study, the efficacy, safety and patient acceptability of BVM in scalp psoriasis were evaluated in comparison with standard therapies (ST, i.e. corticosteroids or vitamin D analogues). ST were chosen by each centre according to its usual therapeutic protocols. METHODS: In total, 241 patients with moderate to severe scalp psoriasis participated in the trial. After a 2-week run-in period, each active treatment (BVM or ST) was applied for 4 weeks, with a wash-out period between the two active treatment phases of at least 4 weeks. Efficacy was evaluated by investigators unaware of treatment sequence analysing a 'target' lesion for erythema, scaling, itching and burning using a five-point grading score. Patient treatment acceptability and assessment of the influence on Psoriasis Disability Index were evaluated using an eight-item modified Finlay-Khan questionnaire at baseline and at the end of each treatment period. Safety was evaluated by recording any adverse event occurring during the study duration. BVM was applied twice daily, and ST were applied once or twice daily, according to the approved scheduled regimens. RESULTS: Analyses were by intention-to-treat. Two hundred and ten patients concluded the study. Fifteen patients withdrew from the study during BVM treatment, and 16 during ST (not significantly different). Both treatments were well tolerated. At baseline, the mean +/- SD clinical global score (the 'Sum' score = erythema + scaling + itching + burning) was 7.6 +/- 2.6. The ST chosen were topical corticosteroids (55% of cases; mainly mometasone and betamethasone dipropionate) or calcipotriol lotion (45% of cases). At the end of active treatments, BVM was significantly superior to ST (P < 0.001) in reducing, as compared with baseline, the mean +/- SD Sum score (1.5 +/- 1.9 with BVM and 3.1 +/- 2.7 with ST). During BVM treatment, 88% (95% confidence interval, CI 82-94%) of patients had a complete or nearly complete resolution of scaling in comparison with 66% (95% CI 58-74%) during ST therapy (P < 0.001). BVM was also considered an easier and more convenient formulation to use in comparison with ST (P < 0.01). CONCLUSIONS: BVM is more effective than lotion-based ST commonly used in the treatment of scalp psoriasis, and has higher patient acceptability.

Administration, Topical↗
PubMed2002

Ultraviolet B radiation induces activation of neutral and acidic sphingomyelinases and ceramide generation in cultured normal human keratinocytes.

The sphingomyelin pathway is an ubiquitous, evolutionary conserved signaling system which transduces an extracellular signal into the cell. During the past few years increasing evidence has shown that the sphingolipid ceramide may play a role as a second messenger in intracellular signal transduction. The ceramide generation via sphingomyelinase (SMase) is followed by three major cellular responses: cell growth arrest, induction of cell differentiation and/or induction of programmed cell death or apoptosis. The aim of this study is to investigate whether activation of SMases and generation of ceramide can be induced by UVB radiation in normal human keratinocytes. The present data show that exposure to UVB radiation results in rapid generation of ceramide. The ceramide accumulation starts 15 min after UV exposure and progressively increases up to 24 h. In vitro measurement of SMase activity following exposure to UVB evidences an activation of both neutral and acidic SMases. Moreover, UVB induces apoptosis in normal human keratinocytes as shown by TUNEL technique and FACS analysis. These data indicate that UVB induced ceramide generation and activation of both neutral and acidic SMases, suggesting that sphingolipids metabolism may be involved in the UVB signaling pathway.

Apoptosis↗
PubMed2001

Keratinocytes from patients with atopic dermatitis and psoriasis show a distinct chemokine production profile in response to T cell-derived cytokines.

BACKGROUND: Atopic dermatitis (AD) and psoriasis are genetically determined inflammatory skin disorders. Keratinocytes actively participate in cutaneous inflammatory responses by elaborating various chemokines. OBJECTIVE: We investigated the capacity of IL-4, IFN-gamma, and TNF-alpha to modulate the expression of CCL and CXCL chemokines in cultured keratinocytes from patients and healthy individuals, as well as chemokine expression in situ. METHODS: Keratinocyte cultures were established from normal-looking skin of adult patients with AD or psoriasis vulgaris and from healthy subjects. Monocyte chemoattractant protein 1 (MCP-1)/CCL2, RANTES/CCL5, IL-8/CXCL8, and IFN-gamma-induced protein of 10 kd (IP-10)/CXCL10 production was evaluated at the mRNA and protein levels by using RNase protection assay and ELISA, respectively. The expression of the same chemokines was studied in chronic lesional skin by means of immunohistochemistry or in situ hybridization. RESULTS: Only IL-8 mRNA was detected in unstimulated ke-ratinocyte cultures. MCP-1 and IP-10 were potently induced by IFN-gamma, whereas IL-8 and RANTES were preferentially upregulated by TNF-alpha and, to a lesser extent, by IFN-gamma. IL-4 weakly induced IP-10, RANTES, and IL-8 but not MCP-1. Keratinocytes of patients with AD invariably responded with significantly earlier and higher RANTES expression. By contrast, keratinocytes of patients with psoriasis displayed much higher levels of both constitutive and induced IL-8 and a stronger induction of MCP-1 and IP-10. RANTES and MCP-1 mRNA(+) keratinocytes were detected in the basal layer of lesions of patients with AD and psoriasis. IP-10 and IL-8 were consistently upregulated in the epidermis of patients with psoriasis but not in lesions of patients with AD. CONCLUSIONS: Keratinocytes of patients with AD and psoriasis show an intrinsically abnormal and different chemokine production profile and may thus favor the recruitment of distinct leukocyte subsets into the skin.

Adult↗
PubMed2000

One-year treatment of chronic urticaria with mizolastine: efficacy and safety. URTOL study group.

AIM: To assess the long-term safety and efficacy of the H1-receptor antagonist mizolastine in the symptomatic treatment of chronic urticaria (CU). BACKGROUND: Mizolastine is a novel second generation antihistamine with additional anti-inflammatory properties which has been shown to be effective in this condition as well as in allergic rhinitis. As the drug is used for chronic treatment, a detailed study of its efficacy and safety over a prolonged period was warranted. METHODS: This open label multicentre trial recruited 211 patients suffering from CU (67% female; mean age 40+/-13 years), with > or = 1 episode/week if untreated. After a 7-day placebo run-in period, patients received mizolastine (10 or 15 mg) for 12 months. Efficacy was assessed by the patient using daily diary cards and overall condition evaluation at study visits. Clinicians also assessed the same parameters at each visit, and gave a global assessment at study termination. Safety was assessed by monitoring adverse events and laboratory parameters. Cardiac safety was monitored every 4 months using 12-lead ECGs, with particular attention to QT intervals. RESULTS: The trial was completed by 127 patients. Mizolastine reduced overall discomfort from the second week of therapy, and reduced itching and the number and size of wheals, as assessed by the patients. The clinician's assessment of the proportion of patients with > 10 wheals decreased from 42% to 28% after 2 months. Clinical assessment also indicated that itch intensity and angioedema were improved by mizolastine, and the improvement was sustained throughout the trial. The investigators estimated that 70% of patients benefited from therapy. There were no drug-related serious adverse events during the study. The cardiac repolarization assessed according to the QTc intervals was not modified during prolonged administration. CONCLUSION: Mizolastine improves CU symptoms, and these improvements are sustained over 12 months with no loss of drug sensitivity. No specific side-effects are associated with its long-term use in the current study.

Adult↗
PubMed2000

Carboxyfullerenes protect human keratinocytes from ultraviolet-B-induced apoptosis.

Carboxyfullerene, a water-soluble carboxylic acid derivative of a fullerene, which acts as a free-radical scavenger, was investigated as a protective agent against ultraviolet-light-induced damage in human keratinocytes. First, we demonstrate that carboxyfullerene is not cytotoxic for these cells. In addition, this compound significantly reduces the ultraviolet-B-induced inhibition of keratinocyte proliferation and protects keratinocytes from apoptosis caused by ultraviolet B irradiation in a time- and dose-dependent fashion. Furthermore, the percentage of cells with depolarized mitochondria is significantly lower in ultraviolet-B-irradiated keratinocytes pretreated with carboxyfullerene than in cells provided with diluent alone. Carboxyfullerene also protects human keratinocytes from apoptosis induced by exposure to deoxy-D-ribose, a sugar that causes cell death through a pathway involving oxidative stress. On the other hand, ultraviolet B downregulates bcl-2 levels in human keratinocytes, and carboxyfullerene fails to prevent this effect. These results suggest that carboxy- fullerene protects human keratinocytes from ultraviolet B damage possibly via a mechanism interfering with the generation of reactive oxygen species from depolarized mitochondria without the involvement of bcl-2.

Apoptosis↗
PubMed2000

Dysregulated activation of activator protein 1 in keratinocytes of atopic dermatitis patients with enhanced expression of granulocyte/macrophage-colony stimulating factor.

Keratinocytes of patients with atopic dermatitis produce high amounts of granulocyte/macrophage colony-stimulating factor, a factor essential for dendritic cell function and thus for the development of skin immune responses. In contrast to keratinocytes cultured from nonatopic, healthy individuals, granulocyte/macrophage colony-stimulating factor mRNA could be detected in unstimulated cultures of atopic dermatitis keratinocytes, and phorbol myristate acetate induced much greater granulocyte/macrophage colony-stimulating factor mRNA levels in these cells, although the decay kinetics were not altered. Using reporter gene (chloramphenicol acetyl transferase) analysis, a minimal granulocyte/macrophage colony-stimulating factor promoter was shown to confer constitutive and phorbol-myristate-acetate-induced regulation of transcriptional activity in keratinocytes, and significantly higher levels of chloramphenicol acetyl transferase activity were measured in lysates of unstimulated and phorbol-myristate-acetate-treated atopic dermatitis keratinocytes than in control keratinocyte cultures. Electrophoretic mobility shift assays showed that low levels of NF-kappa B binding activity could be induced by phorbol myristate acetate in both normal and atopic dermatitis keratinocytes. By contrast, activator protein 1 complexes were efficiently induced, and they were invariably present at higher levels in nuclear lysates of atopic dermatitis keratinocytes. Atopic dermatitis keratinocyte nuclear lysates had higher constitutive levels of c-Jun, and phorbol myristate acetate promoted an earlier and stronger expression of c-Jun, JunB, and of the phosphorylated forms of c-Fos. A dysregulated activation of activator protein 1 may be implicated in the molecular mechanisms leading to increased granulocyte/macrophage colony-stimulating factor expression in atopic dermatitis keratinocytes. J Invest Dermatol 115:1134-1143 2000

Adolescent↗
PubMed2000

Heterogeneity of oral isolates of Candida albicans in HIV-positive patients: correlation between candidal carriage, karyotype and disease stage.

Opportunist infections involving Candida albicans often develop in HIV-positive patients and oral lesions tend to become more frequent as the disease progresses. Previous studies have shown contrasting results concerning the variability of the pulsed-field gel electrophoresis (PFGE) subtypes of C. albicans observed in HIV-positive patients. Carriage of C. albicans was determined by an oral rinse technique; 41 strains of C. albicans (78% serotype A and 22% serotype B) were isolated. There was a direct correlation between candidal load (cfu/ml) and the blood HIV load, whereas there was an inverse correlation with the stage of disease and the CD4 cell counts. The PFGE patterns of isolates were variable with regard to the number and positions of bands. The variability of the band sizes in some run positions showed a Gaussian distribution. Generally, the most frequent size variants were associated with the strains with the highest cfu/ml and lowest CD4 counts (< or =200 cells/microl). These findings suggest a possible strain selection over time during disease progression, especially in HIV-positive subjects with low CD4 counts.

AIDS-Related Opportunistic Infections↗
PubMed2000

Ceramide 2 (N-acetyl sphingosine) is associated with reduction in Bcl-2 protein levels by Western blotting and with apoptosis in cultured human keratinocytes.

BACKGROUND: Ceramides produced by sphingomyelin hydrolysis activate a cycle that is followed by three different major cellular responses: downregulation of cell proliferation, induction of cell differentiation and apoptosis. In the skin, the generation of intracellular ceramide may also provide a link between an extracellular signal and the induction of the apoptosis programme for the elimination of damaged cells. OBJECTIVES: We investigated the effect of ceramides capable of entering cells on cultured keratinocytes. METHODS: Human keratinocytes from neonatal skin were cultured in serum-free medium with or without increasing concentrations of ceramide 2 (CER-2; N-acetyl sphingosine) (5, 10, 20 and 40 micromol L-1). Proliferative effects were studied either by cell counts or by 3H-thymidine incorporation and flow cytometric analysis. Apoptosis was studied by TUNEL staining and Western blot analysis of Bcl-2 protein. RESULTS: Cell counts and DNA synthesis were reduced in a dose-dependent manner following CER-2 treatment. TUNEL staining showed CER-2-induced apoptosis at 48, 72 and 96 h. Western blot analysis showed that CER-2 induces downregulation of Bcl-2 at 24-96 h. CONCLUSIONS: These results demonstrate that CER-2 inhibits cell proliferation and induces apoptosis, possibly via a Bcl-2-dependent mechanism.

Apoptosis↗
PubMed2000

Association between lesional or non lesional S. aureus strains from patients with impetigo and exfoliative toxin production. No association with SmaI PFGE patterns.

Contrasting data are reported in the literature on the percent positivity rates (13.5%-100%) of exfoliative toxin (ET) production by S. aureus strains isolated from impetigo patients in Japan and in France. In the present study, by means of a recently available latex-test, toxin-A (ETA) or toxin-B (ETB) production was found in 67.6% of the 34 S. aureus strains isolated from 19 lesional (63.2%) and 15 non-lesional (nose or pharynx, 73.3%) areas of patients with impetigo (with no significant difference between the lesional and non-lesional isolates). ETA + ETB were produced by 44.1% of the strains, while 32.4% were non-producers. In contrast, the percent positivity rate observed in 40 [20 lesional and 20 non-lesional (nose or pharynx)] strains isolated in patients with atopic dermatitis was 15.0% (p < 0.001 both for the lesional and non-lesional strains versus impetigo, with no significant difference between lesional and non lesional strains). Finally, 26 strains from other types of specimens (abscesses, hemocultures, urine, central venous catheters, bronchoalveolar lavages) showed an 11.5% production rate of ETA or ETB (p < 0.001 versus impetigo strains, no significance versus atopic dermatitis). These data point to a significant association between exfoliative toxin production and S. aureus strains isolated in impetigo, both in lesional areas and in nasal/pharyngeal reservoirs. An attempt to correlate SmaI pulsed-field gel electrophoresis (PFGE) restriction patterns and exfoliative toxin production showed no significant association in either group.

Adolescent↗