Evaluation of non-commercial models for genotoxicity and carcinogenicity in the assessment of EFSA's databases.

Over the past years, the European Food Safety Authority (EFSA) released to the public domain several databases, with the main objectives of collecting and storing hazard data on the substances considered in EFSA's risk assessment and secondly to serve as a basis for further development of in silico tools such as quantitative structure-activity relationship (QSAR) models. In this work, we evaluated the ability of freely available QSAR models to estimate genotoxicity and carcinogenicity properties and their possible use for screening purposes on three different EFSA's databases. With an accuracy close to 90%, the results showed good capabilities of QSAR models to predict genotoxicity in terms of bacterial reverse mutation test, while statistics for in vivo micronucleus test are not satisfactory (accuracy in the predictions close to 50%). Interestingly, results on the carcinogenicity assessment showed an accuracy in prediction close to 70% for the best models. In addition, an example of the potential application of in silico models is presented in order to provide a preliminary screening of genotoxicity properties of botanicals intended for use as food supplements.

Laser removal of tattoos.

In Western countries the phenomenon of "tattooing" is expanding and tattoos are considered a new fashion among young people. In this paper we briefly trace the history of tattooing, the techniques used, the analysis of pigments used, and their possible adverse reactions. We also carried out a review of the international literature on the use of Q-switched laser in tattoo removal and its complications, and we describe our experience in the use of this technique.

Ehlers-Danlos syndrome: case report and an electron microscopy study.

Ehlers-Danlos syndrome (EDS) type III is a inherited connective tissue disorders characterized by extensibility of the skin, hypermobility of the joints, chronic pain, tissue fragility, easy bruising, and delayed wound healing with result of atrophic scars. The patients report commonly a history of recurrent dislocations of the shoulders and knees after low-impact trauma, chronic joint pain, and early osteoarthritis, which lead to diagnosis. The pathogenesis of this condition is unknown, and the diagnosis is generally made in adult age, based only on clinical criteria. In this report, we describe a case of a 50-year-old woman with a 30-year history of recurrent dislocations and atrophic scars. We performed diagnosis of EDS type III after a complete clinical and instrumental evaluation, comprising of histological and electron microscopic studies, that highlighted collagen abnormalities.

Symmetry breaking mechanism for epithelial cell polarization.

In multicellular organisms, epithelial cells form layers separating compartments responsible for different physiological functions. At the early stage of epithelial layer formation, each cell of an aggregate defines an inner and an outer side by breaking the symmetry of its initial state, in a process known as epithelial polarization. By integrating recent biochemical and biophysical data with stochastic simulations of the relevant reaction-diffusion system, we provide evidence that epithelial cell polarization is a chemical phase-separation process induced by a local bistability in the signaling network at the level of the cell membrane. The early symmetry breaking event triggering phase separation is induced by adhesion-dependent mechanical forces localized in the point of convergence of cell surfaces when a threshold number of confluent cells is reached. The generality of the emerging phase-separation scenario is likely common to many processes of cell polarity formation.

Patch coalescence as a mechanism for eukaryotic directional sensing.

Eukaryotic cells possess a sensible chemical compass allowing them to orient toward sources of soluble chemicals. The extracellular chemical signal triggers separation of the cell membrane into two domains populated by different phospholipid molecules and oriented along the signal anisotropy. We propose a theory of this polarization process, which is articulated into subsequent stages of germ nucleation, patch coarsening, and merging into a single domain. We find that the polarization time, t{epsilon}, depends on the anisotropy degree through the power law t{epsilon} infinity epsilon{-2}, and that in a cell of radius R there should exist a threshold value epsilon{th} infinity R{-1} for the smallest detectable anisotropy.

[Smoking cessation course organized by the Italian League for the fight against tumors in Milan and Rome: determinants of cessation after the course and after a year]. / Il corso per smettere di fumare organizzato dalla Lega italiana per la lotta contro i tumori a Milano e Roma: determinanti della cessazione alla fine del corso e dopo un anno.

The Italian League against Cancer organizes a group behaviour therapy program for smoking cessation in Milan and Rome. Groups meet for 8-9 sessions; sessions are managed by a therapist. In the analized courses participants are 43-44 years on the average, with a middle/high level of education. They are heavy smokers with a high level of nicotine dependence and they greatly trust in the program. At the end of the program 67% of participants in Milan and 76% in Rome declare they no longer smoke. One year later, phone interviews show that 22% of participants in Milan and 25% in Rome are still non smokers. At the end of the program quitting-smoking predictors are: attendance at at least 6-7 sessions, smoking less than 30 cigarettes a day before the course and male gender; one year later attendance at at least 6-7 sessions, and scarce nicotine dependence (smoking less than 30 cigarettes a day before the program or a low score at the Fagerström Tolerance Questionnaire).

Mitral valve repair and transesophageal echocardiographic findings in a high-risk subgroup of patients with active, acute infective endocarditis.

BACKGROUND AND AIM OF THE STUDY: Limited data are available regarding the efficacy of mitral valve repair in patients affected by active, acute infective endocarditis. In addition, the predictivity of transesophageal echocardiography (TEE) for guiding the surgical decision-making process in these patients has not yet been reported. The study aim was to evaluate the long-term results of mitral valve repair and role of TEE in active, acute infective endocarditis. METHODS: The study population consisted of patients affected by infective endocarditis of the mitral valve who underwent surgery. TEE was performed intraoperatively to guide the best surgical approach. All patients were followed up (mean 73+/-8 months) after surgery. RESULTS: Twenty-eight patients underwent surgery for infective endocarditis; of these, 13 had mitral valve repair for active, acute infective endocarditis and formed the basis of the study. Sensitivity, specificity, positive predictive value, negative predictive value of TEE in detecting the mechanism of mitral regurgitation were 87%, 100%, 100% and 92%, respectively. The predictivity test of TEE in guiding surgical strategy was 94%. All patients were alive at the time of follow up; 10 (77%) were in NYHA class I and three in class II (23%). Mitral regurgitation was severe in one patient (8%), moderate in three (23%), mild in four (31%), and absent in five (38%). No relapses of active infective endocarditis were observed during the follow up period. CONCLUSION: Mitral valve repair appears to be an effective treatment for active, acute infective endocarditis with mitral regurgitation and should be considered as a therapeutic strategy when surgery is contemplated. TEE has a fundamental role in the surgical decision-making process in these patients.

Continuous retrograde warm blood reperfusion reduces cardiac troponin I release after heart transplantation: a prospective randomized study.

During heart surgery, cardiac troponin I (cTn-I) measurement provides a tool to evaluate different cardioprotective techniques. To investigate myocardial protection during heart transplantation (HTx), cTn-I and creatine kinase (CK)-MB release was measured in 42 patients randomized to receving either continuous retrograde warm blood reperfusion or no reperfusion after cold cardioplegia. A significant linear correlation was found between donor heart ischemic time and peaks and the area under the curve of cTn-I and CK-MB release. In patients with an ischemic time longer than 90 min, cTn-I release was significantly lower in those receiving continuous retrograde warm cardioplegia than in controls. No significant difference was observed for CK-MB, tCK, and myoglobin. Our data suggest that the measurement of postoperative cTn-I release may provide a method to evaluate ischemic cardiac damage after HTx. When the ischemic time is longer than 90 min, warm retrograde blood cardioplegia provides better myocardial protection than no reperfusion.

Epstein-Barr virus-negative lymphoproliferate disorders in long-term survivors after heart, kidney, and liver transplant.

BACKGROUND: Solid organ transplant patients undergoing long-term immunosuppression have high risk of developing lymphomas. The pathogenesis of the late-occurring posttransplantation lymphoproliferative disorders (PTLD) have not yet been extensively investigated. METHODS: We studied 15 patients who developed PTLD after a median of 79 months (range 22-156 months) after organ transplant. Clonality, presence of Epstein-Barr virus (EBV) genome, and genetic lesions were evaluated by Southern blot analysis or polymerase chain reaction. RESULTS: All monomorphic PTLD and two of three polymorphic PTLD showed a monoclonal pattern. Overall, 44% of samples demonstrated the presence of the EBV genome. Within monomorphic PTLD, the EBV-positive lymphomas were even lower (31%). A c-myc gene rearrangement was found in two cases (13%), whereas none of the 15 samples so far investigated showed bcl-1, bcl-2, or bcl-6 rearrangement. The modulation of immunosuppression was ineffective in all patients with monomorphic PTLD independent of the presence of the EBV genome. The clinical outcome after chemotherapy was poor because of infectious complications and resistant disease. With a median follow-up of 4 months, the median survival time of these patients was 7 months. CONCLUSIONS: Late occurring lymphomas could be considered an entity distinct from PTLD, occurring within 1 year of transplant, because they show a histological and clinical presentation similar to lymphomas of immunocompetent subjects, are frequently negative for the EBV genome, are invariably clonal, and may rearrange the c-myc oncogene. New therapeutic strategies are required to reduce the mortality rate, and new modalities of long-lasting immunosuppression are called for.

Multicenter study on hepatitis C virus infection in patients with dilated cardiomyopathy. North Italy Transplant Program (NITP).

Preliminary epidemiological and histological studies from Japan suggested that hepatitis C virus (HCV) infection has a role in the development of dilated cardiomyopathy (DCM). This multicenter study was conducted to verify this hypothesis on a large cohort of Italian patients with end-stage heart failure. Antibodies to HCV were determined in the 752 consecutive patients (608 males and 144 females; age, 53 +/- 13 years) who entered the waiting list for cardiac transplantation from 1995 to 1997 at the six cardiac surgery centers participating in the North Italy Transplant program. Three hundred and nine patients (41%) had dilated, 9 (1%) restrictive, and 4 (0.5%) hypertrophic cardiomyopathy; 284 patients (38%) had ischemic, 65 (9%) valvular, and 22 (3%) congenital heart disease; 5 patients (0.5%) had primary pulmonary hypertension; 54 patients (7%) had other or nonspecified heart disease. Overall, 41 of 752 patients (5.4%) resulted anti-HCV-reactive. Serological evidence of HCV infection was found in 12 of 309 patients with DCM (3.9%; 95% CI, 1.7-6.0), and in 29 of 443 without DCM (6.5%; 95% CI, 4.2-8.8), without statistical difference (difference of prevalence rate: 2.6%; 95% CI, -4.9 to 5.8). In conclusion, HCV does not seem to have a primary role in the pathogenesis of DCM. However, since our findings are in disagreement with those obtained in smaller series of patients of other ethnicity, large studies from different countries should be conducted.

Fatal aortic Myceliophthora thermophila infection in a patient affected by cystic medial necrosis.

A 22-year-old Italian woman developed fungal aortitis after cardiac surgery for aortic insufficiency. She experienced two episodes of septic embolization and subsequently underwent replacement of the aortic root and initial ascending aorta by a homograft. The lumina of the ascending aorta, aortic arch and the origin of the innominate artery were completely filled with vegetation. From the involved tissue the phaeoid thermophilic hyphomycete Myceliophthora thermophila (Apinis) van Oorschot was isolated in pure culture. This is the second report of isolation of this fungus from humans and the first isolation of a human pathogenic strain of M. thermophila causing fatal vasculitis in a patient affected by cystic medial necrosis. A detailed morphological description of the isolate is also provided.

[Successful medical treatment of Candida tropicalis in prosthetic valve endocarditis]. / Tratamiento medico exitoso de una endocarditis en valvula protesica por Candida tropicalis.

Medical cure of fungal prosthetic valve endocarditis (PVE) is rarely reported. We describe a patient with C. tropicalis PVE in whom surgery was believed to be contraindicated. A huge tricuspid valvular vegetation was identified by two-dimensional transthoracic echocardiography. After a total of 2 g of amphotericin B, she continued with fluconazole daily with a follow-up of fifteen months. Our patient represents the first case of long term survival of C. tropicalis PVE successfully managed without surgery.

The risk of coronary artery disease after heart transplantation is increased in patients receiving low-dose cyclosporine, regardless of blood cyclosporine levels.

BACKGROUND: Coronary artery disease (CAD) of allografted hearts is the main cause of late mortality after cardiac transplant, but its etiology is still undetermined. HYPOTHESIS: This study was undertaken to evaluate the relevance of several risk factors, including cyclosporine (CsA) dose and blood CsA levels, to the incidence of CAD. METHODS: In 163 heart transplants performed between November 1985 and August 1994 at our Institution, CAD was diagnosed by coronary angiography or at postmortem examination. Patients in whom postmortem examination or coronary angiography was not performed, as well as those < 15 years of age and those who died within 1 month of surgery, were excluded from the study. The following risk factors were analyzed: recipient age, gender, pretransplant diagnosis, donor age, number of human leukocyte antigen (HLA)-AB mismatches, cytomegalovirus serology, mear serum cholesterol and triglyceride levels, the number of treated acute rejections, mean weighted CsA dose (CsA dosew and weighted blood CsA levels (blood CsA levelw). RESULTS: Coronary artery disease was diagnosed in 32 patients (19.6%). A low mean CsA dosew was the only significant predictor for CAD at multivariate analysis (p < 0.01): there was no correlation with blood CsA levelw. In the patients receiving a CsA dosew > 4 mg/kg/day, the 8.9 year probability of their remaining CAD free was 69% [confidence interval (CI) 50-87%] in comparison with 31% (CI 0-65%) in patients receiving a CsA dosew < 4 mg/kg/day. CONCLUSION: In our experience, a low CsA maintenance dose is the main risk factor for CAD, irrespective of blood CsA levels.

Attitudes toward euthanasia of physician members of the Italian Society for Palliative Care.

BACKGROUND: The problems related to requests for euthanasia by terminal patients; the variations in attitude of palliative care physicians and the possibility that availability of the best palliative care might obviate the problem by eliminating requests for euthanasia, are under discussion. DESIGN: A mailed survey with no possibility of follow-up of all 685 physician members of the Italian Society for Palliative Care (SICP) in 1994. RESULTS: Of the 359 (52.4%) responders, 139 (39%) had received requests for euthanasia; 16 of them (4% of the responders but 11.5% of those who received requests) had complied at least once, while 216 (60%) had not; 125 (35%) thought that euthanasia was 'wrong' under all circumstances; 115 (32%) thought that situations could occur, even in the context of palliative care, in which euthanasia might be ethically 'correct'; 185 (52%) thought that the best palliative care might solve the problem of euthanasia, while 109 (30%) believed otherwise. The variable most strongly associated with a negative attitude toward euthanasia and with the opinion that the best palliative care might be a solution to the problem is religious belief (P < 0.0001). CONCLUSIONS: The attitudes of physicians practising palliative care in Italy are not different from those reported by previous studies which investigated the attitude of other health professionals. There was no agreement about whether the best palliative care might reduce requests for euthanasia by terminal patients.

Reduction of haemorrhagic complications during mechanically assisted circulation with the use of a multi-system anticoagulation protocol.

Two different anticoagulation protocols were used in 49 consecutive patients mechanically supported either for bridge to transplantation (11) or for recovery of myocardial function after cardiac surgery (35). In 46 patients a Biomedicus centrifugal pump was used and in 3 patients a Pierce-Donachy ventricles. Mechanical support was provided to the left ventricle in 14 patients, to the right ventricle in 6 and to both ventricles in 12 patients; an extra-corporeal membrane oxygenator (ECMO) support was used in 17 patients. Thirty-seven males and 12 females, aged 0.2 to 58 years, were supported for an average time of 6.3 days (range 1-43). Anticoagulation was either based on a continuous infusion of heparin in the first 27 patients (group A) or on a multi-system therapy ("La Pitié" protocol) in the other 22 patients (group B). Overall survival rate was 47%. Patients in group A had a 30% (8/27) survival rate, whereas in group B a 68% (15/22) survival rate was observed (p = 0.006). Transplantation and ventricular assist device (VAD) removal was successfully obtained in 59% (16/27) and 91% (20/22) of patients in group A and group B respectively (p = 0.05). Significant bleeding occurred in 21 patients (81%) in group A and in 2 (9%) of group B (p = 0.001). In these patients bleeding averaged 230 +/- 231 ml/kg in group A versus 55 +/- 18 ml/kg in group B (p = 0.001). Surgical revision was necessary for cardiac tamponade or persistent bleeding in 12 patients of group A (25 procedures: mean 0.9/patient) and in 3 patients of group B (one each patient: mean 0.1/patient) (p = 0.01). Infection, thrombo-embolism and brain hemorrhage were also less frequent in group A than in group B. Our data suggest that the "La Pitié" protocol provides a better control of bleeding than the conventional heparin infusion in patients receiving assist device. this reduction in thrombo-hemorrhagic complications might improve the results of mechanical circulatory support.

Recombinant human erythropoietin may correct erythropoietin-deficient hyporegenerative anaemia in children given cardiac transplantation.

Cyclosporin-A reduces erythropoietin production and, together with the inhibitory effect of cytokines on erythropoiesis, may be potentially responsible for the anaemia observed in some patients after heart transplantation. Two children given cardiac transplantation and receiving cyclosporin-A developed transfusion-dependent hyporegenerative anaemia. Erythropoietin production was inappropriately low for the degree of anaemia, with an observed/predicted log(serum EPO) ratio of 0.54 and 0.49, respectively. The children were treated with rHuEPO at a dose of 75 U/kg three times weekly for 1 month and then twice weekly via subcutaneous injection. No further transfusion was necessary and restoration of normal erythroid activity was obtained, with normal haemoglobin values. No adverse effects were observed. Our experience suggests that recombinant human erythropoietin may be useful in treating the anaemia associated with cardiac transplantation.

Pediatric heart transplantation without chronic maintenance steroids.

From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with cyclosporine and azathioprine. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

A therapy impact questionnaire for quality-of-life assessment in advanced cancer research.

The first part of the validation procedure used for a Therapy Impact Questionnaire (TIQ) on quality-of-life assessment in advanced cancer patients is described. The TIQ is composed of 36 items which assess both disease and therapy impact according to four dimensions that operationally define quality of life: physical symptoms (24 items), functional status (3 items), concomitant emotional and cognitive factors (6 items) and social interaction (2 items). A global judgement expressed as "have you been feeling ill" further completes the TIQ. Patients answered each question using a 4-point verbal Likert scale: not at all, slight, a lot and very much. The TIQ was given to 1,000 consecutive patients who were no longer responsive to cancer treatment and presented symptoms due to disease progression. The compliance rate was quite high (87%). Results of confirmatory factor analysis were consistent with the operational dimensions identified during questionnaire construction. In particular, the dichotomized answers to 3 functional status items could be used as a Guttman scale. In a sub-sample of 50 patients, the reproducibility of functional status items was assessed using a 7-item parallel form. The intraclass correlation coefficient obtained indicated a reasonably high reproducibility. On the basis of the analyses conducted, the TIQ appears to be a reliable and concise instrument for studies aimed to assess the effectiveness of therapies in advanced cancer patients.

Psychosocial adjustment of patients surgically treated for head and neck cancer.

Sixty-six patients, surgically treated for head and neck cancer and free of disease, were interviewed at the outpatient clinic from 6 months to 8 years after surgery. The patients were divided by the physician into two groups, according to the patients' degree of disfigurement, i.e., minor (24 patients, 36%, minor disfigurement group = MDG) or extensive (42 patients, 64%, extensive disfigurement group = EDG). Subsequently, the patients were interviewed with close-ended questions. The following subjective aspects were assessed: self-image; relationship with the partner, family, and friends; and the overall impact of the therapy. The results of the study showed a significantly higher impact in the EDG versus the MDG as regards a changed self-image (57% vs 25%, P less than 0.05), a worsened relationship with the partner (27% vs 0%, P less than 0.05), a reduced sexuality (74% vs 39%, P less than 0.01), and an increased social isolation (36% vs 12%, P less than 0.05). On the whole, 18% of the subjects stated that the disadvantages of therapy outweighed the advantages, and 30% fell that the difficulties encountered were "too harsh." In such cases, the opportunity of setting up a rehabilitation program offering psychosocial support should be considered.

Nature and extent of glomerular injury induced by cyclosporine in heart transplant patients.

We sought to clarify whether low-dose cyclosporine (5.0 +/- 2.2 mg/kg/day) given for more than two years to prevent cardiac graft rejection induced glomerular injury and to quantify the extent of the lesions. After renal hemodynamic studies, renal biopsy specimens were obtained from 10 patients on cyclosporine and analyzed by a novel morphometric technique consisting of a tridimensional reconstruction of the glomerular tuft. Autopsy kidney specimens from three patients with no clinical history of renal disease, and from four patients who died with dilatative cardiomyopathy served as controls. The glomerular filtration rate and renal plasma flow were significantly depressed below normal values in transplant recipients given cyclosporine, averaging 35 +/- 8 and 325 +/- 94 ml/min/1.73 m2, respectively. Conventional light microscopy of specimens from controls and from patients who died with dilatative cardiomyopathy did not reveal renal structural abnormalities. By contrast kidney specimens from cyclosporine-treated patients had obliterative arteriolopathy and ischemic-type changes, with thickening and wrinkling of glomerular capillary wall. Morphometrical analysis of 28 control glomeruli and 40 glomeruli from patients with dilatative cardiomyopathy showed glomerular capillary tuft volumes (VCT) ranging between 1.2 and 2.3 microns 3 x 10(-6), whereas of 102 glomeruli from cyclosporine-treated patients 42.1% had VCT lower than 1.2 microns 3 x 10(-6) and 24.4% VCT higher than 2.3 microns 3 x 10(-6).(ABSTRACT TRUNCATED AT 250 WORDS)