Dynamic optical coherence tomography evaluation in locally advanced basal cell carcinoma during sonidegib treatment.

BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer in the Caucasian population. It has a multifactorial pathogenesis, in which constitutive activation of the Sonic Hedgehog signalling (SHH) pathway (via mutations in PTCH1 or SMO genes) represents by far the most common genetic aberration. The introduction of vismodegib and sonidegib, two SHH pathway inhibitors, changed the therapeutic approach of locally advanced and metastatic BCCs. EADO's (European Association of Dermato-Oncology) new staging system refers to these as 'difficult-to-treat' BCCs. OBJECTIVE: The aim was to evaluate sonidegib's effectiveness in patients affected by difficult-to-treat BCCs by using non-invasive diagnostic techniques. METHODS: We retrospectively evaluated 14 patients (4 females, 10 males; mean age 77 ± 11 years) affected by difficult-to-treat BCCs treated with oral sonidegib 200 mg/day that were followed with total body videodermoscopy (V-Track, Vidix 4.0) and dynamic optical coherence tomography (D-OCT, VivoSight Dx) since May 2022. Considering the risk of rhabdomyolysis routine blood tests, especially for creatine kinase concentrations, were performed. All treated patients were inserted in the BasoCare database, which aims to offer support to patients taking sonidegib. Complete and partial responses were evaluated by the overall reduction of the number of lesions and their individual sizes. Safety was evaluated by assessing the occurrence and severity of adverse reactions. RESULTS: Eighty per cent achieved complete clearance and 75% reduction of diameter. D-OCT scans performed at every follow-up showed concordance with clinical appearance and demonstrated reduction of hyporeflective structures, that is, islets of tumour cells and overall improvement of morphology. CONCLUSION: Sonidegib can be considered an effective treatment option in cases where surgery or radiotherapy would be unfeasible or has previously failed, although pigmented lesions did not show complete clearance, suggesting that there are factors other than the SHH pathway involved in tumour growth. Videodermoscopy and D-OCT were useful in the quick and seamless follow-up of lesions and added valuable information in assessing efficacy.

Impact of switching to raltegravir and/or adding losartan in lymphoid tissue fibrosis and inflammation in people living with HIV. A randomized clinical trial.

BACKGROUND: Persistent inflammation and immune activation are associated with lymph node fibrosis and end-organ diseases in treatment-suppressed people living with HIV (PLWH). We investigated the effect of switching to raltegravir and/or adding losartan on lymphoid tissue fibrosis and on the inflammatory/immune-activation mediators in treated HIV patients. METHODS: Chronic HIV-infected patients treated with two nucleoside reverse transcriptase inhibitors (2NRTI) and one non-NRTI (NNRTI) or protease inhibitor (PI) during at least 48 weeks were randomized to four groups (n = 48): 2NRTI + efavirenz (EFV), 2NRTI + EFV + losartan, 2NRTI + raltegravir and 2NRTI + raltegravir + losartan for 48 weeks. Tonsillar biopsy and peripheral blood markers of CD4 and CD8 T-lymphocyte activation and senescence, monocyte activation and soluble markers of inflammation were determined at baseline and at week 48 and compared between groups. RESULTS: No changes in lymphoid tissue architecture were observed. Adding losartan had no impact on lymphocyte subsets. Conversely, patients who switched to raltegravir showed a higher decrease in all activated [CD4+CD38+HLA-DR+, -0.3 vs. 0.48 (P = 0.033); CD8+CD38+ HLA-DR+, -1.6 vs. 1.3 (P = 0.02)] and senescent [CD4+CD28-CD57+, -0.3 vs. 0.26 (P = 0.04); CD8+CD28-CD57+, -6.1 vs. 3.8 (P = 0.002)] T lymphocytes. In addition, the median CD4/CD8 ratio increased by 0.35 in patients in the raltegravir group vs. 0.03 in the other arms (P = 0.002). Differences between groups in monocyte subpopulations or soluble inflammation markers were not observed. CONCLUSIONS: Losartan had no effect on lymphoid fibrosis or immune activation/inflammation. Conversely, switching to a regimen with raltegravir significantly decreased activated and senescent T-lymphocyte subpopulations and increased CD4/CD8 ratio in successfully treated PLWH.

Modelling peak exposure of pesticides in terrestrial and aquatic ecosystems: importance of dissolved organic carbon and vertical particle movement in soil.

In the present work, an existing vegetation/air/litter/soil model (SoilPlusVeg) was modified to improve organic chemical fate description in terrestrial/aquatic ecosystems accounting for horizontal and vertical particulate organic carbon (POC) transport in soil. The model was applied to simulate the fate of three pesticides (terbuthylazine, chlorpyrifos and etofenprox), characterized by increasing hydrophobicity (log KOW from about 3 to 7), in the soil compartment and more specifically, their movement towards surface and groundwater through infiltration and runoff processes. The aim was to evaluate the role of dissolved organic carbon (DOC) and POC in the soil in influencing the peak exposure of pesticides in terrestrial/aquatic ecosystems. Simulation results showed that while terbuthylazine and chlorpyrifos dominated the free water phase (CW-FREE) of soil, etofenprox was mainly present in soil porewater as POC associated chemical. This resulted in an increase of this highly hydrophobic chemical movement towards groundwater and surface water, up to a factor of 40. The present work highlighted the importance of DOC and POC as an enhancer of mobility in the water of poor or very little mobile chemicals. Further studies are necessary to evaluate the bioavailability change with time and parameterize this process in multimedia fate models.

A novel fuzzy expert system to assess the sustainability of the viticulture at the wine-estate scale.

The wine industry is definitely committed in sustainability: the stakeholders' interest for the topic is constantly growing and a wide number of sustainability programs have been launched in recent years. Most of these programs are focusing on the environmental aspects as environmental sustainability indicators, greenhouse gases emissions and the use of Life Cycle Assessment methodology. Among the environmental indicators the carbon and the water footprint are often used. These indicators, while being useful to assess the sustainability performance of the winegrowing farms, do not take into account important aspects related to the agronomic management of the vineyard. To fill this gap a new indicator called "Vigneto" (Vineyard in Italian language) has been developed. "Vigneto" is a multidimensional indicator to evaluate the sustainability of management options adopted at field scale. It considers the main agronomic aspects, which can have an impact on the environment. These include (i) pest management, (ii) soil management (erosion and compaction), (iii) fertility management (soil organic matter management and fertilizer application), (iv) biodiversity management. Those aspects have been related by fuzzy logics and implemented in web GIS software. The application of the model allows obtaining a general judgment of the agronomic sustainability of the vineyard management: the judgment varies from "A" (excellent) to "E" (completely unsustainable). The produced model was validated and tested by four Italian wine estate. The model output reports that the tested wineries have different management strategies: producers manage vineyards in different ways, depending on the different geographical position. The main differences are related to the soil management and to the presence of natural areas different from vineyard. The developed model can be defined as an environmental decision support system that can be used by wine companies' technicians to define the vineyard practices sustainability performance and support them in the definition of more sustainable management practices.

Theoretically exploring direct and indirect chemical effects across ecological and exposure scenarios using mechanistic fate and effects modelling.

Predicting ecosystem response to chemicals is a complex problem in ecotoxicology and a challenge for risk assessors. The variables potentially influencing chemical fate and exposure define the exposure scenario while the variables determining effects at the ecosystem level define the ecological scenario. In absence of any empirical data, the objective of this paper is to present simulations by a fugacity-based fate model and a differential equation-based ecosystem model to theoretically explore how direct and indirect effects on invertebrate shallow pond communities vary with changing ecological and exposure scenarios. These simulations suggest that direct and indirect effects are larger in mesotrophic systems than in oligotrophic systems. In both trophic states, interaction strength (quantified using grazing rates) was suggested a more important driver for the size and recovery from direct and indirect effects than immigration rate. In general, weak interactions led to smaller direct and indirect effects. For chemicals targeting mesozooplankton only, indirect effects were common in (simple) food-chains but rare in (complex) food-webs. For chemicals directly affecting microzooplankton, the dominant zooplankton group in the modelled community, indirect effects occurred both in food-chains and food-webs. We conclude that the choice of the ecological and exposure scenarios in ecotoxicological modelling efforts needs to be justified because of its influence on the prevalence and magnitude of the predicted effects. Overall, more work needs to be done to empirically test the theoretical expectations formulated here.

In vitro effects of the CCR5 inhibitor maraviroc on human T cell function.

BACKGROUND: Several potential immunological benefits have been observed during treatment with the CC chemokine receptor 5 (CCR5) antagonist maraviroc, in addition to its antiviral effect. Our objective was to analyse the in vitro effects of CCR5 blockade on T lymphocyte function and homeostasis. METHODS: Peripheral blood mononuclear cells (PBMCs) from both HIV-negative (n=28) and treated HIV-positive (n=27) individuals were exposed in vitro to different concentrations of maraviroc (0.1-100 µM). Effects on T cell activation were analysed by measuring the expression of the CD69, CD38, HLA-DR and CD25 receptors as well as CCR5 density using flow cytometry. Spontaneous and chemokine-induced chemotaxis were measured by transwell migration assays, and polyclonal-induced proliferation was assessed by a lymphoproliferation assay and carboxyfluorescein succinimidyl ester staining. RESULTS: Maraviroc increases CCR5 surface expression on activated T cells, even at low doses (0.1 µM). Slight differences were detected in the frequency and mean fluorescence intensity of activation markers at high concentrations of maraviroc. Expression of CD25, CD38 and HLA-DR tended to decrease in both CD4+ and CD8+ T lymphocytes, whereas expression of CD69 tended to increase. Maraviroc clearly inhibits T cell migration induced by chemokines in a dose-dependent manner. Moreover, at 100 µM, maraviroc tends to inhibit T cell proliferation. CONCLUSIONS: These data showed that in vitro exposure to maraviroc decreases some activation expression markers on T lymphocytes and also migration towards chemoattractants. These results support the additional immunological effects of CCR5 blockade and suggest that maraviroc might have potential capacity to inhibit HIV-associated chronic inflammation and activation, both by directly affecting T cell activation and by reducing entrapment of lymphocytes in lymph nodes.

Guidance on the selection of efficient computational methods for multimedia fate models.

Dynamic multimedia fate models (MFMs) have to deal with the temporal and spatial variation of physical-chemical properties, environmental scenarios, and chemical emissions. In such complex simulation tools, an analytical solution is not practically feasible, and even a numerical approach requires a suitable choice of the method in order to obtain satisfying speed and reliability, particularly when certain combinations of modeling scenarios and chemical properties occur. In this paper, considering some examples of a wide range of realistic chemical and scenario properties, some sources of stiffness in MFM equations are pinpointed. Next, a comparison of the performances of several numerical schemes (chosen as representatives of three wide classes) is performed. The accuracy and the computational effort required by each method is evaluated, illustrating the general effectiveness of automatically adapted timesteps in numerical algorithms and the pros and cons of implicit timestepping. The results show that automatic error control methods can significantly improve the quality of the computed solutions and most often lead to relevant savings in computing time. Additionally, explicit and implicit methods are compared, indicating that an implicit method of medium order (around 5) is the best choice as a general purpose MFM computing engine.

Effect of a full-grown vegetative filter strip on herbicide runoff: maintaining of filter capacity over time.

Narrow vegetative filter strips (VFS) proved to effectively reduce herbicide runoff from cultivated fields mainly due to the ability of vegetation to delay surface runoff, promote infiltration and adsorb herbicides. Since VFS are dynamic systems, their performance would not remain constant over the years indicating the need to define suitable buffer management. In order to evaluate the performance of different five and six year-old VFS, the runoff of the herbicides metolachlor and terbuthylazine was monitored in 2002 and 2003 in an experimental site in northern Italy. The structure of the herbaceous cover in the buffers changes over time. When rows of trees are present, the grass cover is decreased by the shading action of the trees, but the leaf litter gains importance. In VFS with grass cover only, the cover composition changes because of the substitution of grass by broadleaf species. Six metres wide VFS are very effective in reducing runoff volume and concentration during both wet and dry years. Classification analysis showed that runoff concentration and volume are linked to the characteristics of the rainfall event, buffer, source of herbicides and time after application. Regression analysis showed that the significant predictors for runoff volume are rainfall amount and intensity, total vegetal cover in the VFS, crop leaf area index and time after treatment; for concentration they are rainfall intensity, crop leaf area index and total vegetal cover in the VFS. The role of VFS is complex, so appropriate management is required to maintain its increasing filtering capacity over time.

El complejo TCR/CD3: especificidad con flexibilidad / TCR/CD3 complex: specificity with flexibility

No disponible

A new case of Lazarus phenomenon?

The international medical literature described sporadical cases of an exceptional event called the "Lazarus phenomenon". This is the spontaneous reviviscence of an individual after a long time of asystolia following a cardiac accident depending on different pathogenesis (i.e. arrhythmia, ischaemic stroke, haemorrhage, brainstem death). All of the reported cases concerned patients presenting recovery after discontinuation of cardiopulmonary resuscitation. Different explanations of the physiopathology of the phenomenon can be given, first of all, the latency of catecholamine action in such patients. We report the case of an 81-year-old woman who experienced a cardiac accident on the street. Once the cardiopulmonary resuscitation was interrupted, the patient presented life activities after some minutes.

Classification of environmental pollutants for global mobility potential.

The environmental behaviour of global organic contaminants is known to be controlled by the physico-chemical properties of the compounds themselves. The principal component analysis of some physico-chemical properties, particularly relevant in determining mobility potential (vapour pressure, Henry's law constant, water solubility, K(OW), K(OA) and melting point) allows a multivariate approach to a ranking of organic pollutants according to their intrinsic tendency towards mobility, and the definition of four a priori mobility classes for screening purposes. Quantitative structure-property relationships (QSPRs) were used to predict missing values for octanol/air partition coefficients. Finally, a classification method employing theoretical molecular descriptors was used to assign studied chemicals to four mobility classes. The proposed approach assesses, directly and simply, a pollutant's inherent tendency towards mobility using only knowledge of the pollutant's molecular structure; the approach is particularly useful for a preliminary screening and the prioritisation of organic pollutants of emerging environmental concern.

Estimating temperature dependence of solubility and octanol-water partition coefficient for organic compounds using RP-HPLC.

Temperature dependence data for physical-chemical properties is increasingly required for modelling the fate of chemicals in the environment. Solubility and octanol-water partition coefficient (Kow) are among the most important parameters. A simple and fast method is presented to determine solubility and Kow of organic chemicals at different temperatures (5 degrees C, 15 degrees C, 25 degrees C, 35 degrees C) utilising a variable temperature RP-HPLC column. Correlations between capacity factors (k') and solubility and Kow were determined for some halogenated and methylated benzenes and showed that this approach could be used to predict acceptable results. New values for solubility and Kow as function of temperature for several compounds are presented.

Simulation of pesticide runoff at Rosemaund Farm (UK) using the SoilFug model.

A validation exercise of the SoilFug model using field runoff data from Rosemaund Farm (UK) is described. A comparison has been made of modelled and measured concentrations of several pesticides in surface water and soil during and after specific rain events following application. The field experiments were designed to obtain data on rainfall, outflows of water, pesticide application rates and concentrations in soil and water. The results were satisfactory for the undissociated pesticides (atrazine, carbofuran, dimethoate, isoproturon, lindane, simazine and trifluralin), whose concentrations in water were mostly predicted within an order of magnitude of measured data. The results for the dissociated pesticides (dichlorprop, MCPA, mecoprop) were less satisfactory, giving generally much higher predicted concentrations in water. The use of the SoilFug model is suggested for the calculation of predicted environmental concentrations (PECs) in water, since it generally produces acceptable results from a relatively small set of input data, most of which is generally available.

Tumores segundos primarios de cabeza y cuello / Second primary tumors of head and neck

Se presentan 3 casos (1,11 por ciento) de tumores segundos primarios y un caso (0,37 por ciento) de tercer primario de cavidad bucofaringolaríngea estudiados entre enero de 1982 y abril de 1991 en el consultorio externo de patología de cabeza y cuello del Hospital P. Piñero, sobre un total de 270 consultas por patología bucofaringolaríngea. Se destaca la importancia de los factores predisponentes tales como tabaco, alcohol y mala higiene dental. La terapéutica adoptada en dichos casos fue encarada como si se tratara de un tumor primario en todos los casos, y con un período libre de enfermedad entre primario y secundario de 3,8 años.

Tumores segundos primarios de cabeza y cuello / Second primary tumors of head and neck

Se presentan 3 casos (1,11 por ciento) de tumores segundos primarios y un caso (0,37 por ciento) de tercer primario de cavidad bucofaringolaríngea estudiados entre enero de 1982 y abril de 1991 en el consultorio externo de patología de cabeza y cuello del Hospital P. Piñero, sobre un total de 270 consultas por patología bucofaringolaríngea. Se destaca la importancia de los factores predisponentes tales como tabaco, alcohol y mala higiene dental. La terapéutica adoptada en dichos casos fue encarada como si se tratara de un tumor primario en todos los casos, y con un período libre de enfermedad entre primario y secundario de 3,8 años. (AU)

Levamisole in squamous cell carcinoma of the head and neck.

One hundred and thirty-four patients (118 males and 16 females) with epidermoid carcinoma of the head and neck were studied. After treatment of the primary lesion, they were randomized into two groups: 69 received levamisole, 150 mg/day orally for 3 consecutive days every other week, and 65 received placebo. Immune status was also evaluated. Positive reactions to dinitrochlorobenzene increased significantly after primary tumor therapy in both levamisole- and placebo-treated patients. There were no significant differences in immune responses between the two groups, except in recall antigen reactivity, which was decreased in both groups overall recurrence and death rates at 36 months did not differ between the two groups of patients. However, stage I and II patients treated with levamisole had a significantly higher incidence of recurrence than the placebo-treated patients (P less than 0.02), while there was some evidence that levamisole-treated stage IV patients did better. It is concluded that the overall outcome in patients with squamous cell carcinoma controlled locally by surgery or radiation was not favorably affected by levamisole in the dose and schedule used in this protocol.

Cell-mediated immune response in head and neck cancer patients.

The immune reactivity of 100 head and neck cancer patients was studied by means of DNCB, candidine, blastic transformation with PHA, and lymphocyte counts. DNCB reactivity was strong in only 21% of the population and was found impaired in patients with advanced primitive tumors, with more than one primitive tumor, and in patients after radiation. Candidine reactivity was impaired in bigger primitive tumors, positive nodes, and advanced stages, as well as in postradiation patients. Blastic transformation was significantly worse in patients over 70 years and tended to be lower in patients with more than one primitive tumor. Good blastic transformation was also lowered in postradiation patients.