Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients.

BACKGROUND: Proton-pump-inhibitors (PPIs) are frequently prescribed for the management of anticancer drug-related gastrointestinal symptoms. Palbociclib is a weak base with pH-dependent solubility and potential drug-drug interaction at the absorption level may affect clinical pharmacokinetics. The current study was aimed at investigating the effect of co-administration of PPIs and palbociclib on progression-free survival (PFS) in metastatic breast cancer (mBC) patients. PATIENTS AND METHODS: Patients affected by estrogen receptor-positive, human epidermal growth factor receptor 2-negative mBC, who were candidates for first-line treatment with palbociclib, were enrolled in this retrospective observational study. Patients were defined as 'no concomitant PPIs' if no PPIs were administered during palbociclib treatment, and as 'concomitant PPIs' if the administration of PPIs covered the entire or not less than two-thirds of treatment with palbociclib. All clinical interventions were made according to clinical practice. RESULTS: A total of 112 patients were enrolled in the study; 56 belonged to the 'no concomitant PPIs' group and 56 to the 'concomitant PPIs' group. Seventy-one patients were endocrine-sensitive and received palbociclib and letrozole, and 43 were endocrine-resistant and were treated with palbociclib and fulvestrant. The most prescribed PPI was lansoprazole. Patients taking PPIs had a shorter PFS than those taking palbociclib and endocrine therapy alone (14.0 versus 37.9 months, P < 0.0001). Multivariate analysis confirmed concomitant PPIs as the only independent predictive factor for shorter PFS (P = 0.0002). PFS was significantly longer in estrogen-sensitive mBC with no concomitant PPIs compared with patients taking PPIs or estrogen-resistant patients, with and without PPIs (P < 0.0001). No correlation with adverse events was found when considering grade >2 hematological toxicities [Common Terminology Criteria for Adverse Events (CTCAE) scale]. CONCLUSIONS: The present study demonstrates that concomitant use of PPIs in mBC patients treated with palbociclib has a detrimental effect on PFS. Therefore, it is recommended to prescribe PPIs with caution in these patients, strictly adhering to the indications in the summary of product characteristics (RCP).

Assessing ambient ozone injury in olive (Olea europaea L.) plants by using the antioxidant ethylenediurea (EDU) in Saudi Arabia.

The antiozonant chemical, ethylenediurea (N-[2-(2-oxo-1-imidazolidinyl)ethyl]-N'-phenylurea, abbreviated as EDU), was applied as stem injections or soil drenches to 5-year-old containerized plants of olive (Olea europaea L. cultivar Kalamata) in growth chambers in order to assess its ameliorative effects against realistic ozone (O3) stress. Visible injury symptoms were reduced greatly in individuals treated with EDU, with injection applications having greater protection than soil drenches. EDU application caused increases in the measured ecophysiological parameters compared to untreated individuals. In particular, the stem injection protected plants against photosynthetic impairment (unchanged net photosynthetic rates and intercellular CO2 concentration, in comparison to plants grown in filtered air). EDU application increased the protection of PSII from ambient O3 oxidative stress, although it did not retain the proportion of redox state of QA, pigment composition of photosynthetic apparatus and size of light-harvesting complex of PSII. However, the stem injection of plants with EDU induced lower non-photochemical quenching (NPQ) values in comparison to ambient air (-2 %), indicating a better photoprotection of PSII in comparison to soil drench application. EDU application caused increases in the morphological and biometric parameters compared to individuals exposed to ambient air. To the best of our knowledge, this is the first study highlighting the protection of Kalamata olive trees due to EDU in terms of growth, yield, visible injury, and photosynthetic performance. Furthermore, this study proved that EDU could be a low-cost and a low-technology efficient tool for assessing O3 effects on plant performances in the field in Saudi Arabia.

Meningitis and Riga-Fede disease: an unusual condition.

BACKGROUND: Riga-Fede disease (RFD) is a benign inflammatory disorder characterised by the appearance of a traumatic ulceration of the oral mucosa. Early detection of RFD and its adequate management are very important. CASE REPORT: The authors present a an unusual case of RFD with concomitant Staphylococcus aureus meningitis. A 36-day-old female infant was referred to the emergency room of the Hospital of the University of Siena for a 4-day history of high fever. Clinical evaluation revealed the presence of lingual ulceration caused by natal tooth. Few hours later, clinical manifestations were overshadowed by neurological symptoms. The cerebrospinal fluid examination showed the presence of Staphylococcus aureus. The wound healing after extraction of the tooth and the antibiotic therapy have been important for the resolution of this case. A conservative approach is preferable for natal teeth, but in this case the extraction was suggested since a more radical treatment was more likely to avoid major complications.

Replantation of tooth involved in dentigerous cyst: a case report.

AIM: Dentigerous cyst (DC) is a disembriogenetic lesion. The cyst wall encloses the crown of an impacted tooth. Several therapeutic approaches have been mentioned in the literature for management of this lesion. Case Report This article describes the management of an adolescent with a mandibular DC surgically treated with extraction of the tooth, enucleation of the cyst and replantation of the permanent tooth involved. Final outcome shows complete healing of the bone socket with eruption of a vital tooth. No orthodontic traction was required. No recurrence was detected at the radiographic follow-up at 12 months, thus confirming the success of this therapeutic approach. After a 7-year follow-up period the tooth responded positively to the vitality test. CLINICAL IMPLICATIONS: In selected cases surgical enucleation of the lesion without loss of involved tooth, might be considered as a viable treatment to obtain healing of the lesion, spontaneous eruption of the tooth and physiological restoration of bone.

Validation of air pollution biomonitoring networks and related data modelling: a geostatistical approach.

This paper describes a geostatistical approach for environmental data modeling based on value descriptive analysis, variographic analysis, estimation method and validation. It shows an application related to atmospheric pollutant dispersion (ozone) detected by active biomonitoring in the province of Livorno (Italy). This work proposes a two-stage approach based on: the computation of an index on an exploratory and geostatistical data analysis to assess whether a monitoring network is well distributed in space and allows us to get reliable information about the whole study area; the derivation of a continuous representation of the variable (the Cotyledonous Damage Index) from punctual measurements. The geostatistical approach proposed is useful to define in a structured way the possible problems in a monitoring network, to control the data estimation error in the points not sampled. The case study analysed underlines that the biomonitoring network outline does not have a representative sample station distribution of the study area introducing significant errors related to the territorial generalization of the derived information. The proposed approach allows us to elaborate on the obtained data to carry out the data spatialization associating an error to them and to the evaluation model.

Surgical treatment of bifid mental nerve damaged by root canal therapy. A case report.

This article describes the successful surgical treatment of a case of damage to the inferior alveolar nerve, due to inadvertent extrusion of endodontic material into the mandibular canal. The accident was favoured by an anatomical variant of the nerve canal ending with a double mental foramen, already described in the literature. The complex surgical operation of uncertain outcome was dictated by neuralgia refractory to medical treatment, rather than hypoesthesia associated with compression of the nerve trunk. Problems related to loss of sensitivity and possible causes of nerve damage (traumatic, pathological and iatrogenic) are discussed.

Characterization and isolation of some genes of the shikimate pathway in sensitive and resistant Centaurea jacea plants after ozone exposure.

Centaurea jacea has been suggested as a potential bioindicator for ozone, but little is known about its intraspecific variation in sensitivity, especially at molecular level. The effects of ozone (200 ppb, 5 h) on sensitive and resistant lines of Centaurea have been investigated at the end of fumigation. Sensitive plants showed characteristic symptoms of injury in the form of diffuse discoloration stipples on leaves. A PCR-based approach was used to identify and isolate a partial-length cDNA coding for PAL and CHS genes. The northern analysis of PAL showed accumulation of transcript in both lines correlated with a typical increase of PAL activity (+41 and +91% in resistant and sensitive material, respectively, compared to controls). On the contrary, the transcripts of CHS, in resistant and sensitive plants, did not change after treatment. Total phenols were not affected by ozone, while anthocyanins were quickly utilised by resistant clone as antioxidant compounds.

Prognostic value of differential expression of Laminin-5 gamma2 in oral squamous cell carcinomas: correlation with survival.

In oral squamous cell carcinomas of the head and neck, Laminin-5 gamma2 has been associated with tissue invasion, lymph node metastasis and histopathological grading. In the present study, we compared the expression of the subunit gamma2 of Laminin-5 under normal, dysplastic and invading epithelia in 65 biopsies previously diagnosed for oral squamous cell carcinoma. The number of gamma2-positive cells were analyzed in relation to patients' survival, tumor grading, size of the lesion, TNM stage, histopathological pattern of invasion and inflammatory reaction. Biopsies of oral squamous cell carcinomas were deparaffinised, processed for antigen unmasking procedures and stained with antibody anti-Laminin-5 gamma2. By light microscopy, 4 optical fields of x200 were selected in three different areas including normal, dysplastic and invading epithelia. Positive cells were counted and divided into three categories, which included <20 cells, between 21 and 50 cells and >50 stained cells. Patient survival was analyzed by Kaplan-Mayer curves. gamma2-positive cells were found in the basal layer of dysplastic epithelium, within inflammatory infiltrate, at the margins of differentiated invading islands and at the forefront of undifferentiated invading nests. Observations showed that an increased number of gamma2-positive cells correlated significantly with a shorter life expectancy under invading epithelia (log-rank test p<0.05), not when a count was performed under normal or dysplastic epithelia of the same patient. The number of gamma2-positive cells also correlated with the histopathological pattern of invasion. Our results show that gamma2 may be a reliable prognostic tool for oral squamous cell carcinomas.

Integrated biomonitoring of air quality with plants and lichens: a case study on ambient ozone from central Italy.

A biennial integrated survey, based on the use of vascular plants for the bioindication of the effects of tropospheric ozone together with the use of automatic analysers of ozone, as well as the mapping of lichen biodiversity was performed in the area of Castelfiorentino (Tuscany, central Italy). Photochemically produced ozone proved to be a fundamental presence during the warm season, with maximum hourly means reaching 114 ppb, exceeding the information threshold as fixed by EU: the use of supersensitive tobacco Bel-W3 confirmed the opportunity of carrying out detailed cost-effective monitoring surveys. The potential for didactical and educational implications of this methodology are appealing. Critical levels set up for the protection of vegetation have exceeded considerably. The comparison of biomass productivity in sensitive and resistant individuals (NC-S and NC-R white clover clones, in the framework of an European network) provided evidence that ambient ozone levels are associated with relevant reduction (up to 30%) in the performance of sensitive material; effects on flowering were also pronounced. The economic assessment of such an impact deserves attention. Mapping of epiphytic lichen biodiversity--which has been used to monitor air quality worldwide--was not related to ozone geographical distribution as depicted by tobacco response.

Measuring, modelling and testing ozone exposure, flux and effects on vegetation in southern European conditions--what does not work? A review from Italy.

Ozone (O3) exposure at Italian background sites exceeds UN/ECE concentration-based critical levels (CLe(c)), if expressed in terms of AOT40. Yet the occurrence of adverse effects of O3 on forests and crops is controversial. Possible reasons include (i) ability of response indicators to provide an unbiased estimate of O3 effects, (ii) setting of current CLe(c) in terms of cut-off value and accumulation level, (iii) response functions adopted to infer a critical level, (iv) environmental limitation to O3 uptake and (v) inherent characteristics of Mediterranean vegetation. In particular, the two latter points suggest that critical levels based on accumulated stomatal flux (CLe(f)) can be a better predictor of O3 risk than CLe(c). While this concept is largely acknowledged, a number of factors may limit its applicability for routine monitoring. This paper reviews levels, uptake and vegetation response to O3 in Italy over recent years to discuss value, uncertainty and feasibility of different approaches to risk assessment.

Biological monitoring of ozone: the twenty-year Italian experience.

Tropospheric ozone is a growing environmental menace in Italy and in the whole Mediterranean basin. The importance of active biomonitoring of this pollutant with hypersensitive Bel-W3 tobacco plants is stressed, and several examples of field studies carried out in Italy with this technique are presented. Current limitations are discussed, with special emphasis on data quality assessment and the opportunity of adopting easy-to-use kits based on tobacco germlings instead of adult plants. A standardization of methodologies (from cultivation to scoring and data elaboration), also at an international level, is strongly felt to be needed, in order to get official acknowledgement of biomonitoring procedures. Potential educational implications, with the active involvement of students and environmentalists, are shown. Other biological indicators are used, namely sensitive and resistant white clover (Trifolium repens) clones (as descriptors of biomass reduction in crops species) and Centaurea jacea (brown knapweed) as a model species to evaluate the relationship between ozone exposure and effects on the performance and injury symptoms of native plants which are largely used in the framework of European programmes.

Evaluation of biocompatibility of metallic dental materials in cell culture model.

Biocompatibility of metals for dental use was tested using a three-dimensional model consisting of oral keratinocytes cultured on de-epidermised sub-mucosa. The toxicity of orthodontic metallic wire and soldering material was assessed through parameters such as the morphology and growth rate of the keratinocytes, as well as by classical histology, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The sharp composition of metallic wires and soldering materials was assessed by Auger Electron Spectroscopy (AES). The results of our experiment showed that the new model revealed inhibition of keratinocyte growth and stratification near soldering material, whereas mucosal cells were able to grow and layer out on dental wire. It is concluded that this experimental model, which simulates the oral environment, is useful for studying the effects of materials for dental use for its sensibility and reproducibility. Moreover it can provide morpho-functional information which cannot be achieved by traditional methods.

Lichen distribution and bioindicator tobacco plants give discordant response: a case study from Italy.

Epiphytic lichen biodiversity (LB) distribution was evaluated in a 1000 km2 area in Tuscany (Central Italy). In the same area, a survey was performed to monitor tropospheric ozone (O3) phytotoxic effects using tobacco plants (Nicotiana tabacum) cv. Bel-W3 (O3 supersensitive) and cv. Bel-B (O3 resistant) as bioindicators. The LB proved to be negatively correlated with ambient levels of nitrogen oxides, particulate and carbon monoxide, but not with benzene. LB spatial distribution followed a peculiar trend, with highest values in areas with low population density. Data from an O3 analyser set in evidence a typical circadian profile, confirming the photochemical nature of this pollutant. Quite high nocturnal values along the coast were related to the presence of surrounding mountains which constrained the back-and-forth flow of the air in sea breezes. Long- and short-term phytotoxicity critical levels for O3 were systematically trespassed. Bel-W3 tobacco was always affected in every site involved in the study; average O3 injury distribution was greater in rural areas; tobacco response was positively correlated to several O3 descriptors with second-order functions. Correlation analysis failed to demonstrate any association between lichen and tobacco data, due to the fact that LB values were higher in inland zones, far from the main urban and industrial areas, where instead damage to tobacco plants was generally lower. It is concluded that the lichen biodiversity is not suitable for monitoring O3 levels, at least in the study area.

Monitoring and biomonitoring of surface ozone in Florence, Italy.

An ambient air study was conducted in the city of Florence, Italy, in the summer 1996. Tropospheric ozone was continuously monitored with automatic analyzers in three stations, two located in the urban area and one in the hilly surroundings (Settignano). A biomonitoring campaign based on the tobacco cv. Bel-W3 plants was performed in the same area. The highest values were constantly recorded in the Settignano station. The highest 1-hour mean recorded was 197 nl/l; the accumulated exposure over a threshold of 40 nl/l (AOT40) was well above the critical levels standards for protection of the vegetation. A consistent temporal variation was observed and July proved to be the month with the highest ozone levels. Cumulative frequency distribution of ozone maximum daily concentrations exhibited a good fitting to log-normality. No 'week-end' effect was observed. Biomonitoring data were in good agreement with chemico-physical ones.

Effect of chronic ozone fumigation on the photosynthetic process of poplar clones showing different sensitivity.

Rooted cuttings from two poplar clones (Populus x euramericana, I-214, and Populus deltoides x maximowiczii, Eridano) were exposed for 15 days to diurnal square-wave treatment with ozone (60 nL L-1 for 5 h day-1). Completely fully expanded leaves exposed to ozone showed a reduction in net CO2 assimilation rate as compared to the control leaves during whole exposure period in both the clones. The reduction was related to a strong stomatal closure in clone I-214, but also to an altered mesophyll activity ascribed to limitation of the dark reactions of photosynthetic process. The results obtained in leaves of I-214 subjected to long-term fumigation seem to support the view that the decrease in quantum yield of electron transport may be a mechanism to down-regulate photosynthetic electron transport so that production of ATP and NADPH would be in equilibrium with the decreased demand in the Calvin cycle. In Eridano the CO2 assimilation was reduced because of the exposure and any alteration in stomatal conductance was observed. Thus, chlorophyll fluorescence parameters showed that an inhibition of photosystem II had occurred (reduction in Fv/Fm ratio), while no alterations in quenching parameters were observed upon illumination. The results seem to indicate that an alternative sink for reducing equivalent, other than carbon metabolism is present.

Age-related changes in the urinary excretion of aldehydes in ad libitum fed and food-restricted rats.

Age-related changes in the urinary excretion of aldehydes arising from lipid peroxidation have been investigated in male Sprague-Dawley rats aged 2, 4, 6, 12, 18, 24 and 27 months, fed ad libitum or subjected to two different regimens of calorie restriction (namely every-other-day ad libitum feeding--EOD--and 40% calorie restriction--40%DR). For only some age groups, results were compared with those obtained in ad libitum fed male Fisher 344 and Lewis rats. Results show that the urinary excretion of malondialdehyde (MDA) and formaldehyde (FA) significantly decreases, whereas that of propionaldehyde (PROP) progressively increases with age, and that urinary excretion of acetaldehyde (ACT) does not show any significant age-related variations. Dietary restriction significantly increases the urinary levels of MDA, FA and PROP without affecting their age-related modifications, and does not affect ACT urinary excretion. In conclusion, results indicate that the quantitative pattern of aldehyde production and urinary excretion may be altered by the process of aging.