From single to multivariable exposure models to translate climatic and air pollution effects into mortality risk. A customized application to the city of Rome, Italy.

This study presents an approach developed to derive a Delayed-Multivariate Exposure-Response Model (D-MERF) useful to assess the short-term influence of temperature on mortality, accounting also for the effect of air pollution (O3 and PM10). By using Distributed, lag non-linear models (DLNM) we explain how city-specific exposure-response functions are derived for the municipality of Rome, which is taken as an example. The steps illustrated can be replicated to other cities while the statistical model presented here can be further extended to other exposure variables. We derive the mortality relative-risk (RR) curve averaged over the period 2004-2015, which accounts for city-specific climate and pollution conditions. Key aspects of customization are as follows: This study reports the steps followed to derive a combined, multivariate exposure-response model aimed at translating climatic and air pollution effects into mortality risk. Integration of climate and air pollution parameters to derive RR values. A specific interest is devoted to the investigation of delayed effects on mortality in the presence of different exposure factors.

Climate change and air pollution: Translating their interplay into present and future mortality risk for Rome and Milan municipalities.

Heat and cold temperatures associated with exposure to poor air quality lead to increased mortality. Using a generalized linear model with Poisson regression for overdispersion, this study quantifies the natural-caused mortality burden attributable to heat/cold temperatures and PM10 and O3 air pollutants in Rome and Milan, the two most populated Italian cities. We calculate local-specific mortality relative risks (RRs) for the period 2004-2015 considering the overall population and the most vulnerable age category (≥85 years). Combining a regional climate model with a chemistry-transport model under future climate and air pollution scenarios (RCP2.6 and RCP8.5), we then project mortality to 2050. Results show that for historical mortality the burden is much larger for cold than for warm temperatures. RR peaks during wintertime in Milan and summertime in Rome, highlighting the relevance of accounting for the effects of air pollution besides that of climate, in particular PM10 for Milan and O3 for Rome. Overall, Milan reports higher RRs while, in both cities, the elderly appear more susceptible to heat/cold and air pollution events than the average population. Two counterbalancing effects shape mortality in the future: an increase associated with higher and more frequent warmer daily temperatures - especially in the case of climate inaction - and a decrease due to declining cold-mortality burden. The outcomes highlight the urgent need to adopt more stringent and integrated climate and air quality policies to reduce the temperature and air pollution combined effects on health.

Supporting the improvement of air quality management practices: The "FAIRMODE pilot" activity.

This paper presents the first outcomes of the "FAIRMODE pilot" activity, aiming at improving the way in which air quality models are used in the frame of the European "Air Quality Directive". Member States may use modelling, combined with measurements, to "assess" current levels of air quality and estimate future air quality under different scenarios. In case of current and potential exceedances of the Directive limit values, it is also requested that they "plan" and implement emission reductions measures to avoid future exceedances. In both "assessment" and "planning", air quality models can and should be used; but to do so, the used modelling chain has to be fit-for-purpose and properly checked and verified. FAIRMODE has developed in the recent years a suite of methodologies and tools to check if emission inventories, model performance, source apportionment techniques and planning activities are fit-for-purpose. Within the "FAIRMODE pilot", these tools are used and tested by regional/local authorities, with the two-fold objective of improving management practices at regional/local scale, and providing valuable feedback to the FAIRMODE community. Results and lessons learnt from this activity are presented in this paper, as a showcase that can potentially benefit other authorities in charge of air quality assessment and planning.

Effects of in vivo culture of murine mammary adenocarcinoma cells on tumor and metastatic growth.

We studied the effect of tumoral microenvironments on metastatic phenotypes. Therefore, murine mammary adenocarcinoma cells cultured in vivo in diffusion chambers (DC) were implanted intraperitoneally in BALB/c mice. The behavior of DC-cultured cells was compared with that of cells obtained from tumors growing subcutaneously or intraperitoneally and from primary cultures in vitro of the former. DC-cultured and control cells were inoculated into normal mice to evaluate their tumorigenicity and metastasizing ability. We found that DC-cultured cells were less tumorigenic and metastatic both in spontaneous and in experimental metastasis assays. The host response to tumor progression resulted in an early leukocytosis, probably due to the overproduction of a hematopoietic factor by the tumor cells. Finally, it was found that DC-cultured cells produced lower levels of urokinase-type plasminogen activator activity, while no differences were found in the metalloproteinase production compared to cells obtained from a tumor growing subcutaneously.

Involvement of nitric oxide in the regulation of peripheral blood leukocyte counts.

A role for nitric oxide (NO) in the regulation of blood leukocyte numbers was examined in BALB/c mice by employing the NO synthase inhibitor NG-nitro L-arginine methyl ester (L-NAME). Treatment of animals with a single dose of 50 mg/kg body wt caused a dramatic increase in the number of circulating neutrophils and a moderate decrease in the number of circulating lymphocytes. These effects were partially reversed by the simultaneous inoculation of L-arginine (250 mg/kg body wt.) but not by D-arginine. A second NO synthase inhibitor, NG-nitro L-arginine, induced changes comparable to those elicited by L-NAME. Because catecholamines and glucocorticoids are well-known modulators of blood leukocyte counts, experiments were carried out in adrenalectomized mice. It was found that adrenalectomy did not modify the increase in the number of circulating neutrophils induced by L-NAME but completely prevented the decrease of circulating lymphocytes. Taken together, these findings support the hypothesis that NO plays an important role in the regulation of the peripheral blood number of neutrophils and lymphocytes, and that this function involves, in each case, the participation of different mechanisms.

Graft-vs-host reaction induced by para-aortic lymph nodes during estrous and diestrous stages.

Mouse uterine draining lymph node (UDLN) cells, or soluble factors released by them in both phases of the estrous cycle were examined in the graft-vs-host (GVH) assay. The immune response during the estrous phase was significantly decreased as compared with diestrous phase; 24-hour culture supernatant of UDLN cells was also able to decrease GVH activity mounted in F1 hybrids. This difference in reactivity was not found when peripheral nodes (PN) or spleen cells were tested. These results show that in physiological conditions it is possible to detect an hormonal influence on T lymphocyte function and would suggest that a non-specific immunosuppression would appear even during the estrous phase.

Enhancement of the incidence of metastasis in tumor-resected mice. Influence of soluble tumor extract and splenectomy.

The M3 mammary tumor was transplantable in syngeneic BALB/c mice, and metastasized spontaneously into the lungs. When primary tumors were resected in early stages of evolution (10 days), the number of mice with lung metastasis decreased. When specific soluble tumor extracts, tumor cell culture supernatant or formalinized tumor cells were inoculated 2 and 4 days after surgery, an enhancement of lung metastasis was observed. When splenectomy was performed at the time of tumor resection, this enhancement was abrogated. These results suggest that tumor plasma cell membranes or the products released by them play an important role in dormant metastases growth, but only in the presence of the spleen, suggesting its involvement in the mechanism of the metastatic process.

[A case of hydronephrosis in a newborn infant: prenatal diagnosis and treatment]. / Su di un caso di idronefrosi neonatale: diagnosi prenatale e trattamento.

Experience with the prenatal diagnosis and management of one case of left neonatal hydronephrosis is presented. The ultrasound examination allowed the prenatal diagnosis and justified neither prenatal intervention nor early delivery. The diagnosis was confirmed at the birth and was followed by an early successful conservative treatment.

Tumor delayed hypersensitivity reactions. "In vivo" functional differences between spleen and peripheral blood lymphocytes.

In a syngeneic BALB/c transplantable tumor model, specific delayed hypersensitvity reaction, detected by foot-pad swelling test appeared specifically suppressed or "eclipsed" in advanced tumor bearing mice. This "eclipsed" response could not be reversed after tumor resection. Unresponsiveness was analyzed by local adoptive transfer of lymphocytes from two different sources. When spleen cells (SC) from advanced tumor bearing and advanced tumor resected mice were locally transferred into normal recipients, a positive cutaneous delayed hypersensitivity (CDH) reaction was observed. While when peripheral blood lymphocytes (PBL) from the same anergic donors were transferred, no CDH reactivity was elicited. Functional differences between SC and PBL populations are suggested to explain these findings.