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.

Effective Management Of Topical Nosocomial Aspergillus Spp. Infections In Three Severely Burned Patients.

Nosocomial opportunistic fungal infections by Aspergillus spp. represent increasing morbidity and mortality factors for severely burned patients, who are fragile and immunocompromised. Voriconazole (VRC), a modern antifungal drug, is used as a first-line therapy against systemic mold and yeast infections. Little has been published about the place, relative importance and efficacy of voriconazole in the treatment protocols involving Aspergillus spp. in Burn Centers. The objective of the present work was to assess the place and importance of voriconazole for the treatment of burn patients presenting superficial Aspergillus spp. infections. We performed a retrospective evaluation of VRC treatment in three severely burned patients with superficial nosocomial Aspergillus spp. infections in our Burn Center. Results showed that VRC allowed for control and cure of topical nosocomial Aspergillus spp. infections. In two cases, treatment with VRC had to be discontinued because of hepatotoxicity. In two cases, following or during systemic treatment with VRC, a 1% terbinafine cream was applied to resolve the infection in order to continue standard wound management. Overall, VRC has been shown to be an effective antifungal agent and is an alternative to amphotericin B to fight Aspergillus spp. infections developing in the wounds of severely burned patients.

La survenue d'une aspergillose chez les patients gravement brûlés, dès lors immunodéprimés, est une cause de morbidité et de mortalité. Le voriconazole (VRC) est un antifongique utilisé en première intention dans le traitement des infections à moisissures. La littérature est pauvre au sujet de son utilisation dans l'aspergillose chez le brûlé. Cette étude a pour but de l 'évaluer dans le traitement de l'aspergillose cutanée chez le brûlé et a consisté en l'évaluation rétrospective de la prise en charge de trois patients de notre CTB, gravement brûlés et victimes d'une aspergillose cutanée. VRC en a permis la guérison, mais a dû être suspendu 2 fois en raison d'une toxicité hépatique. Dans 2 cas, il a été associé à de la crème de terbinafine à 1%. Le traitement habituel a pu être repris après guérison de l'aspergillose. Globalement, VRC semble efficace et représente une alternative à l'amphotéricine B dans le traitement de l'aspergillose cutanée chez les brûlés.

Development of a Multi-Dimensional Coastal Vulnerability Index: Assessing vulnerability to inundation scenarios in the Italian coast.

Understanding how natural and human-induced drivers will contribute to rising vulnerability and risks in coastal areas requires a broader use of future projections capturing the spatio-temporal dynamics which drive changes in the different vulnerability dimensions, including the socio-demographic and economic spheres. To go beyond the traditional approaches for coastal vulnerability appraisal, a Multi-dimensional Coastal Vulnerability Index (MDim-CVI) - integrating a composite set of physical, environmental and socio-economic indicators - is proposed to rank Italian coastal provinces according to their relative vulnerability to extreme sea level scenarios, in 2050. Specifically, information on hazard-prone areas, potentially inundated by sea level rise and extreme water levels (under the RCP8.5 climate scenario) is combined with indicators of geomorphic vulnerability (e.g. elevation, distance from coastline, shoreline evolution trend) exposure, and adaptive capacity (e.g. sensible segments of the population, GDP, land use patterns). The methodology is applied to a reference timeframe, representing current climate and land use condition, and a future scenario for the year 2050, integrating both climate projections and data simulating potential evolution of the environmental and socio-economic systems. Results show that most vulnerable provinces are located in the North Adriatic, the Gargano area and other Southern parts of Italy, mostly due to the very high vulnerability scores reported by climate-related indicators (e.g. extreme sea level). The number of vulnerable provinces as well as the magnitude of vulnerability is expected to increase in the future due to the worsening of climate, environmental, and socio-economic conditions (e.g. land use variations and increase of the elderly population). These outcomes can timely inform integrated coastal zone management and support climate adaptation planning.

How important is hydrotherapy? Effects of dynamic action of hot spring water as a rehabilitative treatment for burn patients in Switzerland.

Burn rehabilitation using hydrotherapy can have multiple benefits for the burn patient. The therapy uses specific mineral enriched hot spring water and water jets with varied hydro-pressure to combat hypertrophy, inflammatory reaction signs, abnormal pigmentation, and, more specifically, redness and scarring. Standard operating procedures for burn rehabilitation have been developed and integrated into the Standard of Care at the CHUV hospital using localized hydro-mechanical stimulation of burn sites (20 minutes of alternating anatomical sites) followed by constant pressure large-bore and filiform showers targeting specific scarred areas. These therapeutic regimens are repeated daily for 2 to 3 weeks. Patients showed lasting effects from this regimen (up to 3-6 months), the results becoming permanent with more uniform skin structure, color and visco-elasticity in addition to a decrease in pruritus. The specifications of clinical protocols are described herein along with the virtues of hot spring hydro-pressure therapy for burn rehabilitation. The use of hydrotherapy, which has been a controversial topic among burn units across the world, is also discussed. In North America, hydrotherapy is defined only within the scope of in-patient wound cleansing and is thought to lead to microbial auto-contamination and bacterial resistance. In Switzerland and France the emphasis of hydrotherapy is on rehabilitation after the wound has closed.

L'hydrothérapie pendant la réhabilitation des patients atteints de brûlures peut avoir plusieurs avantages. Le point focal de cette thérapie est l'utilisation d'une source d'eau thermale de source chaude enrichie en minéraux et de jets d'eau avec une variation de pression afin de lutter contre l'hypertrophie, les signes de réaction inflammatoire, une pigmentation anormale et en particulière des rougeurs et des cicatrices. Pour la réhabilitation des brûlures, les procédures d'utilisation normalisées ont été développés et intégrés dans le standard des soins dans notre hôpital. Ces procedures comportent une stimulation hydro-mécanique localisée sur les sites de brûlures (20 minutes en alternant les sites atomiques), suivie par une pression constante localisée directement sur les cicatrices faite à l'aide de douches de gros diamètre et puis de douches filiformes. Ce régime thérapeutique est répétée quotidiennement pendant 2 à 3 semaines. Après le traitement, les patients ont pu observer une structure plus uniforme de leur peau ainsi qu'une amélioration de sa couleur et de sa visco-élasticité, aussi bien que la diminution du prurit, et ce durant 3 à 6 mois. Ici nous présentons les spécificités de notre protocoles cliniques et les avantages d'une traitement d'eau thermale de source sous pression pour la réhabilitation des patients brûlés. Nous parlerons également de l'utilisation de l'hydrothérapie, qui est un sujet de controverse parmi les unités de soins aux brûlures à travers le monde. En Amérique du Nord, l'hydrothérapie est définie uniquement dans le cadre du nettoyage des plaies des patients hospitalisés, et elle peut conduire à l'auto-contamination microbienne et la résistance bactérienne. En Suisse et en France, l'hydrothérapie concerne uniquement la réhabilitation des plaies une fois cellesci fermées.

A rare case of serous papillary cystadenocarcinoma of the testis.

The serous papillary cystadenocarcinoma is a rare testicular neoplasm, which depending on the histological features can behave more or less aggressive, thus leading to a not always predictable prognosis. We present diagnosis and treatment of a case of serous papillary cystadenocarcinoma of the testis with associated adherent mass to the tunica albuginea, which compressed the parenchyma without infiltrating it.

[Epidemiological impact of RV gastroenteritis in the Abruzzo Region: SDO analysis]. / Impatto epidemiologico delle gastroenteriti da Rotavirus nella Regione Abruzzo: analisi delle SDO.

RV represent the principle cause of acute gastroenteritis in infants in the world. In developing countries they are responsible for a high mortality rate in children under the age of five, whereas, in industrialized countries the RV infection is mainly related to hospitalisation. In order to study the epidemiological impact of enteritis caused by RV, we used the SDO files (hospital discharge code) in the Abruzzo Region relative to the years 2003-2006. Of a total number of 3146 children under the age of 5 who were diagnosed with gastroenteritis at the moment of hospitalisation, 1025 presented gastroenteritis of viral origin and 48.4% (496) due to RV. Furthermore, 253 hospital admissions were observed for RV in a second diagnosis. Infants of 12-23 months are those subject to the highest rate of hospitalisation ranging from 295/100.000 and 517/100.000. The use of the SDO files can determine an underestimation of the hospitalisation incidence for RV because to confirm a correct diagnosis the analysis of faeces should be systematically carried out but this is not always undertaken. The implementation of a secure and efficient vaccine strategy seems to be justified in poor countries, whereas in the industrialized countries, such a strategy can reduce the health expenditure for gastroenteritis by RV.

[Poverty and nutrition: a survey on the under age sons of the beneficiaries of the R.M.I. in the L'Aquila District Area]. / La povertà e l'alimentazione: indagine sui figli minori dei beneficiari del R.M.I. nel Comune di L'Aquila.

The alimentary education, let alone the relative behaviour, represent an important preliminary statement for a children perfect growth. The results of a not healthy nutrition or alimentary mistakes can produce several problems. The study aims to analyze the child and adolescent nutrition for families with economic difficulties that receive a (social and economic) benefit called "Reddito Minimo di Inserimento" (RMI), within the L'Aquila district area. For the valuation of nutrition state, it has been used the BMI (Body Mass Index), with the necessary corrections for sex and age. From the made analysis, the children's about 33% is classifiable as "at risk of soprappeso" or as "soprappeso", with prevalence for the males, above all in the classes of younger ages, like the most recent studies on the children's nutrition.

Safety and efficacy of low dose Escherichia coli enterotoxin adjuvant for urease based oral immunisation against Helicobacter pylori in healthy volunteers.

BACKGROUND AND AIMS: Escherichia coli heat labile enterotoxin (LT) at doses of 5 micro g or 10 micro g has adjuvant activity for oral immunisation in humans infected with Helicobacter pylori, but causes severe diarrhoea. This study was undertaken to establish a safe and effective dose of LT, to confirm the safety of recombinant urease, and to compare the immunogenicity of orally compared with enterically delivered urease. METHODS: 42 healthy adults without present or past H pylori infection were randomised to receive 60 mg recombinant H pylori urease in soluble or in encapsulated form, given with doses of LT ranging from 0 micro g to 2.5 micro g. Four oral doses were administered at day 1, 8, 29, and 57. Specific IgG, IgA, and antibody secreting cells were measured as well as total alpha4beta7 integrin positive lymphocyte responses. RESULTS: Enterically delivered urease was well tolerated and no serious adverse events occurred. Mild diarrhoea (one to four loose stools) occurred after the first immunisation in 50% (6 of 12) of the volunteers exposed to 2.5 micro g LT (p=0.06; paired t test, compared with baseline) but not in volunteers exposed to lower LT doses. Immune responses occurred in five (p=0.048; Fisher's exact test), one, two, and one of six subjects exposed to 2.5 micro g, 0.5 micro g, 0.1 micro g, and no LT, respectively. Significant CD4(+), CD69(+), and CD45RO(hi) responses occurred over time among alpha4beta7(hi) lymphocytes in volunteers receiving 2.5 micro g LT. Enterically delivered urease induced higher lymphocyte responses than soluble urease. CONCLUSIONS: The safety of H pylori urease is confirmed. Oral LT may conserve its adjuvant activity at low doses with minimal side effects.

Gastric mucosal alpha(4)beta(7)-integrin-positive CD4 T lymphocytes and immune protection against helicobacter infection in mice.

BACKGROUND & AIMS: The integrin alpha(4)beta(7) mediates homing of effector/memory lymphocytes to the intestine and the mucosa-associated lymphoid tissue. This study examined the ability of alpha(4)beta(7)(hi) CD4(+) T lymphocytes to home to the stomach and their role in immunization-mediated protection against Helicobacter felis infection. METHODS: Gastric lamina propria and circulating mononucleated cells of naive, infected, and immunized Swiss Webster mice were isolated, and alpha(4)beta(7)-integrin expression was quantified by flow cytometry on CD4(+) T lymphocytes. Anti-alpha(4)beta(7)-integrin antibody was used to block alpha(4)beta(7) function in vivo. RESULTS: In naive mice, alpha(4)beta(7)(hi) CD4(+) T cells were enriched approximately 10-fold in the gastric mucosa compared with peripheral blood (P<0.0001). Chronic H. felis infection did not alter these proportions, but oral immunization with H. felis sonicate plus cholera toxin (CT) or with CT alone markedly increased gastric alpha(4)beta(7)(hi) CD4(+) T cells compared with naive and infected controls (P = 0.0008 and P = 0.002 for H. felis sonicate and CT, respectively). Anti-alpha(4)beta(7)-integrin antibody blocked the protection induced by oral immunization with H. felis sonicate and CT. CONCLUSIONS: The integrin alpha(4)beta(7) participates in the homing of CD4(+) T lymphocytes to the stomach and in the protection of the gastric mucosa against H. felis infection.

[A case of primary non-Hodgkin lymphoma of the breast]. / Un caso di linfoma non-Hodgkin primitivo della mammella.

Primary non-Hodgkin's lymphomas (NHL) of the breast represent less than 3% of extranodal NHL; in comparison to extranodal NHL at other sites, they are characterized by rapid progression and worse prognosis. We report a case of primary NHL of the breast treated, after surgery, with a sequential combination of chemotherapy and radiotherapy. Literature data suggest that the most important factors in therapeutic decisions making are the initial stage of the disease and the histological subtype.

N,N-dialkylaminosubstituted chromones and isoxazoles as potential anti-inflammatory agents.

The ability of some N,N-dialkylaminosubstituted chromones and isoxazoles to inhibit the protein kinase C (PKC) dependent signal transduction pathway was tested. As a cellular model, human neutrophils stimulated with either phorbol myristate acetate (PMA) or formylmethionine-leucine-phenylalanine (f-MLF) were used. The efficiency of the compounds was established by their capacity to reduce the O2- production by activated human neutrophils. Compounds carrying a 3-bis(2-methoxyethyl)amino group, a substituent found active in previously tested tricyclic compounds, do not show significant anti-PKC activity in this study. On the other hand, substitution with a 1-piperidinyl group leads all tested compounds to a high biological activity against stimulated neutrophils.

[Metaplastic tumors of the breast: a case of primary squamous cell carcinoma]. / Tumori metaplasici della mammella: un caso di carcinoma squamoso primitivo.

We report a case of primary squamous cell carcinoma of the breast in a 58 years old woman. The diagnosis of this rare tumor is possible after excluding a skin primary lesion or an epidermoid cancer of a distant site. In reviewing the reported cases we didn't find any significant prognostic difference between this form and the breast adenocarcinoma with squamous metaplasia.

Mechanism of action of a new component of the Ca(2+)-dependent proteolytic system in rat brain: the calpain activator.

Rat brain contains a calpain activator specific for the mu-form of the proteinase. We now report that this protein factor binds to the catalytic 80 kDa calpain subunit, promoting the dissociation of the heterodimer structure of the proteinase. The successive steps of the activation process, namely the two autoproteolytic steps producing the 78 kDa and the 75 kDa calpain forms, result in a 100 times faster rate. The activator competes with calpastatin and associates with the inner surface of plasma membranes. Based on its properties, the calpain activator can be visualised as the molecule indicating the sites for calpain activation at which the proteinase can also elude the negative control exerted by calpastatin.

Molecular and functional properties of a calpain activator protein specific for mu-isoforms.

A natural calpain activator protein has been isolated from bovine brain and characterized in its properties and molecular structure. The protein is a homodimer with a molecular mass of about 30 kDa and results in being almost identical to UK114 goat liver protein. Significant similarities with mouse HR12 protein were also observed, whereas a lower degree of similarity was found with a family of heat-responsive proteins named YJGF and YABJ from Haemophilus influenzae and Bacillus subtilis, respectively. The brain activator expresses a strict specificity for the mu-calpain isoform, being completely ineffective on the m-calpain form. As expected, also UK114 was found to possess calpain-activating properties, indistinguishable from those of bovine brain activator. A protein showing the same calpain-activating activity has been also isolated from human red cells, indicating that this factor is widely expressed. All these activators are efficient on mu-calpain independently from the source of the proteinase. The high degree of specificity of the calpain activator for a single calpain isoform may be relevant for the understanding of sophisticated intracellular mechanisms underlying intracellular proteolysis. These data are indicating the existence of a new component of the Ca2+-dependent proteolytic system, constituted of members of a chaperonin-like protein family and capable of promoting intracellular calpain activation.

Calcium-binding properties of human erythrocyte calpain.

The results presented provide more information on the sequential mechanism that promotes the Ca2+-induced activation of human erythrocyte mu-calpain under physiological conditions. The primary event in this process corresponds to the binding of Ca2+ to eight interacting sites, of which there are four in each of the two calpain subunits. Progressive binding of this metal ion is linearly correlated with the dissociation of the proteinase, which reaches completion when all eight binding sites are occupied. The affinity for Ca2+ in the native heterodimeric calpain is increased 2-fold in the isolated 80 kDa catalytic subunit, but it reaches a Kd consistent with the physiological concentration of Ca2+ only in the active autoproteolytically derived 75 kDa form. Binding of Ca2+ in physiological conditions, and thus the formation of the 75 kDa subunit, can occur only in the presence of positive modulators. These are represented by the natural activator protein, found to be a Ca2+-binding protein, and by highly digestible substrates. The former produces a very large increase in the affinity of calpain for Ca2+, and the latter a smaller but still consistent decrease in the Kd of the proteinase for the metal ion. As a result, both dissociation into the constituent subunits and the autoproteolytic conversion of the native 80 kDa subunit into the active 75 kDa form can occur within the physiological fluctuations in Ca2+ concentration. The delay in the expression of the proteolytic activity with respect to Ca2+ binding to native calpain, no longer detectable in the 75 kDa form, can be attributed to a Ca2+-induced functional conformational change, which is correlated with the accessibility of the active site of the enzyme.

Anti-PKC activity of some 3-(dialkylamino)-1H-naphtho [2,1-B] pyran-1-ones.

Some 3-(dialkylamino)-1H-naphtho [2,1-b] pyran-1-ones were tested to evaluate their ability to inhibit Protein Kinase C (PKC) activation. The model consisted in the detection of the superoxide anion in activated neutrophils. Naphthopyrans carrying 3-(diethylamino), 3-(1-piperidinyl) and 3-[bis(2-methoxyethyl)amino] groups emerged as the most active ones. Introduction of alkoxy groups in position 8 and 9 and of bromo substituent in position 8 on the naphthalene moiety was associated with an increase in anti-PKC activity. No activity was found when an electron withdrawing group was placed in position 2 of the 3-(dialkylamino)-1H-naphtho [2,1-b] pyran-1-ones.

Modulation of the calpain autoproteolysis by calpastatin and phospholipids.

The Ca-induced autoproteolysis calpain proceeds through the sequential formation of two forms of active enzyme with molecular masses of 78 kD and 75 kD, respectively. The autolysed calpains are produced by the cleavage of the peptide bond between Ser15-Ala16 and then between Gly27-Leu28. Calpastatin reduces with high efficiency the transition from 78 kD to 75 kD calpain forms. At higher concentration also the first autolytic event is blocked. The data are consistent with the presence of two calpain forms with different susceptibility to calpastatin. Furthermore, calpain, once bound to phospholipid vesicles, undergoes autoproteolysis which preferentially accumulates the 78 kD species. These data provide new information on the activation process of calpain, indicating that a Ca-induced conformational change is the triggering event, followed by the appearance of the active 78 kD calpain which can be considered the preferential form of calpain at the membrane level.

Autolysis of human erythrocyte calpain produces two active enzyme forms with different cell localization.

The 80 kDa human erythrocyte calpain, when exposed to Ca2+, undergoes autoproteolysis that generates a 75 kDa species, with an increase in Ca2+ affinity. It is demonstrated here that this proteolytic modification proceeds through an initial step producing a 78 kDa form which is rapidly converted to the 75 kDa one. In the presence of the calpain inhibitor E-64, the 78 kDa form accumulates and only small amounts of the 75 kDa polypeptide are formed. Following loading of erythrocytes with micromolar concentration of Ca2+, in the presence of the ionophore A23187, the native 80 kDa calpain subunit is extensively translocated and retained at the plasma membrane, this process is accompanied by the appearance of only a small amount of the 75 kDa subunit which is released into the soluble fraction of the cells. Following exposure to microM Ca2+, membrane-bound 80 kDa calpain is converted to the 78 kDa form, this conversion being linearly correlated with the expression of the proteinase activity. Taken together, these results demonstrate that the initial step in calpain activation involves Ca(2+)-induced translocation to the inner surface of plasma membranes. In the membrane-bound form the native inactive 80 kDa subunit is converted through intramolecular autoproteolysis to a locally active 78 kDa form. Further autoproteolytic intermolecular digestion converts the 78 kDa to the 75 kDa form, no longer being retained by the membrane. This process generates two active forms of calpain, with different intracellular localisations.