Évaluation des technologies de réduction des agents pathogènes InterceptMC et MirasolMC pour le traitement des produits sanguins labiles au Québec / Assessment of InterceptTM and MirasolTM Pathogen Reduction Technologies for the Treatment of Labile Blood Products in Quebec

MANDAT: L'Institut national d'excellence en santé et en services sociaux (INESSS) a reçu le mandat de la Direction de la biovigilance et de la biologie médicale (DBBM) du ministère de la Santé et des Services sociaux (MSSS) de réévaluer la pertinence de l'introduction des technologies de réduction des agents pathogènes (TRP) InterceptMC et MirasolMC pour le traitement des produits sanguins labiles au Québec. Il s'agit de la deuxième évaluation de ces technologies par l'INESSS à la suite de la recommandation en 2017 de ne pas introduire le procédé InterceptMC dans la chaîne de production des produits sanguins labiles au Québec. DESCRIPTION: Les TRP InterceptMC et MirasolMC sont des processus qui visent à inactiver certains virus, parasites et bactéries par l'utilisation d'agents chimiques ou physiques. Contrairement aux produits sanguins stables, les produits sanguins labiles (culots globulaires, plasma et plaquettes) offerts au Québec ne sont actuellement pas soumis à un tel processus. Advenant leur introduction, ces technologies pourraient s'ajouter aux

MANDATE: The Institut national d'excellence en santé et en services sociaux (INESSS) was mandated by the Direction de la biovigilance et de la biologie médicale (DBBM) of the Ministère de la Santé et des Services sociaux (MSSS) to reassess the relevance of introducing InterceptTM and MirasolTM pathogen reduction technologies (PRTs) for the treatment of labile blood products in Quebec. This is the second assessment of these technologies by INESSS following the recommendation in 2017 not to introduce the InterceptTM Blood System in the labile blood products' production chain in Quebec. DESCRIPTION: Intercept™ and Mirasol™ are PRTs that aim to inactivate certain viruses, parasites, and bacteria through the use of chemical or physical agents. Unlike stable blood products, labile blood products (packed red blood cells, plasma, and platelets) offered in Quebec are not currently subjected to such a process. If introduced, these technologies could be added to the various preventive measures that are already being used to reduce the risks of contamination. ASSESSMENT PROCESS: The assessment used an approach based on the overall value appraisal that the Institute advocates in its Statement of Principles and ethical fondations. A rapid review of the literature was carried out in order to mobilize evidence and reassess the relevance of introducing PRTs in the labile blood products' production chain in Québec. PRT manufacturers were invited to transmit relevant information. Contextual and experiential data was collected from stakeholders through a meeting with Héma-Québec, an expert advisory committee, a focus group with representatives of patient organizations, and a citizen panel. A budget impact analysis (BIA) aiming to quantify the expected financial impact following the introduction of a PRT for the treatment of plasma and platelets was also conducted. The comprehensive scientific, contextual, and experiential data was interpreted using a multidimensional framework to guide certain consultation processes as well as the deliberation process for the development of recommendations by the "Comité délibératif permanent - Remboursement et accès". Socio-CULTURAL DIMENSION: Héma-Québec deploys the preventive measures it deems necessary to ensure the safety of labile blood products distributed in Quebec. Similarly, the Canadian Blood Services (CBS) is implementing preventive measures for the other Canadian provinces and has gradually been rolling out PRTs since January 2022 for the treatment of platelet units in selected hospitals. Some countries that are socially and economically comparable to Canada have taken divergent positions on PRTs, with some being favourable, such as France and Switzerland, and others being unfavourable, such as England. Considering a partial or complete introduction in other countries and Canadian provinces and based on the precautionary principle, the Comité de biovigilance decided that it would be important to consider a strategic introduction of PRTs in order to prepare for the emergence of various pathogens in Quebec. However, the committee has specified that this technology should not replace current preventive measures and should apply only to a small percentage of labile blood products. Although Héma-Québec deems the infectious risks associated with labile blood products to be minimal, it considers the risks associated with the emergence of known pathogen agents (KPAs) and unknown pathogen agents (UPAs) to be legitimate and it regards PRTs as an insurance policy against these intangible and unpredictable risks. Moreover, following the Coronavirus Disease 2019 (COVID-19) pandemic, the potential risk of an emerging pathogen has become more apparent according to the representatives of patient associations that we consulted. Despite the transfusion safety measures in place for labile blood products, this awareness may, for some, have influenced their risk perception. POPULATION DIMENSION: Transfusion safety is a shared responsibility between Héma-Québec, which ensures the safety of blood products, and transfusion hospitals, which are responsible for the quality of the transfusion procedure for patients. Héma-Québec receives nearly 800 orders of labile blood products daily and delivers more than 295,000 of these products annually to hospital centres. Only plasma and platelet units, which represent 22% of the labile blood products distributed, could potentially be treated by PRTs. In order to meet transfusion safety needs, the blood system in Quebec could benefit from better communication on transfusion complications, more preventive measures for noninfectious complications, alternative treatments to transfusions, and increased selfsufficiency in labile blood products. Since the risk of infectious complications associated with transfusions is currently considered low and acceptable by all stakeholders consulted, the main benefit of a PRT occurs during the hypothetical emergence of an UPA. CLINICAL DIMENSION: Intercept™ and Mirasol™ technologies have been shown to be effective on a wide range of viruses, bacteria, and protozoa in laboratory tests. However, the effectiveness of these two PRTs is limited against certain spores, biofilms, residual endotoxins, prions, multidrug-resistant Gram-negative bacteria, and non-enveloped viruses. In addition, there are concerns about the lack of efficacy of Mirasol™ technology against blood-borne viruses such as hepatitis B and cytomegalovirus (CMV). The effects of Intercept™ and Mirasol™ technologies on the biological properties of platelets or plasma are considered acceptable. Both technologies have no effect on bleeding or haemostatic function. However, treatment with both PRTs is accompanied by a statistically significant decrease in post-transfusion platelet recovery, a decrease in the time interval between transfusions, and a statistically significant increase in the number of transfusions per patient. Finally, some studies report a statistically significant increase in the number of transfusion-refractory patients and an increase in alloimmunization rates for platelets treated with Intercept™ compared to conventional platelets. Long-term toxicity or oncogenicity associated with residual amotosalen is also a concern for the Intercept™ technology, especially in pediatrics. ORGANIZATIONAL DIMENSION: Héma-Québec is facing supply chain challenges due to an increase in demand, a constrained pool of donors and a limited shelf life for labile products. PRTs have the potential to reduce the time it takes to make certain labile blood products available if they are accompanied by the withdrawal of bacterial testing. However, compared to untreated products, PRTs lead to an increase in the frequency and number of transfusions per patient, which can thus affect blood product stocks. However, uncertainty remains as to the actual impact of PRTs on plasma or platelet stocks. Moreover, the introduction of these technologies would require changes in the production chain, such as the rapid treatment of collected blood products. According to HémaQuébec, the scale of these changes as well as the resources mobilized would be limited. CBS has made the decision to remove bacterial screening and irradiation from the production chain of products treated with Intercept™ in other Canadian provinces. However, in Quebec, the withdrawal of certain preventive measures that have shown their effectiveness in ensuring the safety of labile products is not unanimous and is not planned by Héma-Québec in the short term. ECONOMIC DIMENSION: A scientific literature update on economic efficiency identified one recently published study specifically assessing Intercept™. According to this analysis, the use of a PRT would have an incremental cost-utility ratio (ICUR) of $9.3 million per QALY gained compared to current preventive measures. This ICUR could see a downturn in the event of the emergence of an UPA, decreasing to $8.6M or approximately $331K per QALY earned, depending on scenario analyses based on rates of infectious transmission of previous pathogens. The conclusions established in the 2017 assessment by INESSS remain unchanged. Uncertainty remains as to the system's willingness to pay for a health intervention such as a PRT according to an insurance principle. Regarding the budgetary impact estimated by INESSS, the uncertainty surrounding certain BIA parameters, in particular the introduction strategy, supported a scenariobased approach. INESSS estimates that the introduction of a PRT to treat only 10% of platelet units, in a partial introduction scenario, would generate a net budget impact of $11.6 million over 10 years. The net budgetary impact is estimated at $157.4 million over 10 years when it is assumed that PRT would treat 100% of platelets and plasma. INESSS Recommendation: Based on the information available to date and given the importance of the uncertainties raised about the added value of PRTs in the production chain of labile blood products in Quebec, INESSS considers that it would not be fair and equitable to implement such a technology. INESSS may reassess the available PRTs, at the request of the Ministère de la Santé et des Services sociaux (MSSS), when new information likely to influence the recommendation becomes available

Developmental biology meets toxicology: contributing reproductive mechanisms to build adverse outcome pathways.

An adverse outcome pathway (AOP) is a simplified description of the sequence of mechanistic events that lead to a particular toxicological effect, from initial trigger to adverse outcome. Although designed to inform regulatory risk assessors, the AOP framework also provides a platform for innovative collaborations between experts from relevant research fields and the regulatory community. The underpinning for any AOP is basic knowledge about molecular and developmental processes; such knowledge can only be attained by solid bioscientific research. Starting with this fundamental knowledge, the objective is to devise novel testing strategies that focus on key events in a causative pathway. It is anticipated that such a knowledge-based approach will ultimately alleviate many of the burdens associated with classical chemical testing strategies that typically involve large-scale animal toxicity regimens. This hails from the notion that a solid understanding of the underlying mechanisms will allow the development and use of alternative test methods, including both in vitro and in silico approaches. This review is specifically targeted at professionals working in bioscientific fields, such as developmental and reproductive biology, and aims to (i) inform on the existence of the AOP framework and (ii) encourage new cross-disciplinary collaborations. It is hoped that fundamental biological knowledge can thus be better exploited for applied purposes: firstly, an improved understanding of how our perpetual exposure to environmental chemicals is causing human reproductive disease and, secondly, new approaches to screen for harmful chemicals more efficiently. This is not an instructional manual on how to create AOPs; rather, we discuss how to harness fundamental knowledge from the biosciences to assist regulatory toxicologists in their efforts to protect humans against chemicals that harm human reproductive development and function.

[COPD due to Occupational Noxae]. / COPD durch berufliche Noxen.

The chronic obstructive pulmonary disease (COPD) is characterised by mainly non-reversible bronchial obstruction with airflow limitation. Typically, it exhibits a progressive course. It is one of the leading causes of morbidity and mortality worldwide. In addition to dominating causative smoking and environmental exposures (especially biomass smoke from cooking with open fire stoves), about 15 % are due to occupational exposure. Relatively rare cases (ca. 6 %) do not show an external noxious influence. Occupational causes are frequently not recognised because a detailed occupational history has not been taken. This is especially evident by the discrepancy in the identified COPD prevalences and incidences shown in many studies on the one hand and relatively low numbers in the official statistics on reports, acknowledgements and compensations of the disorder on the other hand. Whether occupational exposures to inhalative noxae are - in addition to non-occupational factors (e. g. smoking) - causative according to legal definitions is frequently a challenging question. Respective decisions of social courts in litigations are presented.

Investigation of Mode of Action of Anti Bacterial Activity of Salacia Oblonga Extract Against Drug Resistant Pathogen

Abstract Salacia oblonga Wall belonging to family Celastraceae contains vital phytoconstituents and has been used since long for the treatment of diabetes, inflammation and burn wounds. S. oblonga ethyl acetate root extract was evaluated for antibacterial activity towards drug resistant pathogens Staphylococcus aureus, Pseudomonas aeruginosa and Klebsiella pneumoniae. Further 260 nm absorbing material was estimated in the control and treated cells. Interestingly 260 nm absorbance material is higher in the Staphylococcus aureus. Further the effect of the plant extract on drug resistant pathogen S. aureus was examined by scanning electron microscopy (SEM). SEM results have shown that treated bacterial cells have changed in morphology, size and reduced in number. Based on these results it can be concluded that S. oblonga extract acts on membrane of the drug resistant pathogen S. aureus.

Nociception.

Nociception, the sensory mechanism that allows animals to sense and avoid potentially tissue-damaging stimuli, is critical for survival. This process relies on nociceptors, which are specialized neurons that detect and respond to potentially damaging forms of energy - heat, mechanical and chemical - in the environment. Nociceptors accomplish this task through the expression of molecules that function to detect and signal the presence of potential harm. Downstream of the nociceptive sensory input, the neural signals trigger protective (nocifensive) behaviors, and the sensory stimuli that reach the brain may be perceived as painful.

Intestinal injury in the rat model of 17α-ethynylestradiol-induced intrahepatic cholestasis.

OBJECTIVE: Although the intimate relationship between liver and gut has been previously reported under physiological and pathological conditions, intestinal involvement in the process of intrahepatic cholestasis of pregnancy remains unclear. The aim of this study was to investigate intestinal changes in 17α-ethynylestradiol (EE)-induced cholestatic rat model. METHODS: Liver injury was assessed by HE stain and serum biochemical parameters were measured. Intestinal transit was determined using ink marks. Neuronal protein expressions in the intestine were analyzed by Western blot. RESULTS: EE treatment induced liver damage, including severe bile duct hyperplasia, portal edema, portal infiltration, a loss of hepatic structure in periportal areas and increased serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and total bilirubin. Large areas of inflammatory cell infiltration and increased myeloperoxidase activity were observed in the intestine of EE-induced cholestatic rats. The EE-treated group showed increased intestinal transit and malondialdehyde levels, while the glutathione content and superoxide dismutase activity were notably decreased, together with decreased protein gene product 9.5 and neuronal nitric oxide synthase expression in the ileum and colon. Furthermore, choline acetyltransferase expression was significantly decreased in the ileum, whereas no change was observed in the colon of EE-treated rats. CONCLUSION: EE-induced liver damage is associated with oxidative stress, inflammation and neural loss in the intestine, which may lead to altered intestinal motility.

Doença peri-implantar follow-up microbiológico de 5 anos e revisão sistemática com meta-análise / Peri-implant disease: Microbiological 5-year follow-up and systematic review with meta-analysis

Objetivos: Avaliar, em um estudo longitudinal de 5 anos, a associação entre o diagnóstico da doença peri-implantar (DPi) e a contagem de patógenos na presença e ausência de terapia de manutenção periodontal/peri-implantar (TMPP). Realizar uma revisão sistemática de estudos observacionais para avaliar se dados presentes na literatura indicam uma maior prevalência de peri-implantite (PI) em indivíduos com diagnóstico ou histórico de periodontite (PE). Métodos: O estudo longitudinal microbiológico foi realizado avaliando-se, através da técnica da reação em cadeia da polimerase em tempo real, as seguintes espécies bacterianas: T. forsythia, T. denticola, P. gingivalis, P. intermedia, F. nucleatum e A. naeslundii em 80 indivíduos com mucosite peri-implantar (MP) que realizavam consultas para manutenção periodontal/peri-implantar regular (GTP, n = 39) comparados aos que não realizavam (GNTP, n = 41). Para a revisão sistemática uma busca eletrônica foi conduzida até março de 2016. Foram encontrados 1330 estudos, 17 artigos foram incluídos na análise final (PROSPERO CRD42015009518). A meta-análise foi realizada para presença ou ausência de PI. Medidas de efeito sumário e taxas de razão de chances (OR) com 95% IC foram calculadas. Resultados: Os resultados do estudo longitudinal mostraram que, após 5 anos, houve uma diminuição da carga bacteriana total (CBT), na frequência das bactérias analisadas do complexo laranja (p = 0.013) e nas frequências isoladas de T. forsythia (p = 0.000), P. gingivalis (p = 0.003) e P. intermedia (p = 0.013) no GTP. Indivíduos com PI apresentaram maiores frequências de P. gingivalis (GNTP: p = 0,030; GTP: p = 0,000), T. denticola (GNTP: p = 0,017) e F. nucleatum (GTP e GNTP; p = 0.002) comparados aos com MP. Indivíduos que desenvolveram PI apresentaram um aumento na CBT (GTP: p = 0.047; GNTP: p = 0,055) e na frequência isolada de P. gingivalis (GNTP: p = 0,002) e F. nucleatum (GTP e GNTP; p = 0.000). Não houve diferenças estatisticamente significativas intergrupos em relação aos patógenos do complexo vermelho (p > 0,05). Tanto nos indivíduos com MP (T1 e T2: p = 0,000), quanto nos indivíduos com PI (T2: p = 0,000), a frequência do complexo laranja foi significativamente menor no GTP. A meta-análise dos estudos coorte mostrou que indivíduos (OR = 7.22), e implantes (OR = 5.63) apresentaram maior risco de desenvolver PI. Nos estudos transversais, em análises não ajustadas, indivíduos com PE apresentaram maior chance de ter PI (OR = 3.18). Quando a análise foi ajustada para tabagismo e diabetes não houve aumento estatisticamente significativo no risco para PI (OR = 1.73; IC 95% 0.86- 3.45). Conclusões: Pôde-se concluir que a ausência de consultas regulares para manutenção periodontal/peri-implantar foi associada com pior condição clínica periimplantar, maior incidência de PI e um aumento significativo na CBT. Adicionalmente, indivíduos com diagnóstico de PI apresentaram maiores frequências de P. gingivalis, T. denticola e F. nucleatum e maior CBT. A revisão sistemática permitiu concluir que indivíduos com diagnóstico ou histórico de PE podem apresentar um risco aumentado para PI. Mais estudos prospectivos são necessários para confirmar a evidência, principalmente os ensaios clínicos controlados randomizados

Aims: Evaluate, in a 5-year longitudinal study, the association between peri-implant disease's (DPi) diagnosis and the count of pathogens in the presence and absence of periodontal/peri-implant maintenance therapy. Conduct a systematic review of observational studies to evaluate whether data in the literature indicates a higher prevalence of peri-implantitis (PI) in subjects with diagnosis or history of periodontitis (PE). Methods: the microbiologic study was performed evaluating, through polymerase chain reaction in real time technique, the following bacterial species: T. forsythia, T. denticola, P. gingivalis, P. intermedia, F. nucleatum and A. naeslundii in 80 patients with peri-implant mucositis (PM) that were queries for periodontal/periimplant regular maintenance (GTP, n = 39) compared to those who were not (GNTP, n = 41). For the systematic review an electronic search was conducted until March 2016. It was found 1330 studies, 19 articles were included in the final analysis (PROSPERO CRD42015009518). The meta-analysis was performed for presence or absence of PI. Summary measures and odds ratio (OR) with 95% IC were calculated. Results: the results of the longitudinal study showed that, after 5 years, there was a decrease in the total bacterial load (TBL), the frequency of bacteria analyzed in the orange complex (p = 0.013) and in the frequencies of T. forsythia (p = 0.000), P. gingivalis (p = 0.003) and P. intermedia (p = 0.013) in the GTP. Individuals with PI had higher frequencies of P. gingivalis (GNTP: p = 0.030; GTP: p = 0.000), T. denticola (GNTP: p = 0.017) and T. nucleatum (GTP and GNTP; p = 0.002) compared to those with PM diagnosis. Individuals who have developed PI showed an increase in TBL (GTP: p = 0047; GNTP: p = 0.055) and in the isolated frequencies of P. gingivalis (GNTP: p = 0.002) and F. nucleatum (GTP and GNTP; p = 0.000). There were no statistically significant differences intergroups in relation to red complex pathogens (p > 0.05). Both in individuals with PM (T1 and T2: p = 0.000), as in individuals with PI (T2: p = 0.000), the frequency of orange complex was significantly lower in the GTP. The meta-analysis of cohort studies showed that individuals (OR = 7.22), and implants (OR = 5.63) presented a higher risk of developing PI. In the cross-sectional studies, in unadjusted analyses, individuals with PE presented a higher chance of having PI (OR = 3.18). When the analysis was adjusted for smoking and diabetes, there was no statistically significant increase in risk for PI (OR = 1.73; 95% CI 0.86-3.45). Conclusions: it might be concluded that the absence of regular periodontal/peri-implant maintenance was associated with worse peri-implant clinical condition, higher incidence of PI and a significant increase in TBL. Additionally, individuals diagnosed with PI showed greater frequencies of P. gingivalis, T. denticola and F. nucleatum and largest TBL. The systematic review showed that individuals diagnosed or with PE's history may have an increased risk for PI. More prospective studies are needed to confirm this evidence, especially the randomized controlled clinical trials

Lifelong occupational exposures and hearing loss among elderly Latino Americans aged 65-75 years.

OBJECTIVE: The purpose of this study is to determine the relationship between occupational exposures and hearing among elderly Latino Americans. DESIGN: A descriptive, correlational design used for this secondary analysis with the data from the Sacramento Area Latino Study of Aging (SALSA). STUDY SAMPLE: A total of 547 older adults were included. RESULTS: A majority of participants (58%) reported occupational exposures to loud noise and/or ototoxic chemicals. About 65% and over 90% showed hearing loss at low and high frequencies, respectively. Participants with occupational exposure to loud noise and/or ototoxic chemicals were, significantly, two times more likely to have hearing loss at high frequencies compared to those without exposure (OR = 2.29; 95% CI: 1.17 = 4.51, p = .016), after controlling for other risk factors of hearing loss such as age, gender, household income, current smoking, and diabetes. However, lifelong occupational exposure was not significantly associated with hearing loss at low frequencies (OR = 1.43; 95% CI: 0.94 = 2.18, p = .094). CONCLUSION: Lifelong occupational exposure to loud noise and/or ototoxic chemicals was significantly associated with hearing loss among elderly Latino Americans. Healthy work life through protection from harmful auditory effects of occupational exposures to noise and chemicals will have a positive impact on better hearing in later life.

Colgajo bilateral de perforantes lumbares para reconstrucción glútea tras infiltración por modelantes / Bilateral lumbar perforator flap for gluteal reconstruction in adjuvant human disease

La inyección de sustancias modelantes es un procedimiento usado desde el siglo XIX para mejorar el contorno corporal con fines estéticos. Durante la última década ha aumentado la demanda de técnicas quirúrgicas para la reconstrucción de los defectos originados tras la resección de unidades anatómicas afectadas por infiltración de estas sustancias modelantes, haciendo que en ocasiones tengamos que recurrir al empleo de expansores cutáneos, injertos, colgajos locales, colgajos regionales e incluso, a colgajos libres. Describimos el proceso de reconstrucción glútea en caso de infiltración de sustancias modelantes en el que tuvimos que emplear un colgajo de perforantes lumbares debido a su fiabilidad, a que preserva la musculatura, a su versatilidad de diseño sin comprometer otras posibles alternativas reconstructivas y por su baja morbilidad. Analizamos también la anatomía, diseño, técnica quirúrgica e indicaciones específicas de estos colgajos de perforantes de la región glútea (AU)

The injection of modeling substances is a process used with esthetic purposes since XIX century to improve body contour. In the past decade, there has been an increased demand on surgical techniques for reconstruction of defects arising after resection of anatomical units, such as: expanders, grafts, local flaps, regional flaps and free flaps. These resections are due to the infiltration of modeling substances. We describe a reconstruction process with a bilateral lumbar perforator flaps in a case of gluteal adyuvant disease. We analyze too the anatomy, design, surgical technique and specific indications for gluteal reconstruction (AU)

Analysis of the role of von Willebrand factor, platelet glycoprotein VI-, and α2ß1-mediated collagen binding in thrombus formation.

Rare missense mutations in the von Willebrand factor (VWF) A3 domain that disrupt collagen binding have been found in patients with a mild bleeding phenotype. However, the analysis of these aberrant VWF-collagen interactions has been limited. Here, we have developed mouse models of collagen-binding mutants and analyzed the function of the A3 domain using comprehensive in vitro and in vivo approaches. Five loss-of-function (p.S1731T, p.W1745C, p.S1783A, p.H1786D, A3 deletion) and 1 gain-of-function (p.L1757A) variants were generated in the mouse VWF complementary DNA. The results of these various assays were consistent, although the magnitude of the effects were different: the gain-of-function (p.L1757A) variant showed consistent enhanced collagen binding whereas the loss-of-function mutants showed variable degrees of functional deficit. We further analyzed the impact of direct platelet-collagen binding by blocking glycoprotein VI (GPVI) and integrin α2ß1 in our ferric chloride murine thrombosis model. The inhibition of GPVI demonstrated a comparable functional defect in thrombosis formation to the VWF(-/-) mice whereas α2ß1 inhibition demonstrated a milder bleeding phenotype. Furthermore, a delayed and markedly reduced thrombogenic response was still evident in VWF(-/-), GPVI, and α2ß1 blocked animals, suggesting that alternative primary hemostatic mechanisms can partially rescue the bleeding phenotype associated with these defects.

[Risk assessment for food preparation, cooking and service]. / Rischi da lavoro nel settore della ristorazione.

The restaurant and food preparation, cooking and distribution sector includes hotels, restaurants, catering, fast food, ecc. The restaurant and food preparation, cooking and distribution sector form a significant part of the Italian economy; they provide employment for a large number of people, both direct employees as well as part-time and contract staff. In this sector there are many hazards that can lead to a broad range of injuries and/or diseases to the workers. For the safety these hazards principally are slick floors, open flames, high temperature cooking surfaces, steam, knives and other cutting instruments and machineries. For the health: cleaning and disinfecting chemicals substances, cooking fumes and vapors, biological agents, heavy loads handling, thermal comfort, ecc. The paper presents an overview of the hazards in the sector and then make a focus on chemical risks identification and assessment to evaluate the workers' exposure (by skin adsorption and inhalation).

[Chemical, physical and biological risks in law enforcement]. / Rischi chimici, fisici e biologici nelle Forze dell'Ordine.

Chemical, physical and biological risks among public safety and security forces. Law enforcement personnel, involved in routine tasks and in emergency situations, are exposed to numerous and several occupational hazards (chemical, physical and biological) whith likely health and security consequences. These risks are particularly high when the organization and preparation are inadequate, there is a lacking or insufficient coordination, information, education and communication and safety and personal protective equipment are inadequate or insufficient. Despite the objective difficulties, caused by the actual special needs related to the service performed or the organizational peculiarities, the risk identification and assessment is essential for worker health and safety of personnel, as provided for by Legislative Decree no. 81/2008. Chemical risks include airborne pollutants due to vehicular traffic (carbon monoxide, ultrafine particles, benzene, polycyclic aromatic hydrocarbons, aldehydes, nitrogen and sulfur oxides, lead), toxic gases generated by combustion process following fires (aromatic hydrocarbons, PAHs, dioxins and furans, biphenyls, formaldehyde, metals and cyanides), substances emitted in case of chemical accidents (solvents, pesticides, toxic gases, caustics), drugs (methylamphetamine), riot control agents and self-defence spray, lead at firing ranges, and several materials and reagents used in forensic laboratory. The physical hazards are often caused by activities that induce biomechanical overload aid the onset of musculoskeletal disorders, the use of visual display terminals and work environments that may expose to heat stress and discomfort, high and low pressure, noise, vibrations, ionizing and non-ionizing radiation. The main biological risks are blood-borne diseases (viral hepatitis, AIDS), airborne diseases (eg, tuberculosis, meningitis, SARS, anthrax), MRSA, and vector-borne diseases. Many of these risk factors are unavoidable or are not predictable; so a proper risk assessment is very important, especially in case of emergencies, and also the necessary preventive measures, a careful analysis of alternative options for action and decision-making, implementation of security measures due to the provision of appropriate PPE and effective management of risk communication have great importance. Another important aspect is the education and training of staff, as in emergency situations should be able to take protective measures as quickly as possible.

Chemical characterization of the Allium sativum and Origanum vulgare essential oils and their inhibition effect on the growth of some food pathogens / Caracterização química e efeito inibitório dos óleos essenciais de Allium sativum e Origanum vulgare frente ao crescimento de alguns patógenos de alimentos

This study sought to evaluate the chemical composition of the Allium sativum and Origanum vulgare essential oils and their effect on the growth inhibition of microorganisms, such as P. aeruginosa, S. Choleraesuis, A. flavus, A. niger and P. simplicissimum, important food contaminants. The main constituents of the oregano essential oil were 4-terpineol (27.03%), γ-terpinene (20.04%), and β-cymene (6.34%), and the main constituents of the garlic essential oil were diallyl trisulfide (38, 81%), diallyl disulfide (25.23%), and methyl allyl trisulfide (12.52%). Inhibition zones were formed in in vitro tests on the bacteria S. Choleraesuis and P. aeruginosa, except for A. sativum against P. aeruginosa. The inhibition of mycelial growth caused by the oregano essential oil occurred with the concentrations of 0.10, 0.03 and 0.05 mg mL-1 for the A. flavus, A. niger and P. simplicissimum fungi, respectively. The CMI for the garlic oil began at the 0.03 mg mL-1 concentration for all species of fungi. The oils presented an inhibitory effect against the microorganisms studied and constitute an alternative for microbiological control in food.

Objetivou-se avaliar a composição química e o efeito inibitório dos óleos essenciais de Allium sativum e Origanum vulgare frente ao crescimento dos micro-organismos Pseudomonas aeruginosa, Salmonella Choleraesuis, Aspergillus flavus, Aspergillus niger e Penicillium simplicissimum, importantes patógenos causadores de contaminações em alimentos. Para quantificação e identificação dos constituintes químicos dos óleos, utilizou-se cromatógrafo gasoso acoplado a espectrômetro de massas. Os principais constituintes do óleo essencial de orégano foram o 4-terpineol (27,03%), γ-terpineno (20,04%), β-cimeno (6,34%), e do alho, o dialil trissulfeto (38,81%), dialil dissulfeto (25,23%), metil alil trissulfeto (12,52%). Os resultados dos testes in vitro sobre as bactérias S. Choleraesuis e P. aeruginosa indicaram a formação de halo de inibição e revelaram o efeito inibitório para os referidos óleos, exceto para o óleo de A. sativum frente a P. aeruginosa. Para os fungos A. flavus, A. niger e P. simplicissimum a inibição do crescimento micelial provocada pelo óleo essencial de orégano ocorreu a partir das concentrações de 0,10, 0,03 e 0,05 µg mL-1, respectivamente, sendo que a CMI para o óleo de alho iniciou-se a partir da concentração 0,03 µg mL-1 para todas as espécies de fungos. Foi possível verificar que os óleos possuem efeito inibitório sobre os microrganismos estudados, sendo, portanto, uma alternativa no controle microbiológico de alimentos.

Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo.

The identity of vampire bat saliva anticoagulant remained elusive for almost a century. Sequencing the salivary gland genes from the vampire bat Desmodus rotundus identified Desmolaris as a novel 21.5-kDa naturally deleted (Kunitz 1-domainless) form of tissue factor pathway inhibitor. Recombinant Desmolaris was expressed in HEK293 cells and characterized as a slow, tight, and noncompetitive inhibitor of factor (F) XIa by a mechanism modulated by heparin. Desmolaris also inhibits FXa with lower affinity, independently of protein S. In addition, Desmolaris binds kallikrein and reduces bradykinin generation in plasma activated with kaolin. Truncated and mutated forms of Desmolaris determined that Arg32 in the Kunitz-1 domain is critical for protease inhibition. Moreover, Kunitz-2 and the carboxyl-terminus domains mediate interaction of Desmolaris with heparin and are required for optimal inhibition of FXIa and FXa. Notably, Desmolaris (100 µg/kg) inhibited FeCl3-induced carotid artery thrombus without impairing hemostasis. These results imply that FXIa is the primary in vivo target for Desmolaris at antithrombotic concentrations. Desmolaris also reduces the polyphosphate-induced increase in vascular permeability and collagen- and epinephrine-mediated thromboembolism in mice. Desmolaris emerges as a novel anticoagulant targeting FXIa under conditions in which the coagulation activation, particularly the contact pathway, plays a major pathological role.

A role for benzo[a]pyrene and Slug in invasive properties of fibroblast-like synoviocytes in rheumatoid arthritis: a potential molecular link between smoking and radiographic progression.

OBJECTIVES: To investigate the effects of benzo[a]pyrene (B[a]P), a major toxic component of cigarette smoke, on the expression of Slug and to determine the effect of B[a]P/Slug on the invasive properties of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). METHOD: The expression of Slug was measured by real-time PCR following the stimulation of FLS with different concentrations of B[a]P or EGF. The phosphorylation of the key enzymes in the signaling pathway was analyzed by western blots. Inhibitors of PI3K/Akt/mTOR pathway were used to confirm the critical pathway for Slug expression. An in vitro cell invasion assay was performed using RA FLS treated with Slug cDNA, Slug small interference RNA, or control. RESULTS: Slug expression increased significantly following treatment with B[a]P or EGF in a dose-dependent manner. The stimulation of FLS with B[a]P or EGF induced the phosphorylation of Akt kinase, but not in ERK, JNK and p38. The Slug mRNA expression induced by B[a]P and EGF decreased significantly following the treatment with PI3K/Akt/mTOR inhibitors. Slug overexpression using Slug cDNA upregulated the invasive function of FLS, and Slug depletion using siRNA showed the opposite effect compared with the control. In addition, the stimulation with B[a]P increased the invasive function of the control siRNA-treated FLS but not in the Slug siRNA-treated FLS. CONCLUSION: Our data showed that B[a]P regulates the invasive properties of RA FLS through Slug expression. This mechanism may provide a novel molecular link underlying the association between smoking and increased radiographic progression in RA.

A platelet target for venous thrombosis? P2Y1 deletion or antagonism protects mice from vena cava thrombosis.

A role for platelets in the pathogenesis of venous thrombosis was suggested by clinical and preclinical studies. However, examination of the platelet receptor, P2Y1, in this area has been limited. The goal of the current study was to examine effects of P2Y1 deletion, or selective antagonism with MRS2500, in oxidative venous thrombosis in mice. The P2Y12 antagonist, clopidogrel, was included as a reference agent. Anesthetized C57BL/6 or genetically modified mice underwent 3.5 or 5 % FeCl(3)-induced vena cava thrombosis. Pharmacokinetic properties of MRS2500 were defined for dose selection. Platelet aggregation and renal or tail bleeding times (BT) were measured to put antithrombotic effects into perspective. P2Y1 deletion significantly reduced (p < 0.001) venous thrombus weight by 74 % in 3.5 % FeCl(3) injury compared to P2Y1(+/+) littermates. MRS2500 (2 mg/kg, i.v.) significantly decreased (p < 0.001) thrombus weight 64 % in C57BL/6 mice. In the more severe 5 % FeCl(3)-induced injury model, thrombus weight significantly (p < 0.001) decreased 68 % in P2Y1(-/-) mice versus P2Y1(+/+) mice, and MRS2500 (2 mg/kg) was also beneficial (54 % decrease, p < 0.01). Renal BT doubled in P2Y1(-/-) versus P2Y1(+/+) mice, and increased threefold with MRS2500 compared to vehicle. Tail BT was markedly prolonged in P2Y1(-/-) mice (7.9X) and in C57BL/6 mice given MRS2500. The current study demonstrates that P2Y1 deletion or antagonism significantly reduced venous thrombosis in mice, suggesting that P2Y1 receptors play a role in the pathogenesis of venous thrombosis, at least in this species. However as with many antithrombotic agents the benefit comes at the potential price of an increase in provoked bleeding times.

PACAP is an endogenous protective factor-insights from PACAP-deficient mice.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a widespread neuropeptide with a diverse array of biological functions. Not surprisingly, the lack of endogenous PACAP therefore results in a variety of abnormalities. One of the important effects of PACAP is its neuroprotective and general cytoprotective role. PACAP protects neurons and other tissues against ischemic, toxic, and traumatic lesions. Data obtained from PACAP-deficient mice provide evidence that endogenous PACAP also has protective functions. Mice lacking PACAP are more vulnerable to different in vitro and in vivo insults. The present review summarizes data on the increased sensitivity of PACAP-deficient mice against harmful stimuli. Mice lacking PACAP respond with a higher degree of injury in cerebral ischemia, autoimmune encephalomyelitis, and axonal lesion. Retinal ischemic and excitotoxic injuries also produce increased cell loss in PACAP-deficient mice. In peripheral organs, kidney cell cultures from PACAP-deficient mice are more sensitive to oxidative stress and in vitro hypoxia. In vivo, PACAP-deficient mice have a negative histological outcome and altered cytokine response in kidney and small intestine ischemia/reperfusion injury. Large intestinal inflammation, toxic lesion of the pancreas, and doxorubicin-induced cardiomyopathy are also more severe with a lack of endogenous PACAP. Finally, an increased inflammatory response has been described in subacute endotoxin-induced airway inflammation and in an oxazolone-induced allergic contact dermatitis model. In summary, lack of endogenous PACAP leads to higher vulnerability in a number of injuries in the nervous system and peripheral organs, supporting the hypothesis that PACAP is part of the endogenous cytoprotective machinery.

Adductomics: characterizing exposures to reactive electrophiles.

To understand environmental causes of disease, unbiased methods are needed to characterize the human exposome, which represents all toxicants to which people are exposed from both exogenous and endogenous sources. Because they directly modify DNA and important proteins, reactive electrophiles are probably the most important constituents of the exposome. Exposures to reactive electrophiles can be characterized by measuring adducts from reactions between circulating electrophiles and blood nucleophiles. We define an 'adductome' as the totality of such adducts with a given nucleophilic target. Because of their greater abundance and residence times in human blood, adducts of hemoglobin (Hb) and human serum albumin (HSA) are preferable to those of DNA and glutathione for characterizing adductomes. In fact, the nucleophilic hotspot represented by the only free sulfhydryl group in HSA (HSA-Cys(34)) offers particular advantages for adductomic experiments. Although targeted adducts of HSA-Cys(34) have been monitored for decades, an unbiased method has only recently been reported for visualizing the HSA-Cys(34) 'subadductome'. The method relies upon a novel mass spectrometry application, termed fixed-step selected reaction monitoring (FS-SRM), to profile Cys(34) adducts in tryptic digests of HSA. Here, we selectively review the literature regarding the potential of adductomics to partially elucidate the human exposome, with particular attention to the HSA-Cys(34) subadductome.

[Acute interstitial pneumonia: diagnostic approach and management]. / Les pneumopathies infiltrantes aiguës : démarche diagnostique et approche thérapeutique.

Acute interstitial pneumonia (AIP) encompasses a spectrum of pulmonary disorders characterized by involvement of the lung interstitium and distal airways (bronchioles and alveoli). The onset of respiratory symptoms is acute, most often within two weeks. Most AIP take place de novo, but sometimes represent an acute exacerbation of chronic lung disease. The clinical presentation of AIP comprises rapidly progressive dyspnoea, associated sometimes with cough, fever, myalgia and asthenia. Chest radiography shows diffuse pulmonary opacities. The associated hypoxemia may be severe enough to cause acute respiratory failure. Underlying aetiologies are numerous and variable, particularly in relation to the underlying immune status of the host. Various histopathological entities may be responsible for AIP although diffuse alveolar damage is the predominant pattern. The diagnostic approach to a patient presenting with AIP is to try to determine the most likely underlying histopathological pattern and to search for a precise aetiology. It relies mainly on a meticulous clinical evaluation and accurate biological investigation, essentially guided by the results of bronchoalveolar lavage performed in an area identified by abnormalities on high resolution computed tomography of the lungs. Initial therapeutic management includes symptomatic measures, broad-spectrum antibiotic treatment adapted to the clinical context, frequently combined with systemic corticosteroid therapy.