Drug-Drug Interactions in the Management of Patients With Pulmonary Arterial Hypertension.

The management of pulmonary arterial hypertension (PAH) has become more complex in recent years because of increased pharmacotherapy options and longer patient survival with increasing numbers of comorbidities. As such, more opportunities exist for drug-drug interactions between PAH-targeted medications and medications potentially used to treat comorbid conditions. In this review, we provide an overview of pharmaceutical metabolism by cytochrome P450 and discuss important drug-drug interactions for the 14 Food and Drug Administration-approved medications for PAH in the nitric oxide (NO), endothelin, and prostacyclin pathways. Among the targets in the NO pathway (sildenafil, tadalafil, and riociguat), important interactions with nitrates, protease inhibitors, and other phosphodiesterase inhibitors can cause profound hypotension. In the endothelin pathway, bosentan is associated with more drug interactions via CYP3A4 inhibition; macitentan and ambrisentan have fewer interactions of note. Although the parenteral therapies in the prostacyclin pathway bypass significant liver metabolism and avoid drug interactions, selexipag and oral treprostinil may exhibit interactions with CYP2C8 inhibitors such as gemfibrozil and clopidogrel, which can raise drug levels. Finally, we provide a framework for identifying potential drug-drug interactions and avoiding errors.

Pregnancy and pulmonary arterial hypertension: a case series and literature review.

BACKGROUND: Despite the development of advanced therapies for pulmonary arterial hypertension, pregnancy remains contraindicated in these patients owing to high maternal and fetal morbidity and mortality. Limited data exist regarding pregnancy management and outcome in this unique patient population. We describe a series of pregnant patients diagnosed as having pulmonary arterial hypertension before or during pregnancy who delivered at a tertiary center with a comprehensive and established pulmonary vascular disease program. OBJECTIVE: This study aimed to describe a single institution's experience and review the existing literature for pregnancy management and outcomes in patients with pulmonary arterial hypertension. STUDY DESIGN: A review of all patients with pulmonary arterial hypertension who were admitted for delivery between 2005 and 2019 at our institution was performed. All data were extracted from the electronic health record and included patient demographics, pulmonary arterial hypertension subtype, pulmonary arterial hypertension-targeted therapies, and mode of delivery and anesthesia. RESULTS: A total of 7 patients were identified; 5 patients had a prepartum diagnosis of pulmonary arterial hypertension, whereas 2 patients were diagnosed as having pulmonary arterial hypertension during the third trimester. All patients were started on prostacyclins and the majority were on combination pulmonary arterial hypertension-targeted therapy. The maternal mortality rate was 29%. Elective cesarean delivery was performed in more than 70% of cases, whereas 1 patient required an urgent cesarean delivery and 1 patient had a successful vaginal delivery. Most patients had epidural anesthesia. Notably, 2 patients required extracorporeal membrane oxygenation after delivery and both died. There were no cases of neonatal mortality. CONCLUSION: Our cases series and the published literature to date show that pregnancy in pulmonary arterial hypertension remains poorly tolerated despite marked advancements in pulmonary arterial hypertension-targeted therapies and postpartum care. A multidisciplinary team approach remains essential for the management of these patients.

Titration of pulmonary arterial hypertension therapeutics: Experience-based recommendations.

The availability of new medications has improved exercise capacity, enhanced quality of life, and extended time to clinical worsening in patients with pulmonary arterial hypertension (PAH). For many of these medications, careful individualized dose titration is required to maximize therapeutic effectiveness while minimizing side effects. In addition, specific routes of administration, including intravenous (IV), subcutaneous (SC), and inhaled administration may present additional challenges for patients and healthcare providers. These challenges include the possibility of catheter-related infections (IV), infusion site pain (SC), and adherence to frequent dosing schedules (inhaled). Temporary discontinuations may require re-titration and, in some cases, may even be life threatening. Here, based on our clinical experience, we provide our recommendations for dose titration schemes for PAH medications that require individualized dosing in adult patients, including agents acting on the endothelin-1 pathway (bosentan and ambrisentan), the prostacyclin pathway (epoprostenol, treprostinil, and selexipag), and the nitric oxide pathway (tadalafil and the soluble guanylate cyclase stimulator riociguat). A case study that illustrates the application of best practices for PAH medication dose titration in a real-world setting is presented. Good two-way communication between specialty pharmacies and other healthcare providers promotes optimal medication usage and patient health. Experience has shown that slow, cautious up-titration is generally associated with better long-term outcomes. In all cases, patient education, frequent monitoring and careful management of side effects, and treatment adherence are critical.

Management of prostacyclin side effects in adult patients with pulmonary arterial hypertension.

Therapies that target the prostacyclin pathway are considered effective, yet are complex to dose and may cause dose-limiting side effects for patients with pulmonary arterial hypertension (PAH). Careful side effect management and the ability to discern side effects from worsening disease are essential in order for patients to continue, and benefit from, prostacyclin therapy. This manuscript was developed through a collaborative effort of allied health providers with extensive experience in managing patients with PAH who are treated with medications that target the prostacyclin pathway. This article provides an overview of individual prostacyclin pathway therapies approved in the United States, side effects most commonly associated with these therapies, and practical suggestions for side effect management. Most patients will experience significant side effects on prostacyclin therapy. Creating a proactive and careful side effect management program will increase the likelihood that patients are able to stay on therapy and receive the benefits afforded by prostacyclin therapy.

Pleural mesothelioma in doll manufacture: possible asbestos exposure. / Mesoteliomi pleurici in addette alla fabbricazione di bambole: esposizione ad amianto?

BACKGROUND: The occurrence of malignant mesothelioma is almost always causally associated to asbestos exposure but, considering women occurrences, this association is often difficult to demonstrate and consequently the asbestos exposure is defined as 'unknown'. OBJECTIVES: To describe the working activity and to give occupational asbestos exposure probability estimation related to an uncommon and poorly investigated productive sector: doll manufacture. METHODS: From the Province of Brescia Mesothelioma Registry, established in 1993 on population-based criteria, we have extracted the certified mesothelioma diagnosis cases, related to patients who were employed for some time in doll manufacture. RESULTS: Among the 757 total cases of malignant mesothelioma registered and studied up to 2016, we found 3 cases of pleural epithelial mesothelioma histologically diagnosed in young women who had worked in two doll manufacturing companies and whose asbestos exposure had been initially defined as 'unknown', because an environmental, family or extra-professional asbestos exposure was considered unlikely. However, the judicial autopsy performed on one of the 3 women had allowed examining lung tissue samples with Scanning Electron Microscopy. This technique showed a concentration of amphiboles fibers of about 12,000,000 per gram of dry lung tissue, with a consequent re-classification of asbestos exposure from 'unknown' to 'occupational certified'. DISCUSSION: Mesotheliomas in women with no apparent occupational asbestos exposure are normally referred to life or family environmental exposure. Moreover, it is known that occupational asbestos exposure in women is difficult to recognize. Previously, only one publication had reported two cases of mesothelioma in cloth doll manufacture. The occurrence of two mesothelioma cases in the same company out of the three here presented was suggesting an occupational exposure. The finding of a high amphibole fibers lung concentration confirmed the previous hypothesis, despite the impossibility to determine the circumstances with good evidence. CONCLUSION: The three cases of mesothelioma in doll production workers suggest that also in this restricted manufacturing sector had occurred an occupational asbestos exposure, which is up to now unknown and isn't due only to the use of sewing or ironing machines. The lung asbestos fibers burden analysis is confirmed to be a decisive factor in the assessment of mesothelioma cases with 'unknown' exposure.

[Pleural mesothelioma in a school teacher: asbestos exposure due to DAS paste]. / Mesotelioma pleurico in maestro elementare: esposizione ad amianto dovuta alla pasta DAS.

BACKGROUND: Malignant mesothelioma cases among primary school teachers are usually linked with asbestos exposure due to the mineral contained in the building structure. Among the approximately 12,000 cases of mesothelioma described in the fourth report of the National Mesothelioma Register, 11 cases of primary school teachers are reported, in spite of the fact that the "catalogue of asbestos use" does not describe circumstances of asbestos exposure other than or different to that due to asbestos contained in the buildings. Four cases in the Brescia Provincial Mesothelioma Register are identified as teachers, without this circumstance of exposure. OBJECTIVES: To characterize the asbestos concentration and fibre type retained in the lungs of a teacher reported as a new mesothelioma case and preliminarily classified as of unknown asbestos exposure. METHODS: The mesothelioma case presented here was diagnosed at age 78 and malignant mesothelioma was confirmed at autopsy; the patient was interviewed directly for occupational history. Samples of lung parenchyma from necropsies were collected, stored and analyzed by scanning electron microscope (SEM) and samples of DAS paste were analyzed by SEM to detect asbestos fibre content. RESULTS: It was possible to confirm past exposure to DAS paste in forming and finishing dry items and toys during school recreational activity almost every day from the mid-60s to about the mid-70s. Subsequent SEM analysis showed: i) chrysotile fibres were found in an old and unused pack of DAS paste; ii) a lung burden of 1,400 asbestos bodies, 310.000 total asbestos fibres (33% chrysotile, 67% amphibole) and 210.000 talc fibre per gr/dry lung tissue was detected from necropsies performed on the subject. These results seem to be in agreement with an occupational exposure to asbestos due to past use of DAS paste. After the investigation, this case was reclassified from "unknowun" to " sure" occupational asbestos exposure. The occupational origin of the tumour was recognized by the Italian Workers' Compensation Authority (INAIL). CONCLUSION: This case suggests i) the need to carry out any possible detailed studies of the circumstances and exposure sources whenever any mesothelioma case is classified as "asbestos exposure unknown", according to the guidelines of the National Mesothelioma Register, ii) handling of DAS paste can be considered as sure asbestos exposure and iii) it should be borne in mind that mesothelioma cases can occur even after cumulative low, occupational exposure, even only to chrysotile.

Management of the patient with pulmonary arterial hypertension receiving intravenous prostacyclin: an expert nurse practical guide.

Pulmonary arterial hypertension (PAH) is a severely disabling disorder characterized by elevated pulmonary artery pressure ultimately leading to right heart failure and death. Treatment options have significantly increased over the past decade. Intravenous prostacyclins remain the treatment of choice for advanced PAH, leading to long-term clinical benefits and improved survival. Their administration requires a high level of nursing competency and presents considerable challenges for patients and caregivers. This article reviews the characteristics of currently available intravenous prostacyclins and provides a practical guide for nurses who may have had limited exposure to intravenous prostacyclins and their unique dosing, side effects, and titration characteristics.

Understanding the impact of pulmonary arterial hypertension on patients' and carers' lives.

Pulmonary arterial hypertension (PAH) is a rare, debilitating and rapidly progressive disease. Although there have been important medical advances in PAH management, the search for a cure continues. Despite an increased understanding of the disease, data on the wider effect of PAH on patients and carers, beyond the clinical symptoms, are still limited. In order to explore this, a large-scale international survey investigated four key areas affected by PAH (physical and practical, emotional, social, and information needs) and provides new insight into patients' and carers' experiences of living with the disease. The results from the survey highlight not only the limited ability of patients to carry out everyday tasks, but also the financial impact and social isolation experienced by both patients and carers. The study confirmed that a decline in a patient's World Health Organization functional class, which indicates an increase in clinical severity of the disease, is associated with greater limitations. Results from the survey demonstrate the need for multidisciplinary PAH management and a comprehensive standard of care to assess and improve all aspects of well-being for both patients and carers. In addition, they underline the need for updated PAH guidelines that address these needs.

Bloodstream infections in patients with pulmonary arterial hypertension treated with intravenous prostanoids: insights from the REVEAL REGISTRY®.

OBJECTIVE: To evaluate the rate of and potential risk factors for bloodstream infections (BSIs) using data from the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension [PAH] Disease Management) REGISTRY(®), which provides current information about patients with PAH. PATIENTS AND METHODS: Patients were enrolled from March 30, 2006, through December 8, 2009, and data on reported BSIs were collected through the third quarter of 2010. Bloodstream infection rates were calculated per 1000 patient-days of risk. RESULTS: Of 3518 patients enrolled, 1146 patients received intravenous (IV) prostanoid therapy for more than 1 day (no BSI, n=1023; ≥1 BSI, n=123; total BSI episodes, n=166). Bloodstream infections rates were significantly increased in patients receiving IV treprostinil vs IV epoprostenol (0.36 vs 0.12 per 1000 treatment days; P<.001), primarily due to gram-negative organisms (0.20 vs 0.03 per 1000 treatment days; P<.001). Multivariate analysis adjusting for age, causes of PAH, and year of BSI found that treatment with IV treprostinil was associated with a 3.08-fold increase (95% confidence interval, 2.05-4.62; P<.001) in BSIs of any type and a 6.86-fold increase (95% confidence interval, 3.60-13.07; P<.001) in gram-negative BSIs compared with treatment with IV epoprostenol. CONCLUSION: Compared with IV epoprostenol therapy, treatment with IV treprostinil is associated with a significantly higher rate of gram-negative BSIs; observed differences in BSI rate did not seem to be due to any other analyzed factors. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00370214.

The CC homozygosis of the -174G>C IL-6 polymorphism predicts a lower efficacy of rituximab therapy in rheumatoid arthritis.

Identification of genetic biomarkers of response to biologics in rheumatoid arthritis (RA) is a relevant issue. Being IL-6 a key cytokine for B cell survival, the interleukin-6 (IL-6) -174G>C and the IL-6 receptor (IL-6R) D358A gene polymorphisms were investigated in 158 RA patients treated with rituximab (RTX). One hundred and twenty-eight (81.0%) were RF positive and 126 (79.7%) were anti-CCP positive. Response to therapy was evaluated at the end of the sixth month after the first RTX infusion, by using both the EULAR and the ACR criteria. The possible relationship with IL-6 serum levels was also studied. By univariate analysis, lack of response by the EULAR criteria was more prevalent in RA patients with the IL-6 -174 CC genotypes (39.1%), than in the GC/GG patients (18.5%) (OR 2.83; 95%CI=1.10-7.27; p=0.031). A good response was noticed in only one patient (4.3%) with the IL-6 -174 CC genotype, while it was present in 24.4% of GG/GC cases (p=0.06). By stepwise multivariate analysis (including RA duration, baseline DAS28, baseline HAQ, RF status, anti-CCP status and IL-6 genotype as covariates), the IL-6 -174CC genotype was selected as an independent predictor of no response to RTX by both EULAR and ACR≥50 criteria, while the IL-6R polymorphism resulted as not associated. No definite association between gene polymorphisms and IL-6 serum levels was noticed. Present results suggest a possible role for IL-6 genotyping to better plan treatment with RTX in RA, and larger studies are worthwhile.

Chlamydophila psittaci subclinical infection in chronic polyarthritis.

OBJECTIVES: Recent evidence indicates that Chlamydophila psittaci (Cp) may establish chronic infections, which may promote autoimmunity and/or B cell lymphoproliferation. METHODS: The presence of a subclinical Cp infection was investigated in 293 patients with chronic inflammatory polyarthritis, including 175 patients with rheumatoid factor (RF)-positive and/or anti-CCP-positive rheumatoid arthritis (RA) and 118 with seronegative polyarthritis (46 RF-negative/anti-CCP-negative RA, 36 psoriatic arthritis and 36 undifferentiated spondyloarthritis). One hundred and eighty-five healthy controls were also investigated. The presence of Cp infection was assessed in peripheral blood mononuclear cells using several PCR protocols targeting different regions of the Cp genome (16S-23S spacer rRNA, OMP-A, and Gro-EL). The DNA of other Chlamydia species (C. Pneumoniae and C. Trachomatis) was also investigated. Amplicons were sequenced to confirm the specificity of PCR products. RESULTS: The presence of a subclinical chronic Cp infection was observed in a significantly higher percentage of patients with chronic polyarthritis (38/293; 13%) compared to healthy controls (1/185, 0.5%; OR=27.4, 95%CI:3.73-201.6, p<0.0001). Furthermore, the prevalence of Cp was higher in seronegative polyarthritis (23/118; 19.5%) than in seropositive RA patients (15/175; 7.4%; OR=2.58, 95%CI: 1.28-5.19, p=0.0078). The highest prevalence of Cp infection was found in RF/anti-CCP double-negative RA patients (13/46, 28.3%), followed by patients with psoriatic arthritis (6/36; 16.7%). No differences in age, sex, disease duration and undergoing therapies were noticed between Cp-positive and Cp-negative patients; nor between seropositive and seronegative patients. CONCLUSIONS: Cp may be an infectious trigger possibly involved in the pathogenesis of a fraction of inflammatory polyarthritis, particularly in seronegative patients.

Prostacyclin administration errors in pulmonary arterial hypertension patients admitted to hospitals in the United States: a national survey.

BACKGROUND: Epoprostenol and treprostinil are intravenous prostacyclin medications used to treat pulmonary arterial hypertension (PAH). This survey explored hospital policies regarding prostacyclin infusions, and investigated the type and frequency of errors that occurred in the inpatient setting. METHODS: Information on prostacyclin infusion policies and inpatient errors was obtained through detailed interviews with 18 PAH nurses, and through an electronic survey completed by 97 PAH clinicians. RESULTS: The electronic survey respondents reported wide variability in prostacyclin infusion policies, including variability in the use of home vs hospital infusion pumps, and variability in the use and storage of back-up epoprostenol and treprostinil. Serious or potentially serious errors in medication administration were reported by 68% of survey respondents. The most common error types (reported by >or=25%), included: incorrect cassette placed in the pump; inaccurate pump programming; errant drug dosing; and inadvertent cessation of the pump. Nine errors, all at different centers, were believed to have contributed to patient death. In the separate interviews with the PAH nurses, 94% reported serious errors. These errors prompted many of the centers to implement policy changes in an attempt to reduce future errors, improve safety and optimize patient outcomes. CONCLUSIONS: These findings suggest that prostacyclin infusion therapy is problematic and that an opportunity exists to improve safety. The development of standardized treatment guidelines should be considered.

Long-term effects of rituximab in rheumatoid arthritis: clinical, biologic, and pharmacogenetic aspects.

Rituximab selectively targets the B-cell compartment, including rheumatoid factor-positive B cells. Short-term efficacy and safety of rituximab in rheumatoid arthritis (RA) has been established by multicenter randomized placebo-controlled studies. Results of long-term follow-up of the phase II/III clinical trials have confirmed the efficacy and safety of repeated courses of rituximab in the responders. However, mechanisms of action in humans, retreatment regimens, biologic effects on memory B cells and on immunoglobulin levels of prolonged exposure of the immune system to B-cell depletion over time, and pharmacogenetic aspects remain open and intriguing issues of rituximab therapy. Several studies are ongoing to clarify possible clinical and biologic predictors of response to rituximab in RA and in other autoimmune diseases where rituximab has been proven to be effective. Preliminary clinical and pharmacogenetic results of our cohort of RA patients managed with rituximab from the year 2000 are presented.

[Asbestos fibre lung burden and exposure indices in asbestos-cement workers]. / Carico polmonare di fibre di asbesto e indici di esposizione cumulativa in lavoratori del cementoamianto.

BACKGROUND: In many previous studies, the asbestos fibres retained in the lung were regarded as a good index of cumulative occupational asbestos exposure. Twelve workers suffering from asbestos-related diseases and had been employed in an asbestos-cement factory operating from 1961 to 1994 underwent post mortem investigations in the course of a criminal law suit. OBJECTIVES: Samples of lung tissues were collected for electron microscopy analysis to measure the asbestos fibre burden of the lungs in workers with high exposure, and assess the possible correlation between asbestos fibre lung burden and the estimated levels of cumulative exposure. METHODS: Samples of lung parenchyma obtained from a consecutive series of 12 post-mortem examinations that were performed between 1994 and 2007and included 5 cases of malignant pleural mesothelioma, 4 lung cancers, 1 case of asbestosis and2 ofpleuralplagues, were collected, stored and analysed by SEM electron microscopy, according to the methods suggested by the current scientific literature. For each worker, all males, a detailed occupational history was reconstructed by means ofpersonal interviews; both the measurements of airborne asbestos fibresperformed by the factory in the 1970's and the duration of each single job in the plant were taken into account to estimate an individual cumulative exposure index. RESULTS: A wide variation of total asbestos fibre concentrations in the lung (1,320-118 million) was observed; in all 12 workers, the lung amphibole fibre burden exceeded 1,000,000 fibres per g/dry tissue, The highest values were detected in the mesothelioma cases, in which the mean fibre concentrations differed statistically (t=2.29, p=0.045) from the mean calculated for the other asbestos-related diseases; in 9 subjects only amphibole fibres were detected. There was a good correlation between total asbestos fibre concentration and cumulative exposure index (r=0.91, p<0.0001). CONCLUSION: This study, which was numerically the biggest ever performed in Italy for this category of workers, confirms a wide range of total asbestos fibre burden in heavily occupationally exposed workers and showed that of the asbestos-related diseases, the highest lung concentrations of asbestos fibres were reached in cases of mesothelioma. It was also observed that almost the entire lung burden consists of only amphibole fibres, all exceeding 1 million per gramme of dry tissue. This study tested a synthetic cumulative occupational exposure index, which appears to be well correlated to the level of exposure established by biological analysis.

Resistance to rituximab therapy and local BAFF overexpression in Sjögren's syndrome-related myoepithelial sialadenitis and low-grade parotid B-cell lymphoma.

OBJECTIVE: B-cell expansion is a key feature of Sjögren's syndrome (SS). Accordingly, several studies have reported the benefits of B-cell depletion with anti-CD20 monoclonal antibody (Rituximab) in the treatment of glandular and extraglandular manifestations of SS. Patients with SS are at increased risk of lymphoma development. B-lymphocyte stimulator (BAFF) is an essential cytokine for the control of B-cell maturation and survival, and high levels of BAFF were described in the serum and salivary glands of SS patients, strongly suggesting a crucial role in the proliferation of B cells in SS. PATIENT AND METHODS: We describe the treatments employed, with particular regards to rituximab therapy, and the histopathologic and biologic studies, in particular BAFF levels in serum and in pathologic tissues before and after B-cell depletion therapy, and the characterization of the cultured epithelial cells obtained by the parotid gland MALT-lymphoma, in a case of a 51-year old woman with primary SS and mixed cryoglobulinaemia type II with features of systemic vasculitis, who developed a bilateral parotid MALT-type lymphoma. Rheumatoid factor (RF), cryoglobulins, BAFF levels were assessed monthly up to month +6, then at the end of follow-up (month +12), as well as peripheral blood CD19-positive B-cell level RESULTS: A significant systemic effect of rituximab on B-cell biomarkers was documented, however, the cryoglobulinemic syndrome did not improve and the parotid enlargement did not decrease confirming the failure of B-cell depletion to affect the parotid lymphoma. BAFF levels decreased only under B-cell depletion associated with high-dose steroids. Tissue studies further documented the persistent overexpression of BAFF in the salivary gland pathologic tissue during the disease course. CONCLUSION: Tissue and systemic overexpression of BAFF may have contributed to resistance to rituximab therapy, in MALT lymphoproliferation associated with SS. Thus, alternative treatment strategies should be then considered, possibly including BAFF-targeted approaches.

[Malignant mesothelioma in garment sewing-machine workers]. / Mesoteliomi maligni nelle confezioni abbigliamento: un'ulteriore fonte di esposizione ad amianto.

BACKGROUND: Due to poor information collected through patient interviews, a considerable number of malignant mesothelioma (MM) cases still remain classified as "unknown" asbestos exposure in the Italian Mesotelioma Registry (Re.Na.M). At the same time, some occupational asbestos exposures, which were previously unknown, have been demonstrated in certain types of work, i.e., in agriculture and in the textile industry. OBJECTIVES: The aim of this research was to investigate the possible past occupational exposure to asbestos in clothing workers using sewing-machines. METHODS: The MM cases were collected from the Mesothelioma Registry of Brescia. Work histories were obtained via a standardized questionnaire. Investigations were conducted in sewing-machine maintenance workshop in order to collect information regarding the possible use of asbestos parts. In addition, the use of asbestos friction materials and the use of insulated asbestos materials was checked in the clothing divisions by interviewing the management and maintenance workers of two companies where cases of MM were observed. RESULTS: The Mesothelioma Registry of Brescia identified and collected 10 MM cases with past work in the clothing industry: 6 used sewing-machines and 4 were self-employed tailors. The search for asbestos materials gave positive results as the use of friction materials had been widespread since the 1950's in all types of sewing-machines; in addition, asbestos materials were used to insulate some parts of the ironing equipment and the steam pipelines. CONCLUSION: The results of this investigation suggest assigning at least "possible occupational asbestos exposure" to those cases employed in clothing manufacture since the 1950's, who used sewing-machines or pressing machines, according to the Re.Na.M guidelines. Other possible occupational exposures to asbestos in this working sector cannot be excluded; when the simple interview of patients does not reveal such exposures further investigations are needed in order to demonstrate all the possible circumstances of exposure.

Botulismo associado a alimentos comerciais assados doados, município de São Vicente (SP) – Junho de 2007 / Botulism associated with donated commercial roasted foods, in the city of São Vicente (SP) – june 2007

O botulismo alimentar é uma doença neuroparalítica grave causada pela ingestão de neurotoxinas presentes em alimentos contaminados com a bactéria Clostridium botulinum, freqüentemente relacionados a conservas caseiras de vegetais, frutas e carnes. Este trabalho tem por objetivo relatar a investigação epidemiológica de um caso de botulismo que ocorreu em junho de 2007 no município de São Vicente (SP), associado à ingestão de alimentos comerciais assados, sobras doadas por comerciante. Foi identificada toxina botulínica no soro do paciente. Com base no quadro clínico foi administrado prontamente o soro antibotulínico ao paciente. Medidas sanitárias e educacionais foram desencadeadas para a prevenção de novos casos.

[Cancer of the nasal cavity and paranasal sinuses in poultry breeders. An unsuspected occupation at risk]. / Tumori naso-sinusali in allevatori avicoli: una insospettata occupazione a rischio.

BACKGROUND: Wood dust exposure is strongly associated with the induction of cancer of the nasal cavity and paranasal sinuses (NSC), mainly among furniture production workers. Only limited information is available on wood dust exposure in other industrial sectors, including agriculture. NSC's are defined as "high occupational aetiology fraction" neoplasms, and are therefore indicated as sentinel tumours in occupational medicine. OBJECTIVES: The report concerns two cases of NSC that occurred in two poultry breeders and the investigations performed in order to define their occupational exposure. METHODS AND RESULTS: Epidemiological surveillance of NSC within the framework of routine activity of the Cancer Registry of the Province of Brescia (one million inhabitants) identified the two cases. Initially the first NSC case was considered as "probably exposed to formaldehyde" during shed tile disinfecting operations. After discovery of a similar case and further investigation in the sector formaldehyde exposure was found to be at a very low level. However, the observation that hard and soft wood dust was present, followed by dust monitoring, revealed a high level of exposure. The 23 personal and area air samples, performed in a turkey breeding shed, gave concentrations of between 1.3 and 2.3 mg/mc during low dust exposure jobs and concentrations of between 4 and 43.2 mg/mc during litter replacement (100% exceeded the ACGH TLV limit of 1 mg/cm and 25% were even above the legal limits (5 mg/mc according to Italian D.Lgs. 66/2000)). Since breeders are not aware of this type of risk and the use ofpersonal protection is not scrupulous, the local health and safety unit has started an information campaign for the entire work category as regards the necessity of controlling this cancer risk. The two cases of NSC described here were reported to the National Labour Insurance Institute (INAIL) for compensation. CONCLUSION: NSC epidemiological surveillance performed through a population registry proved to be of great use in the identification of cases among employees in similar sectors, and thus the identification of previously unknown wood dust exposures with consequent implementation of preventive measures.

[Two cases of pleural mesothelioma following unusual and unrecognized exposure to asbestos. The role of Occupational Health and Safety Service in identifying past occupational exposure]. / Mesoteliomi pleurici da insolita e ignorata esposizione professionale ad amianto. Ruolo dei Servizi territoriali di prevenzione nell'individuazione della pregressa esposizione lavorativa.

BACKGROUND: In Italy there was a wide use of asbestos in various manufacturing sectors and for many different uses, some of which are still partly or completely unknown. A detailed reconstruction of the work histories of mesothelioma patients made it possible, in some cases, to identify ignored circumstances of asbestos exposure. Moreover, the identification of cluster of cases takes on special significance in suggesting a possible previous asbestos exposure, where the information collected on single cases do not imply as much. OBJECTIVES: This report concerns two cases of malignant mesothelioma that occurred in two workers employed in the same processes in a small factory that manufactured and repaired electric motors for hand tools. METHODS AND RESULTS: In the Province of Brescia (one million inhabitants) a Mesothelioma Register is in operation. The first case was classified, according to Re.Na.M.1996 criteria (National Mesothelioma Register) as "unknown" occupational exposure. The identification of a second case, that was discovered thanks to the surveillance system of the Mesothelioma Register, encouraged the local Occupational Health and Safety Service to perform a more detailed investigation that revealed, for both subjects, previously unknown occupational exposure. This consisted of grinding, in a damp setting, electric motor parts bushed with phenolic thermosetting resins reinforced with chrysotile asbestos. Moreover, weekly cleaning of the plants could have been an occasion for dust dispersion. It is likely that this exposure did not last long and was limited in extent. Other similar reports of such circumstances of occupational exposure were not available in the literature. CONCLUSIONS: The results confirm the high information value of systematic collection of incidental cases in the population, which is feasible thanks to the disease register, and the significant role of the local Occupational Health Services in demonstrating past asbestos exposure.

Malignant mesothelioma and the working environment: the viewpoint of the occupational physician.

BACKGROUND: Firm scientific evidence supports the causal association between malignant mesothelioma (MM) and occupational exposure to asbestos. Risk attributable to occupation varies from 30 to 80% across different populations. The existence of a threshold level below which there is no risk of MM is still debated. A prompt and thorough assessment of exposure is essential to evaluate and manage MM cases, from diagnostic and epidemiological points of view. OBJECTIVES AND METHODS: To highlight the multiple areas of intervention by Occupational Physicians (OP) in MM evaluation and management, to describe an experience of OP in the province of Brescia. RESULTS: The main areas of interest of the OP are exposure assessment, diagnosis (clinical, etiological), medico-legal issues, social consequences, preventive strategies, risk communication, scientific dispute/uncertainties. By means of an active search, the Brescia MM registry, managed by OP belonging to the local health authority observed 309 MM from 1977 to 2003; the local Institute of Occupational Health, hosted in a hospital of national relevance, evaluated about 200 MM in the last decade. The main outcomes of OP activity are the high percentage of direct interviews, individual case management, expert exposure assessment, etiological diagnosis, counselling, medico-legal assistance, better knowledge of occupational risks, enhanced cooperation among health professionals (oncologists, pathologists, surgeons, pneumologists, general practitioners and OP), important contribution to Registries and to epidemiology (estimates of attributable risks, incidence, survival rates), with positive social and scientific consequences (insurance agencies, trade union organizations, public events, teaching opportunities). CONCLUSIONS: This experience highlights the multifaceted role of OP in active research and evaluation of MM cases, in the context of a multidisciplinary approach.