LRP1/CD91 is up-regulated in monocytes from patients with haemophilia A: a single-centre analysis.

The low-density lipoprotein receptor-related protein 1 (LRP1) is an ubiquitously expressed endocytic receptor that, among its several functions, is involved in the catabolism of coagulation factor VIII (FVIII) and in the regulation of its plasma concentrations. Although LRP1/CD91 polymorphisms have been associated with increased FVIII levels and a consequent thrombotic risk, no data are available on LRP1/CD91 expression in patients with inherited FVIII deficiency. With the aim of elucidating this issue, 45 consecutive patients with haemophilia A (HA) (18 severe, 5 moderate and 22 mild HA) were enrolled in this cross-sectional, single-centre survey. The LRP1/CD91 mean fluorescence intensity (MFI) in monocytes from HA patients was significantly higher than that detected in 90 healthy blood donors (105 vs. 67, P < 0.001). This over-expression was independent of hepatitis C virus infection status and varied according to the severity of the haemophilia, being higher in patients with more severe FVIII deficiency. In conclusion, our study documents for the first time that LRP1/CD91 is over-expressed on monocytes from HA patients, with the intensity of expression varying according to the severity of the FVIII deficiency. Further studies are needed to assess the clinical implications of these findings.

The natural history of mild haemophilia: a 30-year single centre experience.

Although up to 50% of all haemophilic patients followed at haemophilia treatment centres (HTCs) are affected by a mild factor VIII (FVIII) or factor IX (FIX) defect, published data regarding the natural history of these disorders are scarce. To fill this lack of information, a retrospective single centre study was conducted. All cases with mild haemophilia (75 A and 7 B) followed at the regional reference HTC of Parma were evaluated. The patients' median age at diagnosis was 11.5 years and their median age at first bleeding was 5.5 years; 95% of patients had a history of haemorrhagic problems during their life. Twenty-three percent of patients were infected by HCV, and none by HIV. Genetic analysis was performed in 80 patients (97% haemophilia A and 100% haemophilia B) and 21 different mutations were characterized. Eleven percent of patients had never received treatment, whereas 67% were treated with plasma-derived or recombinant FVIII/FIX concentrates (4% developed inhibitors). desmopressin (DDAVP) was used in 80% of the haemophilia A patients. The response to DDAVP was closely related to the patients' genetic profile, as 60% of non-responders had a mutation in the F8 promoter region. Patients with mild haemophilia may experience a variety of medical problems, sometimes challenging for the physicians, during their lifetime. The HTCs play an important role in the management of these patients, whose diagnosis is often delayed. The HTCs should improve patients' knowledge and consideration of their disease and encourage them to maintain regular contact with their haemophilia care provider.

Spectrum of F8 gene mutations in haemophilia A patients from a region of Italy: identification of 23 new mutations.

SUMMARY: Haemophilia A (HA) is an X-linked recessive bleeding disorder caused by a lack or decrease of coagulation factor VIII activity. The molecular diagnosis of HA is challenging and a variety of different mutations have been identified throughout the F8 gene. Our aim was to detect the causative mutation in 266 HA patients from Emilia-Romagna region (Italy) and in all suspected carriers. Molecular analysis of F8 in 201 HA patients (152 index cases) was performed with a combination of several indirect and direct molecular approaches, such as long distance polymerase chain reaction, multiplex ligation-dependent probe amplification, denaturing high performance liquid chromatography and direct sequencing. The analysis revealed 78 different mutations, 23 of which were novel, not having been reported in national or international databases. The detection rate was 100%, 86% and 89% in patients with severe, moderate and mild HA, respectively. The information provided by this registry will be helpful for monitoring the treatment of HA patients in Emilia-Romagna and also for reliable genetic counselling of affected families in the future.

Mortality and causes of death in Italian persons with haemophilia, 1990-2007.

Although a number of studies have analysed so far the causes of death and the life expectancy in haemophilic populations, no investigations have been conducted among Italian haemophilia centres. Thus, the aim of this study was to investigate mortality, causes of deaths, life expectancy and co-morbidities in Italian persons with haemophilia (PWH). Data pertaining to a total of 443 PWH who died between 1980 and 2007 were retrospectively collected in the 30 centres who are members of the Italian Association of Haemophilia Centres that chose to participate. The mortality rate ratio standardized to the male Italian population (SMR) was reduced during the periods 1990-1999 and 2000-2007 such that during the latter, death rate overlapped that of the general population (SMR 1990-1999: 1.98 95% CI 1.54-2.51; SMR 2000-2007: 1.08 95% CI 0.83-1.40). Similarly, life expectancy in the whole haemophilic population increased in the same period (71.2 years in 2000-2007 vs. 64.0 in 1990-1999), approaching that of the general male population. While human immunodeficiency virus infection was the main cause of death (45%), 13% of deaths were caused by hepatitis C-associated complications. The results of this retrospective study show that in Italian PWH improvements in the quality of treatment and global medical care provided by specialized haemophilia centres resulted in a significantly increased life expectancy.

A web-based clinical record 'xl'Emofilia' for outpatients with haemophilia and allied disorders in the Region of Emilia-Romagna: features and pilot use.

The treatment of haemophilia in developed countries is based on home self-infusion of concentrates. Improving communication between haemophilia centres (HC) and patients is very important. The Hub Centre (Parma) designed a new outpatient clinical record, 'xl'Emofilia', as part of a project 'Web Connections of the Region's HC' funded by Emilia-Romagna Health Authority. It is a web-based application suited to the needs of HC, which shares the databases of the region's HC, integrated with regional and national registries that can be accessed from anywhere. Data are managed with the 'https' protocol. Significant innovations are 'pathways' that help with the entry of data and 'problem list', which is a summary (updated automatically) of the patient's clinically significant data that can be consulted at a glance. With a 'web identity' (a personal USB key for secure web access), patients can record bleeds and home infusions, consult their own data and allow access to their general practitioners or in emergency departments anywhere in the world (also in English language). In December 2006, the HC started to use 'xl'Emofilia' and 673 clinical records are now active. Since April 2007, 50 pilot patients have been trained and are successfully using the system. A questionnaire administered to these patients on their level of satisfaction with the system and its ease of use gave excellent results. Our web-based system facilitates communication between patients and HC, improves the quality of care and enables patients to use these information at any time and from anywhere in the world.

Effects of secondary prophylaxis started in adolescent and adult haemophiliacs.

While primary prophylaxis is a well-established and recommended method of care delivery for children with severe haemophilia, fewer studies have documented the benefits of secondary prophylaxis started in adolescence or adulthood. To evaluate the role of secondary prophylaxis started in adolescent and adult severe haemophiliacs, a retrospective observational cohort study was conducted in 10 Italian Centres that investigated 84 haemophiliacs who had bled frequently and had thus switched from on-demand to prophylactic treatment during adolescence (n = 30) or adulthood (n = 54). The consumption of clotting factor concentrates, the orthopaedic and radiological scores, quality of life and disease-related morbidity were compared before and after starting secondary prophylaxis. Prophylaxis reduced the mean annual number of total and joint bleeds (35.8 vs. 4.2 and 32.4 vs. 3.3; P < 0.01) and of days lost from work/school (34.6 vs. 3.0, P < 0.01). A statistically significant reduction in the orthopaedic score was observed during prophylaxis in adolescents, but not in the whole cohort. Patients used more factor concentrates with corresponding higher costs on prophylaxis, but experienced a better quality of life. With respect to on-demand treatment, higher factor consumption and cost of secondary prophylaxis were balanced by marked clinical benefits and greater well-being in this cohort of adolescent/adult haemophiliacs.

A web-based registry of inherited bleeding disorders in the region of Emilia-Romagna: results at three and a half years.

A Registry of inherited bleeding disorders was set up in the Region of Emilia-Romagna (RER) to collect information about these diseases and to improve the quality of care. From January 2003, the eight Haemophilia Centres (HC) in the RER began to use computerized clinical records; every 6 months, they send data to Parma Hospital to be processed and published in a website (http://www.registroemofiliarer.it). Great efforts are made to ensure high quality of data. Results of general interest are included in a free 'public area' and more sensitive data in a 'reserved area' (open only to HC and to health authorities). A total of 610 individuals are included: 249 haemophilia A (HA), 63 haemophilia B (HB), 173 von Willebrand's disease, 69 rare bleeding disorders, seven platelet disorders and 49 haemophilia carriers; 131 were genotyped, 188 were tested for inhibitors (16 affected). The most frequent bleeding was haemarthrosis. The joint score (evaluated in 104 haemophiliacs) was higher in severe HA. There were 22 HIV-positive and 182 hepatitis C virus-positive patients (21% have chronic hepatitis, two hepatocellular carcinoma). In 2005, two patients received primary prophylaxis, 47 secondary prophylaxis, four children were on immune-tolerance induction. From 2003 to 2005 the use of recombinant products was greatly increased and the majority of patients received them. The mean clotting factor consumption for prophylaxis was higher than on-demand treatment. The main features of registry are to collect high quality and comprehensive data of all patients followed by HC, to improve quality of care and it's availability on the web.

Prophylactic treatment of haemophilia patients with inhibitors: clinical experience with recombinant factor VIIa in European Haemophilia Centres.

Many patients with haemophilia develop inhibitors to factor VIII and require bypassing agents to provide haemostatic cover for limb- or life-threatening bleeding episodes. Due to the reduced risk of blood-borne pathogen transmission with recombinant products, on-demand recombinant factor VIIa (rFVIIa; NovoSeven is the treatment of choice for children with inhibitors. In haemophiliac patients without inhibitors, primary prophylaxis has been clinical practice for several years. This paper summarises 13 case histories of rFVIIa secondary prophylaxis for haemophilia patients with inhibitors. This was a retrospective survey of adult and paediatric severe haemophilia patients with inhibitors treated with rFVIIa from ten European Haemophilia Centres. There was a wide variation in administered rFVIIa dose, from 200-250 microg kg(-1) per week to 220 microg kg(-1) daily. In many cases, this was lower than the recommended on-demand dose of rFVIIa. In 12/13 cases, prophylaxis with rFVIIa considerably reduced the number of bleeding episodes compared with previous treatment. Eight/nine patients were satisfied or very satisfied with rFVIIa treatment, and in cases reporting subjective quality of life (QoL), all were improved, much improved, or significantly improved. In haemophilia patients with inhibitors, prophylaxis with rFVIIa is highly effective in reducing the number of bleeding episodes and results in good patient compliance and improved QoL. Randomised controlled trials are needed to confirm these findings. Results of a recently completed clinical trial on secondary prophylaxis with rFVIIa in frequently bleeding haemophilia patients with inhibitors are expected in late 2006.

[The presence of asbestos bodies in induced sputum as an indicator of asbestos exposure]. / La presenza di corpuscoli dell'asbesto nell'espettorato indotto come indicatore di esposizione ad amianto.

BACKGROUND: Very few references on the usability of presence of asbestos bodies (AB) in induced sputum as an indicator of asbestos exposure are to be found in the scientific literature. OBJECTIVES: The purpose of this study was to prove whether the presence of AB in induced sputum is a valid assessor of asbestos exposure. METHOD: This was achieved by comparing the above-mentioned method with the search for AB in bronchoalveolar lavage (BAL) fluid and repeating the trials over time in order to study the reproducibility of the results. RESULTS: There was good agreement of results for the presence/absence of AB in induced sputum and in BAL among subjects who were environmentally exposed and those with 'a medium-high risk occupational exposure (100%), and poor agreement (66%) among subjects with a low risk occupational exposure. Agreement of results regarding the amount of particles per test was low. The method showed a sufficient reproducibility level (Cohen K=0.5). CONCLUSION: Although the presence of asbestos bodies in induced sputum cannot replace bronchoalveolar lavage, it can however be used as a screening test for selecting subjects who should undergo BAL.

[Health surveillance of workers with prior exposure to asbestos. Application in the metallurgy/metal mechanical field]. / La sorveglianza sanitaria dei lavoratori con pregressa esposizione ad amianto. Una applicazione nel settore metallurgico-metalmeccanico.

To improve the health surveillance program for workers with a known previous exposure to asbestos in a big metallurgic-mechanical industry from Lombardy, the sources of risk and the different exposure levels hare been reconstructed based on specific jobs. The eligibility criteria and a specific work program including information and organization supports hare been established by a work group composed by health physicians, workers and industrial hygienists. The major goals of the program were: to listen and support each worker who perceives worries about his health status; to prevent, if possible, diseases, especially cancer, resulting from exposure; to document the existing injuries for legal compensation. The resulting actions consist of counselling; indication to follow an adequate life and work style; indication, based on specific request of worker, of sanitary checks of first or eventually second level.

[The role of the occupational health physician in smoking cessation programmes: the experience of the "Clinica del Lavoro" of Milan]. / Il ruolo del medico del lavoro nella lotta al tabagismo: l'esperienza della Clinica del Lavoro di Milano.

UNLABELLED: <>. BACKGROUND: The "Centre for the prevention, diagnosis and treatment of tobacco dependency", set up at the Occupational and Environmental Respiratory Diseases Section of the Clinica del Lavoro in Milan in September 2000, can count on multidisciplinary expertise, including occupational health physicians, pneumologists and clinical psychologists. Each step of the diagnostic and therapeutic process is based on an integrated approach that considers both the biological aspects of tobacco dependency and the psychological and behavioural aspects. The Centre, moreover, within the framework of "Health Promotion" programmes, offers advice to businesses as regards the new legislation that prohibits smoking at the workplace. METHODS: The proposed treatment programme is based on psychological and motivational support (personal or team work), that can be associated with pharmacological therapy, either as an alternative or an addition. The drug preferred is slow-releasing buproprione, which has proved to be extremely effective compared to other drugs in increasing the probability of smoking cessation and decreasing side effects. RESULTS: In an occupational population of more than 2000 workers, we succeeded in treating about 51% of the subjects, who had stopped smoking, after one year from the beginning of the programme. The best results were achieved using the association of psychological support and buproprione therapy (54%), compared with the other methods (psychological support alone: 42%; psychological support and free nicotine replacement therapy: 33%).

[Clinical research in the field of occupational diseases (pneumonology aspects)]. / La ricerca clinica nel campo delle malattie professionali (aspetti pneumologici).

In the second half of the seventies, at the same time as the control of silicosis was achieved thanks to pathogenetic and preventive developments, the major efforts of the Clinica del Lavoro in the pneumological field were focused on studying dose-response relationship in asbestos-exposed subjects. Thus for the first time biological indicators (and not radiological ones) were mentioned for asbestos diseases. Bronchoalveolar lavage (BAL) allowed to compare an internal dose indicator (number of bodies/ml) and schlerogenous effect indicators (dose-response). Our experience over nearly 20 years for exposure assessment in asbestos-related diseases, based on over 500 cases has produced the following results: parenchymial asbestosis is dose-dependent while pleural plaques are dose-independent; epidemiologic data on existence of asbestos resistant subjects were confirmed; asbestos bodies proved to persist in alveolar cavities for several decades. At present, with the ban of asbestos and the increase in forensic medicine cases regarding past asbestos exposures, our Department demonstrated the importance of asbestos body counting in BAL as an objective indicator of asbestos exposure. Besides the asbestos issue, two less frequent work-related diseases were studied and in this regard bronchoalveolar lavage proved to be a substantial diagnostic tool, sometimes even decisive: these were hard metal disease and hypersensitive pneumonitis. In subjects exposed to hard metals, our experience showed the presence of a large lymphocytic alveolitis with CD4+/CD8+ reverse ratio for bronchial asthma and macrophagic-eosinophylic alveolitis characterized by several "bizarre" giant cells in the case of interstitial disease. In extrinsic allergic alveolitis, we noted the presence of a large lymphocytic alveolitis mostly with CD4+/CD8+ reverse ratio, persisting also during clinical remission of the disease.

[Asbestos risk in the textile industry: final confirmation of data from the Lombardy Mesothelioma Registry]. / Il rischio amianto nel settore tessile: indicazioni dal Registro Mesoteliomi Lombardia e definitiva conferma.

BACKGROUND: Cases of mesothelioma in non-asbestos textile workers have been frequently reported but the identification of asbestos dispersion sources in the workplaces has never been adequately performed. During 3 years of activity of the Mesothelioma Register for Lombardy, 40 cases (10.8% of all cases) were collected in textile workers engaged in all types of productive activities. The hypothesis that a significant asbestos risk for textile workers appeared not negligible. OBJECTIVES: The research was aimed at the identification of asbestos dispersion sources in textile factories. METHODS: Specific information was collected by technicians, maintenance personnel and other experts and direct inspections were carried out in numerous workplaces that had not yet undergone significant changes with respect to the past. Also the industrial machinery utilised in the previous 40-50 years was thoroughly examined. RESULTS: Epidemological evaluation of the recorded cases showed a widespread distribution in the different phases of textile production. Inspections also showed that a large amount of asbestos had been regularly used applied to the ceilings and also to the walls of factories in order to avoid both condensation of steam and reflection of noise. In addition, asbestos had also been widely used to insulate water and steam pipes. The braking systems of most of the machines also had asbestos gaskets, and on several looms some brakes operated continuously in order to keep the warp in constant tension. CONCLUSIONS: Our observations confirmed that since production techniques in the textile industry required working in damp and warm conditions with the noise of the rapidly moving machines, asbestos was very often used because of its absorbent and soundproofing qualities and its resistance to friction. We demonstrated that asbestos was thus widely used in the industry and this certainly produced considerable fibre dispersions in the atmosphere of the workplaces. Asbestos risk must therefore be recognised for all those who have worked in the textile industry in the recent past and, as a result, cases of mesothelioma must be considered occupational diseases.

[Significance of bronchoalveolar lavage in demonstrating previous exposure to asbestos]. / Importanza del lavaggio broncoalveolare nella dimostrazione di pregressa esposizione ad amianto.

A study was made via a clinical approach in the absence of environmental data with the aim of demonstrating a possible past exposure to asbestos in a working population that had never been examined before nor had ever undergone any specific health checks. It was deemed useful to compare this working population with a control population not exposed to asbestos. The population under study consisted of 126 employees of a single (thermonuclear) department of a metal engineering industry who reported having used asbestos as insulation material in all heat processes up to the beginning of the 1980's. Pleural plaques were observed in 13 workers that were also confirmed by high resolution TC (HRTC) except in one case. The control group consisted of subjects seen at the Clinica del Lavoro of Milan for non-asbestos related diseases in whom a fibrobronchoscopy with broncho-alveolar lavage (BAL) was performed for diagnostic purposes. In each group asbestos bodies were counted in the BAL liquid using a method with a detection limit of 0.1 bodies/ml. The asbestos bodies detected in the alveolar liquid of subjects in the control group were between a maximum of 0.25 and a minimum of 0 bodies/ml of liquid (mean = 0.03; SD = 0.64) whereas in the sample of subjects from the population under study who underwent BAL the results gave a concentration of asbestos bodies in the BAL liquid between a maximum of 9.0 and a minimum of 0.15 bodies/ml of liquid (mean = 2.38; SD = 2.72). In order to obtain a statistically significant difference between the control population, which was certainly not exposed, and the sample of subjects undergoing BAL from the population for which an occupational exposure was assumed, we applied the non-parametric Wilcoxon-Mann-Whitney test for independent samples in view of the asymmetric distribution of the values of asbestos body concentration in the alveolar liquid: the result was a statistically significant difference (p < 0.001) between the two populations. We also calculated the total asbestos bodies recovered in the BAL liquid of subjects from both populations. In the control group total asbestos bodies were between a maximum of 15 and a minimum of 0 (mean = 1.8; SD = 3.9) while in the group under study the concentration of total asbestos bodies recovered in BAL liquid was between a maximum of 990 and a minimum of 12.7 (mean = 206.5; SD = 270). The Wilcoxon-Mann-Whitney test was also applied to these data, the result of which was that the difference in exposure between the two populations was statistically significant (p < 0.001). Concluding, the study demonstrates the importance of asbestos body count in BAL liquid as an objective indicator of past occupational exposure to asbestos, thus providing documented proof that overcomes any doubts arising from case history and any lack of environmental data that could prove exposure.