Lung Ultrasound in COVID-19: Clinical Correlates and Comparison with Chest Computed Tomography.

Lung ultrasound (LUS) and chest computed tomography (chest CT) are largely employed to evaluate coronavirus disease 2019 (COVID-19) pneumonia. We investigated semi-quantitative LUS and CT scoring in hospitalized COVID-19 patients. LUS and chest CT were performed within 24 h upon admission. Both were analyzed according to semi-quantitative scoring systems. Subgroups were identified according to median LUS score. Patients within higher LUS score group were older (79 vs 60 years, p<0.001), had higher C-reactive protein (CRP) (7.2 mg/dl vs 1.3 mg/dl, p<0.001) and chest CT score (10 vs 4, p=0.027) as well as lower PaO2/FiO2 (286 vs 356, p=0.029) as compared to patients within lower scores. We found a significant correlation between scores (r=0.390, p=0.023). Both LUS and CT scores correlated directly with patients age (r=0.586, p<0.001 and r=0.399, p=0.021 respectively) and CRP (r=0.472, p=0.002 and r=0.518, p=0.002 respectively), inversely with PaO2/FiO2 (r=-0.485, p=0.003 and r=-0.440, p=0.017 respectively). LUS score only showed significant correlation with hs-troponin T, NT-pro-BNP, and creatinine (r=0.433, p=0.019; r=0.411, p=0.027, and r=0.497, p=0.001, respectively). Semi-quantitative bedside LUS is related to the severity of COVID-19 pneumonia similarly to chest CT. Correlation of LUS score with markers of cardiac and renal injury suggests that LUS might contribute to a more comprehensive evaluation of this heterogeneous population.

Assessing Malnutrition in Systemic Sclerosis With Global Leadership Initiative on Malnutrition and European Society of Clinical Nutrition and Metabolism Criteria.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Gastrointestinal tract (GIT) involvement may lead to malnutrition, which can in turn negatively affect morbidity, mortality, and quality of life. The aim of the study was to assess the prevalence of malnutrition in SSc patients with both the European Society of Clinical Nutrition and Metabolism (ESPEN) and the Global Leadership Initiative on Malnutrition (GLIM) criteria and to assess whether it relates with disease activity and severity. METHODS: Adult SSc patients were included in the study. Biochemical analyses, disease activity index (DAI), disease severity scale (DSS), anthropometric data, and body composition parameters for GLIM and ESPEN assessment were recorded at enrollment. RESULTS: One hundred and two SSc patients were enrolled (86 females, mean age 55 ± 14 years). The prevalence of malnutrition was 8.8% (9 of 102), according to ESPEN, and 16.6% (17 of 102), according to GLIM criteria. GLIM severity grading of malnutrition was moderate in 12.7% (13 of 102) and severe in 3.9% (4 of 102) . In SSc patients with malnutrition according to GLIM criteria, DAI and DSS were significantly higher than in SSc patients without malnutrition (P < .0001), whereas no association was observed between malnutrition and DAI or DSS when using the ESPEN criteria. CONCLUSION: Prevalence of malnutrition is higher with GLIM than with ESPEN criteria. Irrespective of the method used, prevalence of malnutrition in SSc is lower than one would expect in a chronic, autoimmune disease with GIT involvement.

Vaccine-preventable disease in healthcare workers in Sicily (Italy): seroprevalence against measles.

Aim: Measles is one of the most infectious communicable diseases. The objective of this study was to determine the immunity to measles of healthcare workers (HCWs) operating in three hospitals of Catania. Methods: A total of 549 HCWs underwent measles screening. A 5 ml blood sample was taken from each worker to measure IgG antibody levels. Results: Overall seroprotection was 86%. Unvaccinated HCWs agreed to undergo the vaccination offered by the hospital. Furthermore, it was found that younger workers are less seroprotected than older ones. Conclusion: Model legislation may be helpful to countries wishing to implement immunization requirements in healthcare settings in order to virtually eliminate the risk of acquiring and spreading measles in healthcare settings.

The Plasminogen System and Transforming Growth Factor-ß in Subjects With Obstructive Sleep Apnea Syndrome: Effects of CPAP Treatment.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) has emerged as a risk factor for cardiovascular disease. A prothrombotic state may affect coagulation and participate in the atherosclerotic process in subjects with OSAS. These alterations in coagulation seem to involve the plasminogen activation system. We evaluated the imbalances of the plasminogen activation system related to OSAS, and we assessed the effects of CPAP on the plasminogen activation system. METHODS: Thirty-nine subjects were submitted to a home-based cardiorespiratory sleep study, and 14 healthy subjects (apnea-hypopnea index < 5) were used as controls. Serum levels of urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and active transforming growth factor-ß (TGF-ß) were measured. These molecules were reassessed in only 17 of the subjects after 1 month of CPAP. RESULTS: PAI-1 and tPA were significantly higher in the subjects with OSAS compared with the controls, whereas TGF-ß and uPA levels were lower. PAI-1 showed a significant positive correlation with the apnea-hypopnea index, percentage of time spent at O2 saturation < 90%, and oxygen desaturation index, whereas TGF-ß was inversely related to all 3 of these parameters. After the CPAP therapy, PAI-1 significantly decreased, whereas TGF-ß showed a significant increase, although the values did not reach those of the controls. uPA and tPA did not show significant differences after the treatment. CONCLUSIONS: Our results suggest an imbalance of fibrinolysis related to OSAS and an improvement of the prothrombotic state after the CPAP treatment.

Professional exposure to basaltic rock dust: assessment by the Vibrio fischeri ecotoxicological test.

BACKGROUND: A recent study demonstrates that inhalation of airborne particulate from Mount Etna eruptions may induce fibrotic lung disease. The occupational exposure of construction workers from the Etna area, who excavate building sites and use basalt dust to make mortar, has never been assessed. METHODS: Samples of basalt, volcanic ash, basalt + cement and cement dust were collected on the construction site of a subway tunnel, ground to dust and subjected to the Microtox(®) solid-phase test to evaluate the toxicity of dust suspensions. Samples were investigated by scanning electron microscopy equipped with energy dispersive X-ray analysis (EDX). Minerals were identified and characterized by their morphology and elemental composition. RESULTS: The elements found most frequently were C, Na, Mg, Al, Si, K, Ca, Ti, Mn, Fe and O. All four dusts were toxic: basalt and ash were significantly less toxic than basalt + cement and cement, which shared a similar and very high degree of toxicity. Higher Fe, Ca and Mg concentrations were associated with greater toxicity. CONCLUSIONS: The risk related to long-term occupational exposure to various dusts on constructions sites in the Mount Etna area should be further assessed.

[Potential exposure to carcinogens in low-melting alloys processing]. / Potenziale esposizione a cancerogeni nella lavorazione di leghe bassofondenti.

The objective in our study was to evaluate the worker's exposition to lead and cadmium in 32 radiology technicians in an eastern Sicily hospital in workers of low melting point alloy of lead, tin, cadmium and bismuth (league that can be melted at 73 degrees C as CERROBEND). Such alloy is used for the fabrication of objects used for the personal protection of cancer patients subject to high energy treatment. The parameters taken into consideration for this study were sex, age and smoking habits. In the test subject's working cycle reported in our case, there were traces of smoke formation containing lead, tin, bismuth and cadmium. Cadmium is a substance considered by IARC to be cancerous and can be found in both work and living environments, therefore it is often difficult to establish rather its presence in the organism is due to working activities and/or the living environment. In these cases it is necessary to evaluate whether the work represents an added risk to develop neoplasia, compared to the consequences due to normal environmental exposure. The added risk linked to work is evaluated comparing the concentration of toxic substances found in the living environments (Environmental Reference Value) with the toxic and/or metabolite found in the working environment, and comparing the biological reports of the population not directly exposed by work (Biological Reference Value) and those exposed. We performed a biological monitoring for lead and cadmium on the workers examined. The Italian Legislature, aside from lead, has not yet issued guidelines pertaining to professional exposure to cadmium, and therefore it is mandatory to take reference to the American Hygienist's charts both for environmental exposure (TLVs) andfor biological monitoring (BEI). Biological monitoring, which allows to evaluate the absorption by both inhalation and gastrointestinally, was performed through measuring the levels of lend and cadmium in the bloodstream (PbB and CdB) and the Cd in urine (CdU). The results show that in no case the levels of lead in the bloodstream (PbB) were above the reference value and BEI. The levels of cadmium urine (CdU) weren't above the reference level and the BEI, while the haematic levels of cadmium (CdB) were higher than the reference value in 8 subjects, each long time smokers, each of about 20 cigarettes a day. This data shows how, in the evaluation of exposition to cadmium, aside from the exam of data pertaining to work, the study of ways of absorption and the interpretation of the results of environmental and biological monitoring, it is important to consider the possibility of intoxication outside of the workplace. Cigarette smoke, as already indicated by other authors, is also confirmed in our studies as one of the major fonts of non professionally linked inhalation of cadmium.

A tailored health surveillance program unveils a case of MALT lymphoma in an HCV-positive health-care worker.

Non-Hodgkin lymphoma (NHL) may occur among hepatitis C virus (HCV)-infected individuals. HCV is one of the most common blood-borne pathogens transmitted from patients to health-care workers (HCWs). The development of NHL among HCV-infected HCWs has recently been shown. To investigate this issue further a tailored health surveillance program was applied to 3,138 HCWs from four Medical Institutions. To this aim, all employees were screened for both anti-HCV antibodies and HCV-related extrahepatic manifestations. The HCV prevalence rate, similar among all the HCW subgroups, was 7.3%. The occurrence of a gastric mucosa-associated lymphoma tissue (MALT) lymphoma, diagnosed in a physician following a long history of HCV chronic infection, was observed. Molecular characterization of MALT tissue indicated that immunoglobuline gene combinations were those usually found among HCV-associated lymphomas. Furthermore, B-cell expansion exhibited t(14;18) translocation, as a genetic abnormality associated with the development of MALT lymphomas from HCV-positive patients. Overall, these findings support the hypothesis that HCV viral infection potentially affects the pathway of transformation and progression of lymphoma cells. The occurrence of B-cell NHL, among HCV-positive HCWs, is an additional reason to apply the standard precautions to reduce the risk of blood-borne pathogen transmission.

Long-term persistence of seroprotection by hepatitis B vaccination in healthcare workers of southern Italy.

BACKGROUND: The impact of hepatitis B virus (HBV) vaccination campaigns on HBV epidemiology needs to be evaluated, in order to assess the long-term immunity offered by vaccines against HBV. OBJECTIVES: To evaluate the current status of anti-HBV vaccine coverage among healthcare workers (HCWs) in Southern Italy, and to determine the long-term persistence of antibodies to hepatitis B surface antigens (anti-HBs) in such a cohort of subjects. PATIENTS AND METHODS: A longitudinal, retrospective seroepidemiological survey was conducted among 451 HCWs, who were working at or visiting, the Occupational Health Department of a city hospital, in Catania, Italy, between January 1976 and December 2010. RESULTS: At the 30-year follow-up (mean follow-up 10.15 ± 5.96 years, range 0.74-30), 261 HCWs had detectable anti-HBs titers indicating a persistence of seroprotection of 89.4% (out of 292 anti-HBs positive results, three months after vaccination). An inadequate vaccination schedule was the strongest predictor of antibody loss during follow-up (OR = 8.37 95% CI: 5.41-12.95, P < 0.001). A Kaplan-Maier survival curve revealed that the persistence of anti-HBs 30 years after vaccination, was 92.2% for high responders, while it was only 27.3% for low responders (P = 0.001). CONCLUSIONS: A good level of seroprotection persisted in 57.9% of the subjects after 30 years. Factors related to this immunization status confirmed the importance of vaccinating HCWs early in their careers and ensuring an adequate vaccination schedule. However, with particular reference to the low rate of hepatitis B vaccine coverage among HCWs in Southern Italy, the implementation of a new educational intervention as part of an active vaccination program is needed.

Correlation of the risk of breast cancer and disruption of the circadian rhythm (Review).

Breast cancer is the worldwide leading cause of cancer incidence among women. Night shift work exposure has been recently considered one of the significant breast cancer risk factors in industrialized countries. The mechanisms by which this work exposure may be responsible for cancer development is still discussed. In the last 15 years, many authors have paid attention to the relationship between night shift work and breast cancer risk. In the current study, eight case-control studies and four prospective epidemiological studies describing such relationship are discussed. A positive correlation between night shift work and breast cancer risk was described in 8 out of 12 studies. However, different reasons suggest that some of these studies have an Achilles heel according to the International Agency of Cancer (IARC) indications. Both the circadian system alteration and the melatonin output reduction, related to the exposure to light-at-night during night shift work, remain the most valid hypotheses on the causal relation of shift work and breast cancer. Overall, the results of the present study suggest that there is an association between night shift work and breast cancer development in western countries. However, further studies are needed to confirm such association and to understand which biomolecular mechanisms may be involved in the pathogenesis of cancer diagnosed in patients with night shift work exposure.

Prevalence of hepatitis C virus infection among health-care workers: A 10-year survey.

Hepatitis C virus (HCV) is one of the most common blood-borne pathogens transmitted from patients to health-care workers (HCWs). HCV infection status among HCWs and occupational blood exposure accidents were monitored to assess the risk of HCV infection among 403 HCWs from a single institution between 1999 and 2009. Additionally, HCV-related malignancies were evaluated in the HCV-positive HCWs. HCV infection was detected in 3% of the subjects at the first survey. The HCWs that initially tested negative for HCV remained negative during the 10 years of the survey. Of note, a statistically significant decrease was observed in the number of HCWs that experienced occupational blood exposure accidents, from 116 in 1999 to 72 in 2009 (p=0.0002). One HCV-infected HCW developed B-cell non-Hodgkin lymphoma (NHL) of the liver. The heavy chain gene combinations detected in the DNA from the NHL tissue were of the type usually found in HCV-associated lymphomas, supporting the role of HCV infection in the lymphomagenesis of this patient. The set of universal precautions recommended by the US Center for Disease Control and Prevention aided in the prevention of HCV transmission from patients to HCWs, as all 390 HCV-negative HCWs remained negative for the duration of the survey. Consequently, these recommendations also serve to prevent the development of HCV-associated malignancies such as hepatocellular carcinoma or B-cell NHL.

Preventive and curative effects of cyclophosphamide in an animal model of Guillain Barrè syndrome.

The immunosuppressive agent cyclophosphamide (CY) was tested in rat experimental allergic neuritis (EAN), a preclinical model of Guillain Barrè syndrome (GBS). CY prophylaxis (day 0 and 14 post-immunization [p.i.]) effectively prevents clinical and histological signs of EAN and also reduces the cytokine and the NF-kappaB p65 expression in the nervous tissue. When administered therapeutically (day 14th p.i.) to rats with established disease CY only affects the clinical symptoms. Both the prophylactic and therapeutic treatment with CY reduced ex vivo antigen-specific T cell proliferative responses. These results warrant studies with CY in those cases of GBS resistant to conventional therapies.

Cigarette smoking is associated with a greater risk of incident asthma in allergic rhinitis.

BACKGROUND: Asthma and rhinitis are often comorbid conditions, and several studies have suggested that rhinitis often precedes asthma. Sensitization to allergen has been shown to be one of the strongest determinants of incident asthma, but little is known about the effects of cigarette smoking among individuals with allergic rhinitis. OBJECTIVE: We sought to evaluate the importance of cigarette smoking as an additional risk factor for incident asthma in a cohort of hospital-referred nonasthmatic adult subjects with allergic rhinitis. METHODS: The study population selected at baseline was invited for a follow-up visit 10 years later to check for possible asthma features. Categories of smokers, exsmokers, and never smokers were used in the analyses together with pack-years to calculate the level of cumulative exposure. RESULTS: Complete data were available from 325 patients. Smoking was significantly related to the risk of incident asthma, with the odds ratio (OR) being 2.67 (95% CI, 1.70-4.19) for univariate and 2.98 (95% CI, 1.81-4.92) for multivariate analyses. A clear dose-response association for exposure to tobacco and risk of new-onset asthma was observed in the multivariate analyses: those with 1 to 10 pack-years had an OR of 2.05 (95% CI, 0.99-4.27), those with 11 to 20 pack years had an OR of 3.71 (95% CI, 1.77-7.78), and those with 21 or more pack-years had an OR of 5.05 (95% CI, 1.93-13.20) compared with never smokers. CONCLUSIONS: The current findings support the hypothesis that cigarette smoking is an important independent risk factor for the development of new asthma cases in adults with allergic rhinitis.

Analysis of BRAF mutation in primary and metastatic melanoma.

Mutation of BRAF has been proposed to contribute to melanoma development. However, it remains unclear whether or not BRAF mutation is associated with any particular stage of melanoma progression. Tumor biopsy specimens from patients with melanoma were analyzed to determine whether the frequency of BRAF mutation in metastatic melanoma differed from primary melanoma. BRAF mutation was present in 15 of 23 (61%) patients with primary melanoma and in 7 of 12 (58%) patients with metastatic melanoma. These results suggest that BRAF mutation in melanoma is most likely to occur prior to the development of metastatic disease.

[Adverse reaction following suspected inhalation of nickel tetracarbonyl: case report]. / Reazione avversa da sospetta inalazione di nichel tetracarbonile: un caso clinico.

BACKGROUND: Nickel tetracarbonyl (Ni(CO)4) is a highly toxic chemical that is produced as an intermediate compound in the Mond process of nickel refining. Occupational poisoning due to Ni(CO)4 is not frequent, and up to now about 300 cases have been reported in the medical literature worldwide. OBJECT: A clinical case is reported of an industrial worker who developed clinical symptoms of respiratory distress probably due to accidental exposure to Ni(CO), METHODS: Clinical examination, chest X-ray data, history of exposure to nickel in the presence of carbon monoxide (CO) from a production plant that was located close to the reactor containing nickel, led to diagnosis of respiratory distress due occupational poisoning. RESULTS: Patient history, clinical symptoms that were characteristic of Ni(CO)4 poisoning: mild transient initial symptoms followed within 24 hours by more severe life-threatening events environmental data, history of exposure to nickel near a carbon monoxide (CO) production plant that was located close to the nickel containing reactor, indicated a putative causal relationship between diagnosis and exposure to nickel tetracarbonyl. CONCLUSIONS: The accident that without adequate respiratory therapy might have had fatal consequences, could have been avoided if the rules of technical and procedural prevention had been carefully observed.

[Prevalence of respiratory symptoms, reduction in lung function and allergic sensitization in a group of traffic police officers exposed to urban pollution]. / Prevalenza di sintomi respiratori, riduzione della funzionalità polmonare e sensibilizzazione allergica in un gruppo di vigili urbani esposti al traffico urbano.

BACKGROUND: Environmental factors are believed to play a critical role in the development of allergic respiratory diseases, such as asthma and rhinitis. Particularly, the role of urban pollution in the pathogenesis of these diseases is debated. OBJECTIVES: The aim of the study was to investigate whether subjects with a well-defined occupational history of exposure to road traffic fumes presented an increased prevalence of respiratory symptoms of chronic bronchitis (cough), asthma (wheeze), and allergic sensitisation to the most common allergens and reduced lung function compared with an unexposed control group. METHODS: The study was conducted on 484 traffic police in Catania (465 men and 19 women), with a mean age of 45 +/- 7.9 years, who were subdivided into three groups. The first group included traffic police assigned to traffic direction, the second group included traffic police working in administrative offices, the third group included all traffic police who did not fall into the previous groups. In the first group, "truly exposed" subjects were identifed as police officers assigned to traffic direction in the last 8 years. Similarly, in the second group, "truly non-exposed" subjects were identified as police officers working in offices in the last 8 years. RESULTS: Statistical analysis showed a significant difference in mean age between the truly exposed group and the truly non-exposed group (p < 0.01). The truly exposed group showed a greater prevalence of symptoms (cough, wheeze and dyspnoea), and positive reaction to skin allergy tests compared with the "truly non-exposed group", but this increase did not reach statistical significance. Alterations of the respiratory function tests were more frequent in the non-exposed (14.3%) compared to the exposed group (9.6%). The highest prevalence of cough, dyspnoea and wheezing was detected in smokers compared to non-smokers and to ex-smokers within each group. CONCLUSIONS: Our results show a major prevalence of respiratory symptoms and allergic sensitisation in exposed traffic police compared with non-exposed police, although this did not reach statistical significance. Further epidemiological studies conducted on larger samples are required to better understand the role of road traffic pollution in inducing allergic respiratory diseases.

[Latex allergy prevalence and atopy in 1300 health care workers]. / Allergia a lattice ed atopia in un gruppo di operatori della sanità.

The aim of our research was to evaluate the latex allergy prevalence in 1300 health care workers by means of a self-administered questionnaire, clinical evaluation and specific allergological tests to confirm this condition. The results showed that all the questionnaire were completed, 60 subjects reported work-related symptoms, and 35 subjects out of 60 had latex allergy, 2.7% out of 1300 workers, lower than others studies, all 35 subjects were also atopic. This study confirms that the atopy is an important risk for the development of latex allergy.

[Results of a study on formaldehyde pollution as a cause of discomfort in public sector office workers]. / Risultati di una indagine sull'inquinamento da formaldeide responsabile di malessere negli impiegati di alcuni uffici pubblici.

Medical surveillance of Catania public sector employees who use video display terminals (VDTs) revealed complaints of eye and upper respiratory tract irritation, skin rash, headache, mental fatigue and reduced concentration in some of the workers. These were employed in three recently renovated offices and showed the above symptoms while at work. Investigations were performed to verify whether contaminants that may cause the above symptoms were present in the indoor air. In particular, levels of formaldehyde and CO2 were continuously monitored. CO2 levels were found to be higher in offices open to the general public as compared to other offices (including the three renovated ones). However, CO2 levels were never above 1,000 ppm. Formaldehyde was found in the indoor air of all three renovated offices in approximately equal concentrations, ranging from a minimum of 0,07 - 0,09 ppm to a maximum of 0,3 -0,4 ppm. In addition, a strong pungent odor typical of this substance was present in all three renovated offices but not in the others. Formaldehyde pollution must always be considered and assessed whenever new furnishings that may have required the use of glues that emit formaldehyde are brought into an indoor environment.

Nitric oxide production in fluoro-edenite treated mouse monocyte-macrophage cultures.

In the present study, we investigated the involvement of NO in the cytotoxic and genotoxic effects caused by fluoro-edenite in mouse monocyte-macrophage cell line J774. Fluoro-edenite is a new asbestos-like amphibole present in the benmoreitic lavas recently extracted from stone quarries in Biancavilla, a village located in the Etnean Volcanic Complex (Catania, Italy) of eastern Sicily, in which an epidemiological survey evidenced a cluster of cases of the mortality due to pleural mesothelioma. Fluoro-edenite appears as a probable carcinogenic agent. Nitrite and nitrate concentration (NO) in the supernatant was quantified by colorimetric assay based on the Griess reaction and iNOS (inducible nitric oxide synthetase) expression was determined by immunostaining in mouse monocyte-macrophage cell line J774 treated with different concentrations of fluoro-edenite (5, 50 and 100 microg/ml) for 24, 48, 72 and 96 h. Parallel experiments were performed treating the cultures also with lipopolysaccharides (LPS), used as inflammation-inducing molecule. In our experimental conditions, fluoro-edenite did not modify the level of NO and the expression of iNOS at the experimental used concentrations for 24, 48 and 72 h. These parameters were significantly modified at the higher doses (50 and 100 microg/ml) of fluoro-edenite for 96 h and were further more increased, in concentration- and time-dependent manner, when cell cultures were treated with fluoro-edenite and LPS. These findings provide convincing evidence that NO is involved in the fluoro-edenite-induced cytotoxicity and geno-toxicity in mouse monocyte-macrophage cell line J774 when the fiber remain for longer times and particularly in cultures treated with LPS, demonstrating that inflammatory disorders appear to increase the risk for lung cancer induced by fluoro-edenite probably by the involvement of NO.

[Malignant pleural mesothelioma in housewives in the province of Catania]. / Mesotelioma pleurico maligno in casalinghe della provincia di Catania.

Our study reports pleural malignant mesothelioma (PMM) in seven female patients. All patients were resident in Catania area (Sicily), the median age was 69.2 years and ranged from 59 to 81 years. They were housewife. Their anamnesis was negative for both direct and indirect previous exposure to asbestos; the partners of all patients were also not exposed to asbestos. The exposure to X-rays was also excluded for these patients. Different pathogenetic mechanisms for the appearance of PMM in these patients can be hypothesized, for example, SV40 infection and genetic susceptibility; a minimal domestic exposure to asbestos can be not excluded. Therefore, further studies in a more large number of subjects are necessary to determine whether one or all of these hypothetic pathogenetic mechanisms are more significant for the develop of PMM.