[Professional societies and conflict of interests governance.] / Società scientifiche e governo dei conflitti di interesse.

The complexity of health systems often implies a condition of conflict of interests for many of the players involved: health professionals, managers of the NHS, pharmaceutical, medical devices or food industries, publishers and communication agencies, conference event organizers. Conflict of interests is a condition of risk, not a sentence of guilt: for this reason, conflict of interests should be managed through information and training of health personnel. Scientific societies play an important role being active in updating their members (conferences, meetings, e-learning and residential training courses) and influencing healthcare with the production of clinical practice guidelines. Professional associations must be active to foster the integrity of their members and to minimize the risk of conflict of interests, also to avoid wasting resources, making the health system fairer and more sustainable.

Frailty Syndromes in Persons With Cerebrovascular Disease: A Systematic Review and Meta-Analysis.

Background: Frailty can change the prognosis and treatment approach of chronic diseases. Among others, frailty has been associated with cerebrovascular diseases such as stroke. However, the extent to which the two conditions are related is unclear, and no systematic review of the literature has been conducted. Objectives: To conduct a systematic review and meta-analysis assessing the association of cerebrovascular diseases and frailty, as well as prefrailty, in observational studies. The project was carried out on behalf of the Joint Action ADVANTAGE WP4 group. Methods: The review was performed according to PRISMA guidelines. We searched PubMed, Web of Science, and Embase from 01/01/2002-26/05/2019. Pooled estimates were obtained through random effect models and Mantel-Haenszel weighting. Homogeneity was assessed with the I2 statistic. Publication bias was assessed with Egger's and Begg's tests. Results: Of 1027 studies searched, 18 studies were included (n = 48,009 participants). Stroke was the only cerebrovascular disease studied in relation to frailty syndromes. All studies except one reported an association between stroke and prefrailty or frailty. However, most studies were not of high quality and there was heterogeneity between results. The pooled prevalence of prefrailty and frailty in stroke patients was 49% (95% CI = 42-57) and 22% (95% CI = 16-27), respectively. The prevalence of frailty was 2-fold in persons with stroke compared to those without stroke (pooled odds ratio = 2.32, 95% CI = 2.11-2.55). Only two studies longitudinally examined the association between stroke and frailty, producing conflicting results. Conclusions: Frailty and prefrailty are common in persons with stroke. These results may have clinical implications, as they identify the need to assess frailty in post-stroke survivors and assess how it may affect prognosis. Better quality, longitudinal research that examines the temporal relationship between stroke and frailty are needed, as well as studies on other types of cerebrovascular disease.

The OPTimization of interferon for MS study: 375 microg interferon beta-1b in suboptimal responders.

We aimed to evaluate the safety and MRI efficacy of interferon beta-1b (IFNbeta-1b) 375 microg (subcutaneously [sc] every other day [eod]) in relapsing-remitting multiple sclerosis (RRMS) patients with a suboptimal response to IFNbeta-1b 250 microg, i.e., with MRI activity or relapses. The OPTimization of Interferon for MS (OPTIMS) study was a prospective multicenter randomized phase 2 trial comprising a 6-month run-in phase (to identify suboptimal responders) and a 6-month randomized phase of open-label clinical and blinded MRI follow-up. During run-in all patients were treated with IFNbeta-1b 250 microg sc eod; during the study phase suboptimal treatment responders were randomized either to IFNbeta-1b 250 or 375 microg sc eod. Primary outcome was the proportion of patients without MRI activity during study Months 9-12 according to the intention-to-treat principle. 216 RRMS patients entered the study: 83 suboptimal responders were identified and randomized, 7 refused to continue treatment, 76 were included in the analysis. More patients treated with 375 microg had no MRI activity at Months 9-12 (30/36 vs.16/40; relative risk, 0.28; 95 % confidence interval, 0.08-0.47; p = 0.0001). Sensitivity analysis ("worst case scenario") confirmed the results. No new or unexpected adverse events were observed, but there was a trend towards more withdrawals in the 375 microg group. Increasing the dose of IFNbeta-1b from 250 microg to 375 microg is a successful strategy for reducing subclinical signs of disease activity in RRMS patients. Further studies are needed to show whether this dose may also improve clinical efficacy.

The therapy of multiple sclerosis with immune-modulating or immunosuppressive drug. A critical evaluation based upon evidence based parameters and published systematic reviews.

Today many different drugs are available for treatment of multiple sclerosis (MS). Interferons, glatiramer acetate, mitoxantrone, and natalizumab have been approved by the regulatory authorities of many countries for the treatment of MS. Evidence based medicine (EBM) principles allow physicians to better address the correct treatment for patients. This article aimed to review all the clinical trials on immune-modulating and immunosuppressive drugs on the basis of the EBM principles. Based on the evidence to date interferon beta represents the best therapeutic option, particularly if given at high doses and with multiple injections per week. Due to its lower efficacy, glatiramer acetate should be used as a second choice in case of intolerable side effects or toxicity of interferon beta. Great efficacy has been demonstrated for mitoxantrone and natalizumab. These drugs should be, however, used with particular attention for their potential toxic effects.

Lack of association between the apolipoprotein E gene and aneurysmal subarachnoid hemorrhage in an Italian population.

OBJECT: The results of genome-wide scan studies have suggested the presence of a genetic risk factor for aneurysmal subarachnoid hemorrhage (SAH) on chromosome 19 (at 19p13). The apolipoprotein E (APOE) gene is located in this chromosomal region and encodes a protein that exerts several neuroprotective and neurotrophic functions in the brain. The purpose of this study was to evaluate whether a particular allele or genotype of the APOE gene would modify the occurrence or the clinical features of SAH. METHODS: Genomic DNA was extracted from 146 patients with aneurysmal SAH and 222 age- and sex-matched healthy controls and genotyped for the triallelic polymorphism of the APOE gene (epsilon2, epsilon3, and epsilon4). Allele and genotype frequencies were compared between patients and controls. The clinical characteristics of the disease were compared according to the different APOE genotypes. Allele and genotype frequencies of the APOE gene polymorphism were nearly identical in cases and controls. Patients carrying the APOE epsilon4 allele had a significantly higher Hunt and Hess grade on admission (p = 0.0014). There was no significant relationship between any of the other clinical characteristics and the APOE genotype. CONCLUSIONS: The authors' data do not support the hypothesis that genetic variations within the APOE gene are associated with aneurysmal SAH. However, the APOE gene influences the disease phenotype and may be regarded as a disease modifier gene.

HLA-DRB1 genotyping in Italian migraine patients.

We examined the distribution of HLA-DRB1 alleles in a cohort 255 Italian migraine patients and in a control group of 325 healthy subjects. 214 patients fulfilled the ICHD-II criteria for migraine without aura and 41 patients the criteria for migraine with aura. The frequency of DRB1*16 allele was found to be significantly increased in migraine without aura patients (p=0.02; OR 1.97, 95% CI: 1.10-3.54) than in healthy controls. The frequencies of HLA-DRB1 alleles were not significantly different between migraine with aura patients and controls. We did not detect any effect of DRB1 alleles on age at onset, duration of the disease, frequency and duration of migraine attacks. Our data suggest the presence of a genetic susceptibility factor for migraine without aura within the HLA region.

[The risk for illegal behaviour and corruption in the healthcare sector: what preventive measures can be taken?]. / Condizioni di rischio per illegalità e corruzione in ambito sanitario. Quali strumenti di prevenzione?

In the healthcare sector risk factors for illegal behavior and corruption are peculiar and greater than in other social areas, as it plays a crucial role in the community's economical, political and cultural life. The healthcare services is a complex network that require interaction between may people, constant contacts with the industry, safety and adequate facilities that require regular maintenance, upgrade and replacement of medical technology, connection with local and regional policy makers. This provides the opportunity of being exposed to improper influence. However, illegal behaviors can be prevented: first of all supporting all professionals that everyday work to protect our health with ethics and expertise; then with all instruments that anti-corruption action plans, such as the one introduced in Italy in 2012, aim to identify and target those areas most at risk of corruption phenomena.

Apolipoprotein E gene polymorphisms in patients with migraine.

To investigate the role of apolipoprotein E (APOE) polymorphisms in migraine, we analyzed the APOE genotypes of 241 migraine patients and 587 controls. The results of a Chi-square analysis indicated that APOE alleles were similarly distributed (chi(2)=2.89, P=0.24) between cases and controls. However, we found a significant (P<0.001) increase of the varepsilon2-varepsilon4 genotype in the group of migraine patients. Patients were divided into three subgroups: migraine with aura; migraine without aura; and mixed headaches (migraine associated with tension-type headache). Subgroup analysis showed that the varepsilon2-varepsilon4 genotype was significantly increased only in patients with mixed headaches. The stratification of patients by APOE status did not reveal significant associations with the clinical features of the disease. In conclusion, we observed no significant association between APOE polymorphisms and migraine. The association between the APOE varepsilon2-varepsilon4 genotype and the tension-type headache deserves further evaluation.

Absence of linkage between the interleukin-6 gene (-174 G/C) polymorphism and migraine.

To assess the role of interleukin-6 (IL-6) in migraine, we analyzed the -174 G/C IL-6 gene polymorphism in 268 patients with migraine and 305 controls. No significant difference in the distribution of IL-6 genotypes (chi(2)=0.601, P=0.74) and allelic frequencies (chi(2)=0.024, P=0.876) was found. When patients were subdivided into subgroups (migraine with aura, migraine without aura and mixed headaches), IL-6 alleles were similarly distributed. Comparison of the clinical features of the disease with the -174 G/C IL-6 genotypes showed no significant difference. In conclusion, we found no significant association between the -174 G/C IL-6 polymorphism and the occurrence or the clinical features of migraine.

Genetic association study of PINK1 coding polymorphisms in Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder with a substantial genetic component (which is more pronounced in earlier onset cases). In addition to three well-confirmed PD genes (SNCA, parkin and DJ-1), mutations in the PTEN Induced Kinase (PINK1) gene have recently been identified in families with recessive early onset PD. We tested the hypothesis that three common coding variations (Leu63Leu, Ala340Thr and Asn521Thr) could increase the risk of PD. We performed a case control association study in a series of 91 PD cases (Caucasian of Canadian origin) and 182 normal controls. The patients were largely pre-selected for having an early age of onset (<50 years) and/or a positive family history. Our results did not reveal any evidence of association between PD and any of the three SNPs at the allelic or genotypic levels (p > 0.25). Furthermore, we did not detect a modifying effect for any genotype upon the age of onset in the PD group (p > 0.19). Nevertheless, it remains to be evaluated whether PINK1 variations contribute to the risk of common late onset sporadic PD.

Genetics of cluster headache: an update.

Up to a few years ago, cluster headache (CH) was not thought to be an inherited disorder. However, several recent studies have suggested that genetic factors play a role in the disease. Genetic epidemiological surveys have shown that first-degree relatives of CH patients are more likely to have CH than the general population. CH has been reported in some concordant monozygotic twin pairs. At present, the type and the number of genes involved in the disease are still unclear. No mutation in the CACNA1A and NOS genes was found in CH patients. Recently, we have reported a significant association between the HCRTR2 gene and the disease. The purpose of this review is to describe recent advances in the genetics of CH.

Prevalence of HFE (hemochromatosis) gene mutations in patients with cluster headache.

OBJECTIVE: To evaluate whether polymorphisms of the HFE gene would modify the occurrence and the clinical features of cluster headache (CH). BACKGROUND: Recent studies suggested that iron metabolism may be involved in the pathophysiology of primary headaches. The HFE gene encodes for a protein that modulates iron absorption. Mutations in this gene are responsible for toxic iron overload in several body organs. METHODS: Genomic DNA was extracted from 109 CH patients and 211 age and sex-matched healthy controls and genotyped for the C282Y and H63D mutations of the HFE gene. Allele and genotype frequencies of the HFE gene were compared between cases and controls. The clinical characteristics of the disease were compared according to the different HFE gene genotypes. RESULTS: No C282Y mutation was found in both cases and controls. The prevalence of the H63D mutation was nearly identical in cases and controls. The four patients carrying the HFE D63D genotype showed a significantly (P < .001) later age at onset of the disease in comparison with both H63H and H63D patients. The remaining clinical characteristics of the disease did not significantly differ in the presence or absence of the H63D mutation. CONCLUSION: Our data do not support the hypothesis that genetic variations within the HFE gene are associated with CH. However, the HFE gene may influence the disease phenotype and may be regarded as a disease modifier gene.

Association between migraine and HLA-DRB1 gene polymorphisms.

We examined the distribution of HLA-DRB1 alleles in a cohort of 255 Italian migraine patients and in a control group of 325 healthy subjects. The frequency of DRB1*12 allele was found to be significantly reduced (p=0.02) in patients with migraine while the DRB1*16 allele was significantly increased (p=0.04) in comparison with controls. When the patients were divided into disease subgroups (migraine with and without aura), HLA-DRB1**16 allele was significantly increased (p<0.05) only in migraine without aura patients. We conclude that, in Italian patients, migraine is associated with different alleles of the HLA-DRB1 locus. Our data suggest the presence of a genetic susceptibility factor for migraine within the HLA region.

A polymorphism in the interleukin-1alpha gene influences the clinical features of migraine.

OBJECTIVE: To evaluate whether a particular genotype of the interleukin-1alpha (IL1A) gene affects the clinical features of migraine. BACKGROUND: Proinflammatory mediators have been reported to play a role in the pathophysiology of migraine. Recent studies suggest that polymorphisms in the interleukin-1 genes influence the age at onset and subsequent course of several chronic inflammatory diseases. METHODS: In a group of 269 patients with migraine, we tested the association of the -889 C/T biallelic polymorphism of the IL1A gene with several clinical features of the disease. RESULTS: Patients with migraine carrying the T/T genotype show an age at onset of the disease that is significantly (P <.01) lower than IL1A C/C or C/T carriers. In addition, the same genotype was significantly (P <.05) more frequent in patients with migraine with aura than in patients with migraine without aura. CONCLUSIONS: The results of our study suggest a role for the IL1A gene in modifying the clinical features of migraine.