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1.  Paternal therapy with disease modifying drugs in multiple sclerosis and pregnancy outcomes: a prospective observational multicentric study 
BMC Neurology  2014;14:114.
Background
Most of Multiple Sclerosis (MS) patients undergo disease modifying drug (DMD) therapy at childbearing age. The objective of this prospective, collaborative study, was to assess outcomes of pregnancies fathered by MS patients undergoing DMD.
Methods
Structured interviews on pregnancies fathered by MS patients gathered in the Italian Pregnancy Dataset were collected; pregnancies were divided according to father exposure or unexposure to DMD at time of procreation. Treatment were compared with multivariable logistic and linear models.
Results
Seventy-eight pregnancies fathered by MS patients were tracked. Forty-five patients were taking DMD at time of conception (39 beta-interferons, 6 glatiramer acetate), while 33 pregnancies were unexposed to DMD. Seventy-five pregnancies ended in live-births, 44 in the exposed and 31 in the unexposed group. No significant differences between the two groups were found in the risk of spontaneous abortion or malformations (p > 0.454), mean gestational age (p = 0.513), frequency of cesarean delivery (p = 0.644), birth weight (p = 0.821) and birth length (p = 0.649). In comparison with data of the Italian general population, the proportion of spontaneous abortion and caesarean delivery in exposed pregnancies fell within the estimates, while the proportion of pre-term delivery in the exposed group was higher than expected.
Conclusions
Our data indicate no association between paternal DMD exposure at time of conception and risk of spontaneous abortion, adverse fetal outcomes and congenital malformations. Further studies clarifying the role of DMD fathers intake prior and during pregnancy are desirable, to supply guidelines for clinical practice.
doi:10.1186/1471-2377-14-114
PMCID: PMC4059028  PMID: 24884599
Multiple sclerosis; Paternity; Pregnancy; Interferon beta; Glatiramer acetate
2.  Persistence on Therapy and Propensity Matched Outcome Comparison of Two Subcutaneous Interferon Beta 1a Dosages for Multiple Sclerosis 
Kalincik, Tomas | Spelman, Timothy | Trojano, Maria | Duquette, Pierre | Izquierdo, Guillermo | Grammond, Pierre | Lugaresi, Alessandra | Hupperts, Raymond | Cristiano, Edgardo | Van Pesch, Vincent | Grand’Maison, Francois | La Spitaleri, Daniele | Rio, Maria Edite | Flechter, Sholmo | Oreja-Guevara, Celia | Giuliani, Giorgio | Savino, Aldo | Amato, Maria Pia | Petersen, Thor | Fernandez-Bolanos, Ricardo | Bergamaschi, Roberto | Iuliano, Gerardo | Boz, Cavit | Lechner-Scott, Jeannette | Deri, Norma | Gray, Orla | Verheul, Freek | Fiol, Marcela | Barnett, Michael | van Munster, Erik | Santiago, Vetere | Moore, Fraser | Slee, Mark | Saladino, Maria Laura | Alroughani, Raed | Shaw, Cameron | Kasa, Krisztian | Petkovska-Boskova, Tatjana | den Braber-Moerland, Leontien | Chapman, Joab | Skromne, Eli | Herbert, Joseph | Poehlau, Dieter | Needham, Merrilee | Bacile, Elizabeth Alejandra Bacile | Arruda, Walter Oleschko | Paine, Mark | Singhal, Bhim | Vucic, Steve | Cabrera-Gomez, Jose Antonio | Butzkueven, Helmut | Roger, Elaine | Despault, Pierre | Marriott, Mark | Van der Walt, Anneke | King, John | Kilpatrick, Trevor | Buzzard, Katherine | Jokubaitis, Vilija | Byron, Jill | Morgan, Lisa | Skibina, Olga | Haartsen, Jodi | De Luca, Giovanna | Di Tommaso, Valeria | Travaglini, Daniela | Pietrolongo, Erika | di Ioia, Maria | Farina, Deborah | Mancinelli, Luca | Paolicelli, Damiano | Iaffaldano, Pietro | Ignacio Rojas, Juan | Patrucco, Liliana | Roullet, Etienne | Correale, Jorge | Ysrraelit, Celica | Elisabetta, Cartechini | Pucci, Eugenio | Williams, David | Dark, Lisa | Shaygannejad, Vahid | Zwanikken, Cees | Vella, Norbert | Sirbu, Carmen-Adella
PLoS ONE  2013;8(5):e63480.
Objectives
To compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics.
Methods
Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded.
Results
Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as “lack of efficacy” (3.3% vs. 1.7%), “scheduled stop” (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages.
Conclusions
Treatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from “real-world” database the results of the pivotal randomised trial. Propensity score matching effectively minimised baseline covariate imbalance between two directly compared sub-populations from a large observational registry.
doi:10.1371/journal.pone.0063480
PMCID: PMC3660604  PMID: 23704913
3.  Pregnancy and fetal outcomes after Glatiramer Acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study 
BMC Neurology  2012;12:124.
Background
Only few studies have assessed safety of in utero exposure to glatiramer acetate (GA). Following a previous study assessing the safety of interferon beta (IFNB) pregnancy exposure in multiple sclerosis (MS), we aimed to assess pregnancy and fetal outcomes after in utero exposure to GA, using the same dataset, with a specific focus on the risk of spontaneous abortion.
Materials and methods
We recruited MS patients, prospectively followed-up in 21 Italian MS Centres, for whom a pregnancy was recorded in the period 2002–2008. Patients were divided into 2 groups: drug-exposed pregnancies (EP: suspension of the drug less than 4 weeks from conception); non-exposed pregnancies (NEP: suspension of the drug at least 4 weeks from conception or never treated pregnancies). All the patients were administered a structured interview which gathered detailed information on pregnancy course and outcomes, as well as on possible confounders. Multivariate logistic and linear models were used for treatment comparisons.
Results
Data on 423 pregnancies were collected, 17 were classified as EP to GA, 88 as EP to IFNB, 318 as NEP. Pregnancies resulted in 16 live births in the GA EP, 75 live births in the IFNB EP, 295 live births in the NEP. GA exposure was not significantly associated with an increased risk of spontaneous abortion (OR = 0.44;95% CI 0.044-4.51;p = 0.49). Mean birth weight and length were not significantly different in pregnancies exposed to GA than in non exposed pregnancies (p = 0.751). The frequency of preterm delivery, observed in 4 subjects exposed to GA (25% of full term deliveries), was not significantly higher in pregnancies exposed to GA than in those non exposed (p > 0.735). These findings were confirmed in the multivariate analysis. There were neither major complications nor malformations after GA exposure.
Conclusions
Data in our cohort show that mother’s GA exposure is not associated with a higher frequency of spontaneous abortion, neither other negative pregnancy and fetal outcomes. Our findings point to the safety of in utero GA exposure and can support neurologists in the therapeutic counselling of MS women planning a pregnancy.
doi:10.1186/1471-2377-12-124
PMCID: PMC3487812  PMID: 23088447
Glatiramer acetate; Multiple sclerosis; Pregnancy; Pregnancy outcome; In utero exposure
4.  Patient adherence to and tolerability of self-administered interferon β-1a using an electronic autoinjection device: a multicentre, open-label, phase IV study 
BMC Neurology  2012;12:7.
Background
Achieving good adherence to self-injected treatments for multiple sclerosis can be difficult. Injection devices may help to overcome some of the injection-related barriers to adherence that can be experienced by patients. We sought to assess short-term adherence to, and tolerability of, interferon (IFN) β-1a administered via electronic autoinjection device in patients with relapsing-remitting multiple sclerosis (RRMS).
Methods
BRIDGE (RebiSmart to self-inject Rebif serum-free formulation in a multidose cartridge) was a 12-week, multicentre, open-label, single-arm, observational, Phase IV study in which patients self-administered IFN β-1a (titrated to 44 μg), subcutaneously (sc), three times weekly, via electronic autoinjection device. Patients were assessed at baseline and 4-weekly intervals to Week 12 or early termination (ET) for: physical examinations; diary card completion (baseline, Weeks 4, 8 only); neurological examinations (baseline, Week 12/ET only); MS Treatment Concern Questionnaire (MSTCQ; Weeks 4, 8, 12 only); Convenience Questionnaire (Week 12 only); Hospital Anxiety and Depression Scale (HADS); and Paced Auditory Serial Addition Task (PASAT; baseline only). Adherence was defined as administration of ≥ 80% of scheduled injections, recorded by the autoinjection device.
Results
Overall, 88.2% (105/119; intent-to-treat population) of patients were adherent; 67.2% (80/119) administered all scheduled injections. Medical reasons accounted for 35.6% (31/87) of missed injections, forgetfulness for 20.6% (18/87). Adherence did not correlate with baseline Expanded Disability Status Scale (P = 0.821) or PASAT (P = 0.952) scores, or pre-study therapy (P = 0.303). No significant changes (baseline-Week 12) in mean HADS depression (P = 0.482) or anxiety (P = 0.156) scores were observed. 'Overall convenience' was the most important reported benefit of the autoinjection device. Device features associated with handling and ease of use were highly rated. Mean MSTCQ scores for 'flu-like' symptoms (P = 0.022) and global side effects (P = 0.002) significantly improved from Week 4-12. Mean MSTCQ scores for pain at injection site and injection pain increased from Week 4-12 (P < 0.001). Adverse events were mild/moderate. No new safety signals were identified.
Conclusion
Convenience and ease of use of the autoinjection device may improve adherence and, therefore, outcomes, in patients with RRMS receiving sc IFN β-1a.
Trial registration
EU Clinical Trials Register (EU-CTR; http://www.clinicaltrialsregister.eu): 2009-013333-24
doi:10.1186/1471-2377-12-7
PMCID: PMC3368780  PMID: 22390218
Relapsing-remitting multiple sclerosis; IFN beta; Medication adherence; Drug delivery systems; Self administration
5.  Relation between Pro-inflammatory Cytokines and Acetylcholine Levels in Relapsing-Remitting Multiple Sclerosis Patients 
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disorder. Since acetylcholine (ACh) is known to participate in the inflammatory response, we investigated the possible relationship between pro-inflammatory cytokines and acetylcholine levels in relapsing-remitting multiple sclerosis (RR-MS) patients. Levels of ACh and pro-inflammatory cytokines IL1-β and IL-17 were measured both in cerebrospinal fluid (CSF) and sera of 22 RR-MS patients in the relapsing phase and in 17 control subjects affected by other non-neurological diseases (OND). We observed higher levels of pro-inflammatory cytokines such as IL-1β and IL-17 in both CSF and serum of RR-MS patients compared to control subjects. Moreover, ACh levels were lower in CSF and serum of RR-MS patients compared to levels of control subjects. Although the relationship between high inflammatory cytokine levels and low ACh levels need to be further investigated in the future, our data suggest that IL-1β, and cytokines induced by it, such as IL-17 and ACh, may be involved in the pathogenesis of MS.
doi:10.3390/ijms131012656
PMCID: PMC3497293  PMID: 23202919
acetylcholine; pro-inflammatory cytokines; multiple sclerosis
6.  Neopterin production and tryptophan degradation during 24-months therapy with interferon beta-1a in multiple sclerosis patients 
Background
Increased synthesis of neopterin and degradation of tryptophan to kynurenine, measured as kynurenine/tryptophan ratio (kyn/trp ratio), are considered in vitro markers of interferon beta-1a (IFNβ-1a) activity. The aim of the study was to investigate the dynamic profile of neopterin and kyn/trp ratio in patients with relapsing remitting multiple sclerosis (RRMS) treated with two different doses of IFNβ-1a over a period of 24 months.
Methods
RRMS patients (n = 101) received open-label IFNβ-1a 22 mcg (low dose, LD) or 44 mcg (high dose, HD) subcutaneously (sc), three times weekly for 24 months. Serum measurements of neopterin, kyn/trp ratio and neutralizing antibodies (NAbs) were obtained before treatment (i.e., at baseline) and 48 hours post-injection every 3 months thereafter. Clinical assessments were performed at baseline and every 6 months. Changes in biomarkers over time were compared between LD- and HD-group as well as between patients with/without relapses and with/without NAbs using Analysis of Variance and Mann-Whitney tests.
Results
Neopterin (p < 0.001) and kyn/trp ratio (p = 0.0013) values increased over time vs baseline in both treatment groups. Neopterin values were higher (p = 0.046) in the HD-compared to the LD-group at every time point with the exclusion of months 21 and 24 of therapy. Conversely, there were no differences between the two doses groups in the kyn/trp ratio with the exclusion of month 6 of therapy (p < 0.05). Neopterin levels were significantly reduced in NAb-positive patients starting from month 9 of therapy (p < 0.05); the same result was observed for kyn/trp ratio but only at month 9 (p = 0.02). Clinical status did not significantly affect neopterin production and tryptophan degradation.
Conclusions
Although differences in serum markers concentration were found following IFNβ administration the clinical relevance of these findings needs to be confirmed with more detailed studies.
doi:10.1186/1479-5876-9-42
PMCID: PMC3102623  PMID: 21501517
7.  Legionella Infection Risk from Domestic Hot Water 
Emerging Infectious Diseases  2004;10(3):457-464.
We investigated Legionella and Pseudomonas contamination of hot water in a cross-sectional multicentric survey in Italy. Chemical parameters (hardness, free chlorine, and trace elements) were determined. Legionella spp. were detected in 33 (22.6%) and Pseudomonas spp. in 56 (38.4%) of 146 samples. Some factors associated with Legionella contamination were heater type, tank distance and capacity, water plant age, and mineral content. Pseudomonas presence was influenced by water source, hardness, free chlorine, and temperature. Legionella contamination was associated with a centralized heater, distance from the heater point >10 m, and a water plant >10 years old. Furthermore, zinc levels of <20 μg/L and copper levels of >50 μg/L appeared to be protective against Legionella colonization. Legionella species and serogroups were differently distributed according to heater type, water temperature, and free chlorine, suggesting that Legionella strains may have a different sensibility and resistance to environmental factors and different ecologic niches.
doi:10.3201/eid1003.020707
PMCID: PMC3322798  PMID: 15109413
Legionella spp.; Pseudomonas spp.; water microbial contamination; domestic hot water systems home colonization; Legionella multicentric survey; community legionellosis

Results 1-7 (7)