Oral contraceptives combined with interferon β in multiple sclerosis

Objective: To test the effect of oral contraceptives (OCs) in combination with interferon b (IFN-b) on disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: One hundred fifty women with RRMS were randomized in a 1:1:1 ratio to receive IFNb-1a subcutaneously (SC) only (group 1), IFN-b-1a SC plus ethinylstradiol 20 mg and desogestrel 150 mg (group 2), or IFN-b-1a SC plus ethinylestradiol 40 mg and desogestrel 125 mg (group 3). The primary endpoint was the cumulative number of combined unique active (CUA) lesions on brain MRI at week 96. Secondary endpoints included MRI and clinical and safety measures. Results: The estimated number of cumulative CUA lesions at week 96 was 0.98 (95% confidence interval [CI] 0.81–1.14) in group 1, 0.84 (95% CI 0.66–1.02) in group 2, and 0.72 (95% CI 0.53–0.91) in group 3, with a decrease of 14.1% (p 5 0.24) and 26.5% (p 5 0.04) when comparing group 1 with groups 2 and 3, respectively. The number of patients with no gadoliniumenhancing lesions was greater in group 3 than in group 1 (p 5 0.03). No significant differences were detected in other secondary endpoints. IFN-b or OC discontinuations were equally distributed across groups. Conclusions: Our results translate the observations derived from experimental models to patients, supporting the anti-inflammatory effects of OCs with high-dose estrogens, and suggest possible directions for future research

Relationship between prolactin plasma levels and white matter volume in women with multiple sclerosis

BACKGROUND: The role of prolactin (PRL) on tissue injury and repair mechanisms in multiple sclerosis (MS) remains unclear. The aim of this work was to investigate the relationship between PRL plasma levels and brain damage as measured by magnetic resonance imaging (MRI). METHODS: We employed a chemiluminescence immunoassay for measuring plasma levels of PRL. We used a 1.5 T scanner to acquire images and Jim 4.0 and SIENAX software to analyse them. RESULTS: We included 106 women with relapsing remitting (RR) MS and stable disease in the last two months. There was no difference in PRL plasma levels between patients with and without gadolinium enhancement on MRI. PRL plasma levels correlated with white matter volume (WMV) (rho = 0.284, p = 0.014) but not with grey matter volume (GMV). Moreover, PRL levels predicted changes in WMV (Beta: 984, p = 0.034). CONCLUSIONS: Our data of a positive association between PRL serum levels and WMV support the role of PRL in promoting myelin repair as documented in animal models of demyelination. The lack of an increase of PRL in the presence of gadolinium enhancement, contrasts with the view considering this hormone as an immune-stimulating and detrimental factor in the inflammatory process associated with MS

Diabetes mellitus in a girl with thyroid hormone resistance syndrome: A little recognized interaction between the two diseases

The syndrome of resistance to thyroid hormone (RTH) is characterized by elevated serum free thyroid hormones (FT4 and FT3) in the presence of unsuppressed TSH levels, reflecting resistance to the normal negative feedback mechanisms in the hypothalamus and pituitary. The degree of resistance within peripheral tissues determines whether thyrotoxic clinical features are associated with this condition. Classic features include attention deficit hyperactivity disorder, growth delay, tachycardia, and goiter. However, other features, such as frequent ear, nose and throat infections, hearing deficit, and decreased bone mass have recently been recognized. The phenotype of RTH is variable, with most patients presenting with mild to moderate symptoms. In this report we describe a girl with familiar RTH and diabetes mellitus. This is, to our knowledge, the first report regarding this association. Nearly one year after long-term triiodothyroacetic acid (Triac) therapy, we observed a reduction of thyroid hormone levels with an amelioration of insulin resistance. The possible interactions between these disorders are discussed

Effect on cognition of estroprogestins combined with Interferon beta in multiple sclerosis: analysis of secondary outcomes from a randomized controlled trial

Introduction Cognitive impairment is a disabling symptom in multiple sclerosis (MS). While its management remains challenging, beneficial effects on cognition of interferon beta (IFN-β) have been reported and a positive effect from estroprogestins has been hypothesised, suggesting that the combination of the two medications in women with MS could offer a promising treatment strategy. Objectives We investigated whether a combination of estroprogestins and IFN-β can improve cognition in women with MS. Methods Women with relapsing-remitting (RR) MS were randomly assigned (1:1:1) to receive subcutaneous IFN-β-1a (Rebif®, Merck Serono, Geneva, Switzerland) 44 mcg three times a week (tiw) (group 1), subcutaneous IFN-β-1a 44 mcg tiw plus ethinyl estradiol 20 mcg and desogestrel 150 mcg (Mercilon®, MSD Italia SRL, Rome, Italy) (group 2) or subcutaneous IFN-β-1a 44 mcg tiw plus ethinyl estradiol 40 mcg and desogestrel 125 mcg (Gracial®, Organon Italia S.p.A., Rome, Italy) (group 3) in a randomised controlled trial, for which we report the analysis of secondary outcomes. At baseline and at 24 months, all patients underwent magnetic resonance imaging (MRI) and a comprehensive cognitive assessment, including Rao’s Brief Repeatable Battery (RBRB) and questionnaires for depression, fatigue and quality of life. Failure in at least two of the RBRB tests defined ‘cognitive impairment’. Results At baseline, there was no difference in the proportion of cognitively impaired patients. At month 24, the proportion of patients with cognitive impairment was lower in group 3 (34.8%) than in group 1 (47.6%) (p = 0.03). The risk of developing cognitive impairment over 24 months was lower in group 3 (p = 0.02). Mood and fatigue scores were comparable across the groups over time at both time points. However, at month 24, group 3 showed worsening on the sexual function subscale of the 54-item MS quality-of-life questionnaire (p = 0.03). Conclusions This study suggests that the combination of high-dose estroprogestins and IFN-β may have positive effects on cognition. However, the effect of this treatment on sexual function requires caution to be exercised

Bioaccumulation of Trace Elements in the Muscle of the Blackmouth Catshark Galeus melastomus from Mediterranean Waters

Environmental pollution, particularly in the marine environment, has become a significant concern due to the increasing presence of pollutants and their adverse effects on ecosystems and human health. This study focuses on the bioaccumulation of trace elements in the muscle tissue of the blackmouth catshark (Galeus melastomus) from different areas in the Mediterranean Sea. Trace elements are of interest due to their persistence, toxicity, and potential for bioaccumulation. This research aims to assess the distribution and accumulation of trace elements in the muscle tissue of G. melastomus and investigate their potential impact on the deep-sea environment of the Mediterranean. The focused areas include the Ligurian Sea, the northern and central Tyrrhenian Sea, the southern Tyrrhenian Sea, the Ionian Sea, the Pantelleria Waters, and the Gela Waters. Samples were collected following established protocols, and trace element analysis was conducted using inductively coupled plasma mass spectrometry. The study provides data on the concentrations of 17 trace elements, namely aluminum, arsenic, cadmium, cobalt, copper, manganese, molybdenum, nickel, zinc, selenium, strontium, lead, chromium, iron, barium, bismuth, and uranium. The findings contribute to a better understanding of trace element bioaccumulation patterns in elasmobranch species, specifically G. melastomus, and highlight the potential risks associated with chemical contamination in the Mediterranean Sea. This research emphasizes the importance of studying the impacts of pollutants on marine organisms, particularly those occupying key ecological roles, like sharks, to support effective conservation and management strategies

Association between preoperative evaluation with lung ultrasound and outcome in frail elderly patients undergoing orthopedic surgery for hip fractures: study protocol for an Italian multicenter observational prospective study (LUSHIP)

Hip fracture is one of the most common orthopedic causes of hospital admission in frail elderly patients. Hip fracture fixation in this class of patients is considered a high-risk procedure. Preoperative physical examination, plasma natriuretic peptide levels (BNP, Pro-BNP), and cardiovascular scoring systems (ASA-PS, RCRI, NSQIP-MICA) have all been demonstrated to underestimate the risk of postoperative complications. We designed a prospective multicenter observational study to assess whether preoperative lung ultrasound examination can predict better postoperative events thanks to the additional information they provide in the form of "indirect" and "direct" cardiac and pulmonary lung ultrasound signs

A framework for human microbiome research

A variety of microbial communities and their genes (the microbiome) exist throughout the human body, with fundamental roles in human health and disease. The National Institutes of Health (NIH)-funded Human Microbiome Project Consortium has established a population-scale framework to develop metagenomic protocols, resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 or 18 body sites up to three times, which have generated 5,177 microbial taxonomic profiles from 16S ribosomal RNA genes and over 3.5 terabases of metagenomic sequence so far. In parallel, approximately 800 reference strains isolated from the human body have been sequenced. Collectively, these data represent the largest resource describing the abundance and variety of the human microbiome, while providing a framework for current and future studies

Structure, function and diversity of the healthy human microbiome

Author Posting. © The Authors, 2012. This article is posted here by permission of Nature Publishing Group. The definitive version was published in Nature 486 (2012): 207-214, doi:10.1038/nature11234.Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat’s signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81–99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome.This research was supported in part by National Institutes of Health grants U54HG004969 to B.W.B.; U54HG003273 to R.A.G.; U54HG004973 to R.A.G., S.K.H. and J.F.P.; U54HG003067 to E.S.Lander; U54AI084844 to K.E.N.; N01AI30071 to R.L.Strausberg; U54HG004968 to G.M.W.; U01HG004866 to O.R.W.; U54HG003079 to R.K.W.; R01HG005969 to C.H.; R01HG004872 to R.K.; R01HG004885 to M.P.; R01HG005975 to P.D.S.; R01HG004908 to Y.Y.; R01HG004900 to M.K.Cho and P. Sankar; R01HG005171 to D.E.H.; R01HG004853 to A.L.M.; R01HG004856 to R.R.; R01HG004877 to R.R.S. and R.F.; R01HG005172 to P. Spicer.; R01HG004857 to M.P.; R01HG004906 to T.M.S.; R21HG005811 to E.A.V.; M.J.B. was supported by UH2AR057506; G.A.B. was supported by UH2AI083263 and UH3AI083263 (G.A.B., C. N. Cornelissen, L. K. Eaves and J. F. Strauss); S.M.H. was supported by UH3DK083993 (V. B. Young, E. B. Chang, F. Meyer, T. M. S., M. L. Sogin, J. M. Tiedje); K.P.R. was supported by UH2DK083990 (J. V.); J.A.S. and H.H.K. were supported by UH2AR057504 and UH3AR057504 (J.A.S.); DP2OD001500 to K.M.A.; N01HG62088 to the Coriell Institute for Medical Research; U01DE016937 to F.E.D.; S.K.H. was supported by RC1DE0202098 and R01DE021574 (S.K.H. and H. Li); J.I. was supported by R21CA139193 (J.I. and D. S. Michaud); K.P.L. was supported by P30DE020751 (D. J. Smith); Army Research Office grant W911NF-11-1-0473 to C.H.; National Science Foundation grants NSF DBI-1053486 to C.H. and NSF IIS-0812111 to M.P.; The Office of Science of the US Department of Energy under Contract No. DE-AC02-05CH11231 for P.S. C.; LANL Laboratory-Directed Research and Development grant 20100034DR and the US Defense Threat Reduction Agency grants B104153I and B084531I to P.S.C.; Research Foundation - Flanders (FWO) grant to K.F. and J.Raes; R.K. is an HHMI Early Career Scientist; Gordon&BettyMoore Foundation funding and institutional funding fromthe J. David Gladstone Institutes to K.S.P.; A.M.S. was supported by fellowships provided by the Rackham Graduate School and the NIH Molecular Mechanisms in Microbial Pathogenesis Training Grant T32AI007528; a Crohn’s and Colitis Foundation of Canada Grant in Aid of Research to E.A.V.; 2010 IBM Faculty Award to K.C.W.; analysis of the HMPdata was performed using National Energy Research Scientific Computing resources, the BluBioU Computational Resource at Rice University

Biofunctionalized systems for drug discovery and delivery

During this doctoral research work new potential drug delivery vehicles for targeted treatment of cancers were developed. For this purpose, both soft and hard materials were subject of study. Firstly, the synthesis, the characterization and the biological evaluation of monomeric â-cyclodextrins functionalized with folic acid (FA) were the focus of this research. In particular, four new conjugates (CyD-FAs), both 3- and 6-functionalized â-CyDs (â-CyD3 and â-CyD6) linked to the á- or ã-carboxylic group of the FA were synthesized, isolated and fully characterized. Furthermore, the ability of these compounds to include the anticancer drug LA-12 and to deliver it selectively to FR (+) tumor cell lines was investigated. Since the promising results obtained with these CyD-FA conjugates as carriers for LA-12, polymeric nanoparticles based on cross-linked cyclodextrins were designed for drug delivery purposes. These systems, offer the advantages of CyD-type complexation in a synergistic way, resulting more effective than the parent CyDs. In particular, CyD-based polymers and oligomers were synthesized, functionalized with FA and tested as delivery systems towards different hydrophobic anticancer or anti-inflammatory agents. Furthermore, for selected systems, the binding constants of the formed inclusion complexes were determined as well. Concerning hard materials, mesoporous silica nanoparticles were investigated. A new disc-shaped mesoporous material, the nanodiscs (NDs), was synthesized, isolated and fully characterized. This material was firstly used for the preparation of self-assembled monolayers (SAM), to be employed in targeted cancer cell adhesion and in-situ drug delivery. For this purpose, the NDs-monolayers were functionalized with FA as targeting moiety. Thanks to their large surface area and the possibility of high density of superficial functionalization with bioactive molecules, these systems resulted effective in binding cancer cells even upon short contact times. Moreover, exploiting the porosity of the synthesized particles, the intracellular release of small hydrophobic molecules pre-loaded in the channels of the NDs were achieved. Secondly, preliminary biological experiments carried out to test the cellular uptake of NDs, and the drug-carrier ability were performed. Finally, in the attempt to increase the biodegradability of these interesting structures, disulfide-doped mesoporous silica nanodiscs (ss-NDs) were also prepared. Full characterization and preliminary biological assays of these hybrid materials was also performed, and their degradation in redox conditions investigated. This novel material, taking advantage of bio-redox reactions, undergoes a controlled disintegration process in presence of reducing agents (i.e. glutathione), displaying an improved drug delivery action