Adherence to interferon β-1b treatment in patients with multiple sclerosis in Spain

BACKGROUND Adherence to interferon β-1b (INFβ-1b) therapy is essential to maximize the beneficial effects of treatment in multiple sclerosis (MS). For that reason, the main objectives of this study are to assess adherence to INFβ-1b in patients suffering from MS in Spain, and to identify the factors responsible for adherence in routine clinical practice. METHODOLOGY/PRINCIPAL FINDINGS This was an observational, retrospective, cross-sectional study including 120 Spanish patients with MS under INFβ-1b treatment. Therapeutic adherence was assessed with Morisky-Green test and with the percentage of doses received. The proportion of adherent patients assessed by Morisky-Green test was 68.3%, being indicative of poor adherence. Nevertheless, the percentage of doses received, which was based on the number of injected medication, was 94.3%. The main reason for missing INFβ-1b injections was forgetting some of the administrations (64%). Therefore, interventions that diminish forgetfulness might have a positive effect in the proportion of adherent patients and in the percentage of doses received. In addition, age and comorbidities had a significant effect in the number of doses injected per month, and should be considered in the management of adherence in MS patients. CONCLUSION/SIGNIFICANCE Among all the available methods for assessing adherence, the overall consumption of the intended dose has to be considered when addressing adherence.

IL2RA/CD25 gene polymorphisms: uneven association with multiple sclerosis (MS) and type 1 diabetes (T1D).

BACKGROUND: IL-2 receptor (IL2R) alpha is the specific component of the high affinity IL2R system involved in the immune response and in the control of autoimmunity. METHODS AND RESULTS: Here we perform a replication and fine mapping of the IL2RA gene region analyzing 3 SNPs previously associated with multiple sclerosis (MS) and 5 SNPs associated with type 1 diabetes (T1D) in a collection of 798 MS patients and 927 matched Caucasian controls from the south of Spain. We observed association with MS in 6 of 8 SNPs. The rs1570538, at the 3'- UTR extreme of the gene, previously reported to have a weak association with MS, is replicated here (P = 0.032). The most associated T1D SNP (rs41295061) was not associated with MS in the present study. However, the rs35285258, belonging to another independent group of SNPs associated with T1D, showed the maximal association in this study but different risk allele. We replicated the association of only one (rs2104286) of the two IL2RA SNPs identified in the recently performed genome-wide association study of MS. CONCLUSIONS: These findings confirm and extend the association of this gene with MS and reveal a genetic heterogeneity of the associated polymorphisms and risk alleles between MS and T1D suggesting different immunopathological roles of IL2RA in these two diseases.

Epigenetics and neonatal nutrition.

Epigenetic changes have long-lasting effects on gene expression and are related to, and often induced by, the environment in which early development takes place. In particular, the period of development that extends from pre-conception to early infancy is the period of life during which epigenetic DNA imprinting activity is the most active. Epigenetic changes have been associated with modification of the risk for developing a wide range of adulthood, non-communicable diseases (including cardiovascular diseases, metabolic diseases, diseases of the reproductive system, etc.). This paper reviews the molecular basis of epigenetics, and addresses the issues related to the process of developmental programming of the various areas of human health.

Nutrición enteral en el paciente neurológico: ¿es suficiente el contenido en vitamina D en las fórmulas de uso habitual?

INTRODUCTION Vitamin D deficiency produces inadequate bone mineralization, proximal muscle weakness, abnormal gait and increased risk of falls and fractures. Moreover, in epidemiological studies, has been associated with increased risk of cancer, autoimmune diseases, type 1 and 2 diabetes, rheumatoid arthritis, multiple sclerosis, infectious diseases, cardiovascular diseases and depression. When synthesis through the skin by sun exposure is not possible and the patient can not eat by mouth, as in the advanced stages of various neurological diseases, the supply of vitamin D has to be done by enteral nutrition. OBJECTIVES The aim of this study is to review the role of vitamin D in a common group of neurological conditions that often require artificial nutrition and analyze whether the vitamin D of different enteral nutrition formulas is adequate to meet the needs of this group of patients. RESULTS Numerous studies have shown the association between vitamin D deficiency and increased incidence of dementia, stroke and other neurodegenerative diseases. Interventions aimed to increase levels of vit. D and its effects on functional (falls, pain, quality of life) and cardiovascular goals (cardiovascular death, stroke, myocardial infarction, cardiovascular risk factors) have obtained as highlight data a clear reduction of falls and fractures, while the evidence for the other parameters studied is still limited and inconsistent. The content of calcium and vitamin D of enteral formulas is legislated in our country. The total amount of vitamin D for a daily intake of 1,500-2,000 kcal ranges between 300 and 1,600 IU/d (mean ± SD: 32.9 ± 8.5 mg/100 kcal) in the complete formulas for enteral nutrition most commonly used. 50% of the diets studied, for an intake of 2,000 kcal/d, and 90% for an intake of 1,500 kcal/d, provide less than 600 IU/d of vitamin D. DISCUSSION Some revised recently guidelines published recommendations of daily intake of vitamin D. The document published by the U.S. Institute of Medicine recommended for adults between 19 and 70 years, 600 IU/d and up from 70, proposes 800 IU/d of vitamin D. These amounts are deemed insufficient by other scientific societies to state that to achieve blood levels of 25 (OH) D equal or greater than 30 ng/ml may be required a daily intake of 1,500-2,000 IU and a number two or three times higher if previous deficiency exists. CONCLUSIONS Further controlled studies are needed to ascertain which is the appropriate dose of vitamin D in advanced stages of neurological disease, where sun exposure is difficult and unlikely. We suggest that the vitamin D content should probably be reconsidered in enteral nutrition formulas, which, in light of recent publications appear as clearly insufficient for standard energy intakes (1,500-2,000 kcal).

Connexins in lymphatic vessel physiology and disease.

Connexins are transmembrane proteins that form gap junction- and hemi-channels. Once inserted into the membrane, hemi-channels (connexons) allow for diffusion of ions and small molecules (<1kDa) between the extracellular space and the cytosol. Gap junction channels allow diffusion of similar molecules between the cytoplasms of adjacent cells. The expression and function of connexins in blood vessels has been intensely studied in the last few decades. In contrast, only a few studies paid attention to lymphatic vessels; convincing in vivo data with respect to expression patterns of lymphatic connexins and their functional roles have only recently begun to emerge. Interestingly, mutations in connexin genes have been linked to diseases of lymphatic vasculature, most notably primary and secondary lymphedema. This review summarizes the available data regarding lymphatic connexins. More specifically it addresses (i) early studies aimed at presence of gap junction-like structures in lymphatic vessels, (ii) more recent studies focusing on lymphatic connexins using genetically engineered mice, and (iii) results of clinical studies that have reported lymphedema-linked mutations in connexin genes.

Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins.

OBJECTIVE To describe the response to rituximab in patients with treatment-resistant chronic inflammatory demyelinating polyneuropathy (CIDP) with antibodies against paranodal proteins and correlate the response with autoantibody titers. METHODS Patients with CIDP and IgG4 anti-contactin-1 (CNTN1) or anti-neurofascin-155 (NF155) antibodies who were resistant to IV immunoglobulin and corticosteroids were treated with rituximab and followed prospectively. Immunocytochemistry was used to detect anti-CNTN1 and anti-NF155 antibodies and ELISA with human recombinant CNTN1 and NF155 proteins was used to determine antibody titers. RESULTS Two patients had a marked improvement; another patient improved slightly after 10 years of stable, severe disease; and the fourth patient had an ischemic stroke unrelated to treatment and was lost to follow-up. Autoantibodies decreased in all patients after rituximab treatment. CONCLUSIONS Rituximab treatment is an option for patients with CIDP with IgG4 anti-CNTN1/NF155 antibodies who are resistant to conventional therapies. CLASSIFICATION OF EVIDENCE This study provides Class IV evidence that rituximab is effective for patients with treatment-resistant CIDP with IgG4 anti-CNTN1 or anti-NF155 antibodies.

Análisis de anticuerpos antifosfolipídicos y cistatina C en pacientes con esclerosis múltiple

Cystatin C is considered the most important physiological inhibitor of endogenous cysteine proteases; the role of cystatin C is believed to be to modulate the activity of proteases secreted or released from damaged cells or in the process of necrosis, therefore cystatins being fundamental regulatory processes and a potential prevention of local proteolytic damage. Antiphospholipid antibodies are used to clarify the diagnosis of diseases like multiple sclerosis (MS) and other pathologies could present similar symptoms or paraclinical findings. The objective of the present work is to analyze the concentration of cystatin C and the presence or absence of antiphospholipid antibodies in patients diagnosed with relapsing remitting multiple sclerosis (RRMS) as markers of demyelization. This work was carried out jointly by the Vascular Risk Laboratory, the Laboratory of Autoimmunity and Multiple Sclerosis Unit, Hospital Universitario Virgen Macarena in Seville in one year. Two types of people were selected: Group 1 (n = 30) RRMS group and a control group, n = 30. Cystatin C and antiphospholipid antibodies IgG and IgM, IgG and IgM anticardiolipin, β2 glycoprotein IgG and IgM were determined. Patients showed negative titers of antiphospholipid antibodies IgG and IgM, IgG and IgM anticardiolipin, β2 glycoprotein IgG and IgM. Cystatin C concentration is lower in the group of patients diagnosed with MS, which could give rise to a decrease in the modulation of endogenous cysteine proteases. This would exacerbate the progress of demyelization in MS.

Natalizumab-related anaphylactoid reactions in MS patients are associated with HLA class II alleles.

OBJECTIVES We aimed to investigate potential associations between human leukocyte antigen (HLA) class I and class II alleles and the development of anaphylactic/anaphylactoid reactions in patients with multiple sclerosis (MS) treated with natalizumab. METHODS HLA class I and II genotyping was performed in patients with MS who experienced anaphylactic/anaphylactoid reactions and in patients who did not develop infusion-related allergic reactions following natalizumab administration. RESULTS A total of 119 patients with MS from 3 different cohorts were included in the study: 54 with natalizumab-related anaphylactic/anaphylactoid reactions and 65 without allergic reactions. HLA-DRB1*13 and HLA-DRB1*14 alleles were significantly increased in patients who developed anaphylactic/anaphylactoid reactions (p M-H = 3 × 10(-7); odds ratio [OR]M-H = 8.96, 95% confidence interval [CI] = 3.40-23.64), with a positive predictive value (PPV) of 82%. In contrast, the HLA-DRB1*15 allele was significantly more represented in patients who did not develop anaphylactic/anaphylactoid reactions to natalizumab (p M-H = 6 × 10(-4); ORM-H = 0.2, 95% CI = 0.08-0.50), with a PPV of 81%. CONCLUSIONS HLA-DRB1 genotyping before natalizumab treatment may help neurologists to identify patients with MS at risk for developing serious systemic hypersensitivity reactions associated with natalizumab administration.

Inmunopatología de la esclerosis múltiple.

Multiple sclerosis is an inflammatory demyelinating disease affecting the central nervous system and considered one of the leading causes of disability in young adults. The precise cause of multiple sclerosis is unknown, although the current evidence points towards a combination of genetic and environmental factors leading to an autoimmune response that promotes neuronal degeneration. In this review, we will describe the association between the immune response and neurodegeneration in multiple sclerosis.

Estudio de las subpoblaciones linfocitarias y secreción intratecal en pacientes con esclerosis múltiple defnida

Multiple sclerosis is an infammatory demyelinating autoimmune disease that affects the brain and spinal cord. The aim of the study was to quantify lym-phocyte subpopulations in cerebrospinal fuid and blood of patients diagnosed with multiple sclerosis and in patients whit degenerative diseases not (control) in order to fnd some relationships between them that make it possible to differentiate the immune status of patients in each group. This work was jointly carried out with Hospital Universitario Virgen Macarena in Seville during 2008, 2009 and 2010. It is a descriptive, transversal and cohort study. The selected population is composed of 142 subjects who were subjected to lumbar puncture and a blood sample. Group 1 (n=70), control, Group 2 (n=53), patients with relapsing remitting multiple sclerosis, Group 3 (n=5), patients with primary type progressive multiple sclerosis, and Group 4 (n=14) patients with isolated neurological syndrome. The results show an increase in CSF B cells in MS patients suggesting an increase in focal infammatory activity in the CNS. Regarding NKCD8, reduced total levels of NK and NKCD8 regard-ing controls were observed, and it showed an increased IgG index value in patients with RRMS.

Healthy Iowans 2010 Mid-Course Revision, July 2005

In the past century, public health has been credited with adding 25 years to life expectancy by contributing to the decline in illness and injury. Progress has been made, for example, in smoking reduction, infectious disease, and motor vehicle and workplace injuries. Besides its focus on traditional concerns such as clean water and safe food, public health is adapting to meet emerging health problems. Particular troublesome are health threats to youth: teenage pregnancies, violence, substance abuse, sexually transmitted diseases, and other conditions associated with high-risk behaviors. These threats add to burgeoning health care costs. A conservative estimate of $69 billion in medical spending could be averted through the impact of public health strategies aimed at heart disease, stroke, fatal and nonfatal occupational injuries, motor vehicle-related injuries, low birth weight, and violence. These strategies require the collaboration of many groups in the public and private sectors. Collaboration is the bedrock of public health and Healthy Iowans planning. At the core of Healthy Iowans 2000 and its successor, Healthy Iowans 2010, is the idea that all Iowans benefit when stakeholders decide on disease prevention and health promotion strategies and agree to work together on them. These strategies can improve the quality of life and hold down health care costs. The payoff for health promotion and disease prevention is not immediate, but it has long-lasting benefits. The Iowa plan is a companion to the national plan, Healthy People 2010. An initiative to improve the health of Americans, the national plan is the driving force for federal resource allocation for disease prevention and health promotion. The state plan is used in the same way. Both plans have received broad support from Republican and Democratic administrations. Community planners are using the state plan to help assess health needs and craft health improvement plans. Healthy Iowans 2010 was written at an unusual point in history – a new decade, a new century, a new millennium. The introduction was optimistic. “The 21st century,” it says, “promises to add life as well as years through improved health habits coupled with medical advances. Scientists have suggested that if these changes occur, the definition of adulthood will also change. An extraordinary number of people will live fuller, more active lives beyond that expected in the late 20th century.” At the same time, the country has spawned a new generation of health hazards. According to Dr. William Dietz of the Centers for Disease Control and Prevention (CDC), it has replaced “the diseases of deficiency with diseases of excess” (Newsweek, August 2, 1999). New threats, such as childhood overweight, can reverse progress made in the last century. This demands concerted action.

Workloads and strain process in Community Health Agents

ABSTRACT OBJECTIVE To identify the workloads present in the work activities of community health agents (CHAs) and the resulting strain processes. METHOD A descriptive, exploratory, cross-sectional and quantitative study conducted with 137 CHAs. Data were collected through a questionnaire and interview guided by the health surveillance software called SIMOSTE (Health Monitoring System of Nursing Workers), following the ethical codes of the current law. RESULTS In total, were identified 140 workloads involved in 122 strain processes, represented by the occurrence of health problems of the CHAs. The mechanical (55.00%) and biological (16.43%) loads stood out. The most common strain processes were the external causes of morbidity and mortality (62.31%) and diseases of the musculoskeletal system and connective tissue (10.66%). CONCLUSION From the identified overloads, it became evident that all workloads are present in the work process of CHAs, highlighting the mechanical load, represented mainly by external causes of morbidity and mortality that are related to occupational accidents.

Electrically assisted ocular gene therapy.

Electrotransfer and iontophoresis are being developed as innovative non-viral gene delivery systems for the treatment of eye diseases. These two techniques rely on the use of electric current to allow for higher transfection yield of various ocular cell types in vivo. Short pulses of relatively high-intensity electric fields are used for electrotransfer delivery, whereas the iontophoresis technique is based on the application of low voltage electric current. The basic principles of these techniques and their potential therapeutic application for diseases of the anterior and posterior segments of the eye are reviewed. Iontophoresis has been found most efficient for the delivery of small nucleic acid fragments such as antisense oligonucleotides, siRNA, or ribozymes. Electrotransfer, on the other hand, is being developed for the delivery of oligonucleotides or custom designed plasmids. The wide range of strategies already validated and the potential for targeting specific types of cells confirm the promising early observations made using electrotransfer and iontophoresis. These two nonviral delivery systems are safe and can be used efficiently for targeted gene delivery to ocular tissues in vivo. At the present, their application for the treatment of ocular human diseases is nearing its final stages of adaptation and practical implementation at the bedside.

Mutation hot spots in 5q31-linked corneal dystrophies.

Mutations in the BIGH3 gene on chromosome 5q31 cause four distinct autosomal dominant diseases of the human cornea: granular (Groenouw type I), Reis-Bücklers, lattice type I, and Avellino corneal dystrophies. All four diseases are characterized by both progressive accumulation of corneal deposits and eventual loss of vision. We have identified a specific recurrent missense mutation for each type of dystrophy, in 10 independently ascertained families. Genotype analysis with microsatellite markers surrounding the BIGH3 locus was performed in these 10 families and in 5 families reported previously. The affected haplotype could be determined in 10 of the 15 families and was different in each family. These data indicate that R555W, R124C, and R124H mutations occurred independently in several ethnic groups and that these mutations do not reflect a putative founder effect. Furthermore, this study confirms the specific importance of the R124 and R555 amino acids in the pathogenesis of autosomal dominant corneal dystrophies linked to 5q.

Gonadal alterations in male whitefish Coregonus fatioi: no evidence for genetic damage reducing viability in early life stages.

In recent years, numerous cases of morphological gonadal alterations in fish have been recorded throughout the world and across a wide range of species. In the whitefish Coregonus fatioi from the pre-alpine Lake Thun (Switzerland), the frequency of gonadal alterations is particularly high and the variety of alteration types large. Little is known about the proximal causes and the direct consequences of these morphological features on population persistence. In particular, the potential for the observed alterations to be the phenotypic expression of reduced genetic quality has not yet been addressed. In this study, we used offspring survival during embryogenesis as a proximate indicator of male genetic quality and tested whether the presence of gonadal alterations in males is an indicator of reduced quality. Embryos resulted from in vitro fertilizations of gametes from 126 males and females. We found no significant correlation between embryo survival and gonadal alteration in adults. Our findings suggest that in C. fatioi of Lake Thun, alterations in gonad morphology are not a phenotypic expression of variation in genetic quality.