Impact of surgical aortic valve replacement on global and regional longitudinal strain across four flow gradient patterns of severe aortic stenosis

The International Journal of Cardiovascular Imaging - To evaluate the impact of surgical aortic valve replacement (SAVR) on global (GLS) and regional longitudinal strain (RLS) across four...     

Combination Therapy Reverses Hyperglycemia in NOD Mice With Established Type 1 Diabetes

An increasing number of therapies have proven effective at reversing hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D), yet situations of successful translation to human T1D are limited. This may be partly due to evaluating the effect of treating immediately at diagnosis in mice, which may not be reflective of the advanced disease state in humans at disease onset. In this study, we treated NOD mice with new-onset as well as established disease using various combinations of four drugs: antithymocyte globulin (ATG), granulocyte-colony stimulating factor (G-CSF), a dipeptidyl peptidase IV inhibitor (DPP-4i), and a proton pump inhibitor (PPI). Therapy with all four drugs induced remission in 83% of new-onset mice and, remarkably, in 50% of NOD mice with established disease. Also noteworthy, disease remission occurred irrespective of initial blood glucose values and mechanistically was characterized by enhanced immunoregulation involving alterations in CD4⁺ T cells, CD8⁺ T cells, and natural killer cells. This combination therapy also allowed for effective treatment at reduced drug doses (compared with effective monotherapy), thereby minimizing potential adverse effects while retaining efficacy. This combination of approved drugs demonstrates a novel ability to reverse T1D, thereby warranting translational consideration.     

Fcgamma receptor IIIA polymorphism as a risk-factor for coronary artery disease

BACKGROUND: Inflammation is important in the pathogenesis of atherosclerosis. Polymorphisms of Fc receptors for IgG (FcgammaR) are associated with modifying effects of several infectious and autoimmune diseases. We have assessed the relationship between polymorphisms in three different FcgammaR genes and coronary artery disease (CAD). METHODS AND RESULTS: We genotyped for the FcgammaRIIA-R/H131, the FcgammaRIIIB-Na1/Na2, and the FcgammaRIIIA-F/V158 polymorphisms in 882 patients undergoing diagnostic coronary angiography. Significant CAD was defined as >/=50% lumen diameter stenosis in at least one coronary artery. In the analysis, no association was found between the FcgammaRIIA and FcgammaRIIIB genotypes and CAD, whereas the FcgammaRIIIA genotype was strongly related. Compared to those being heterozygous, or homozygous for the F allele, patients homozygous for the V allele had significantly reduced risk: OR, 0.53; (CI, 0.32-0.90). Additional adjustment for classical risk factors and sedimentation rate did not affect the results. The V/V genotype was also inversely related to the extent of CAD defined as no CAD, single, double or triple vessel disease (P trend=0.002). CONCLUSIONS: Our data provide evidence for an association between FcgammaRIIIA allelic variants and coronary atherosclerosis. Genetic variation in this IgG-receptor may influence the clearance of antibodies by monocyte-derived macrophages involved in the pathogenesis of CAD.     

Upregulation of Immunoglobulin‐related Genes in Cortical Sections from Multiple Sclerosis Patients

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). Microarray‐based global gene expression profiling is a promising method, used to study potential genes involved in the pathogenesis of the disease. In the present study, we have examined global gene expression in normal‐appearing gray matter and gray matter lesions from the cortex of MS patients, and compared them with cortical gray matter samples from controls. We observed a massive upregulation of immunoglobulin (Ig)‐related genes in cortical sections of MS patients. Using immunohistochemistry, the activation of Ig genes seems to occur within plasma cells in the meninges. As synthesis of oligoclonal IgGs has been hypothesized to be caused by the activation of Epstein–Barr virus (EBV)‐infected B‐cells, we screened the brain samples for the presence of EBV by real‐time quantitative polymerase chain reaction (qPCR) and immunohistochemistry, but no evidence of active or latent EBV infection was detected. This study demonstrates that genes involved in the synthesis of Igs are upregulated in MS patients and that this activation is caused by a small number of meningeal plasma cells that are not infected by EBV. The findings indicate that the Ig‐producing B‐cells found in the cerebrospinal fluid (CSF) of MS patients could have meningeal origin.     

ω-3 Fatty Acid Treatment in Multiple Sclerosis (OFAMS Study): A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE To investigate whether ω-3 fatty acids reduce magnetic resonance imaging (MRI) and clinical disease activity in patients with multiple sclerosis, both as monotherapy and in combination with interferon beta-1a treatment. DESIGN Multicenter, randomized, double-blind, placebo-controlled clinical trial conducted from 2004 to 2008. SETTING Thirteen public neurology departments in Norway. PARTICIPANTS Patients aged 18 to 55 years with active relapsing-remitting multiple sclerosis, with a disability score equivalent to 5.0 or less on the Kurtzke Expanded Disability Status Scale. Ninety-two patients were randomized to ω-3 fatty acids (n?=?46) or placebo capsules (n?=?46). INTERVENTIONS Administration of 1350 mg of eicosapentaenoic acid and 850 mg of docosahexaenoic acid daily or placebo. After 6 months, all patients in addition received subcutaneously 44 μg of interferon beta-1a 3 times per week for another 18 months. MAIN OUTCOME MEASURE The primary outcome measure was MRI disease activity as measured by the number of new T1-weighted gadolinium-enhancing lesions during the first 6 months. Secondary outcome measures included MRI disease activity after 9 months and 24 months, relapse rate, disability progression, fatigue, quality of life, and safety. RESULTS The cumulative number of gadolinium-enhancing MRI lesions during the first 6 months were similar in the ω-3 fatty acids and placebo groups (median difference, 1; 95% CI, 0 to 3; P?=?.09). No difference in relapse rate was detected after 6 (median difference, 0; 95% CI, 0 to 0; P?=?.54) or 24 (median difference, 0; 95% CI, 0 to 0; P?=?.72) months. The proportion of patients without disability progression was 70% in both groups (P?>?.99). No differences were detected in fatigue or quality-of-life scores, and no safety concerns appeared. Serum analyses of fatty acids showed an increase in ω-3 fatty acids (mean difference, 7.60; 95% CI, 5.57 to 7.91; P?<?.001) in the patients treated with ω-3 fatty acids compared with the placebo group. CONCLUSION No beneficial effects on disease activity were detected from ω-3 fatty acids when compared with placebo as monotherapy or in combination with interferon beta-1a. Magnetic resonance imaging disease activity was reduced as expected by interferon beta-1a. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00360906.     

The cuprizone model for demyelination

Background –  Important advances in multiple sclerosis (MS) research have been made as a direct or indirect result of experiments in animal models for the disease, although MS is a disease only affecting humans. The cuprizone model is a model for toxic demyelination. In this model, young mice are fed with the copper chelator cuprizone, leading to oligodendrocyte death and a subsequent reversible demyelination. Spontaneous remyelination can be seen as early as 4 days after withdrawal of cuprizone.
Materials and methods –  This article reviews previous research on this model and discusses the potential of the model for future application in MS research.
Discussion –  The cuprizone model correlates with newer histopathological data in MS and is a valuable tool for studies on de- and remyelination. The use of the C57BL/6 strain offers the potential for future studies on transgene and knockout mice.     

Lumbar iohexol myelography and diagnostic lumbar puncture. Headache and associated side effects in relation to neurological signs and diagnosis, previous mental symptoms and pain history

Various possible risk factors for postlumbar puncture (and postiohexol-myelographic) headache and associated side effects were analysed. Headache and nausea occurred significantly more often in patients without clinical findings than in those with findings. We found significantly different incidences of severe headache and nausea between diagnostic subgroups after a lumbar puncture. The greatest headache incidence was found in patients without a definite neurological diagnosis, while nausea occurred most frequently in patients with various painful disorders. Following iohexol myelography, nausea occurred most often in patients who had a history of previous mental symptoms and in patients with a history of previous headache disorders. Mental symptoms were more frequently reported in patients who also had experienced mental symptoms previously. The relationship between side effects and negative clinical findings was stronger than the relationship between side effects and previous mental symptoms.     

Side effects after ambulatory lumbar iohexol myelography

Summary Side effect incidences after ambulatory (22G needle and two h bed rest) and after non-ambulatory (22 and 20G needles and 20 h bed rest) lumbar iohexol myelography have been estimated and compared. Headache incidence was significantly greater in ambulatory (50%, n=107) as compared to non-ambulatory myelography (26%, n=58). Headaches in the ambulatory group tended to be of shorter duration and the difference between severe headaches in ambulatory and non-ambulatory groups was not significant. Serious adverse reactions did not occur and none of the ambulatory patients required readmission because of side effects. The headache was predominantly postural and occurred significantly earlier in the ambulatory group. Headache incidence was significantly greater after 20G needle myelography (44%, n=97) as compared to 22G needle iohexol myelography (26%, n=58). The results supports the hypothesis that CSF leakage is a major cause of headache after lumbar iohexol myelography.