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Background: Dietary intervention in multiple sclerosis carries potential therapeutic implications. While studies utilizing animal models of multiple sclerosis (MS) have demonstrated intriguing findings, well-designed clinical trials are few in number. Objective: The objective of this study is to review the animal model and clinical literature regarding dietary factors in experimental autoimmune encephalitis (EAE) and MS. Methods: This manuscript provides a comprehensive review of current animal model and clinical knowledge related to dietary factors in MS. Results: While there is currently little data for any specific diet in MS, there is growing evidence that certain dietary factors may influence the disease. Conclusions: Definitive information regarding dietary factors as a modifiable risk factor in MS will require larger randomized clinical trials.

AimsTo quantify the number of immune cells in the bladder urothelium and concentrations of urinary cytokines in patients with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). To identify differences in these measures in IC/BPS patients with Hunner’s lesions (IC/BPS-HL) and without Hunner’s lesions (IC/BPS-NHL).MethodsBladder tissue biopsies were obtained from 48 patients with IC/BPS-HL and unaffected controls (UC) and stained with antibodies for various immune cell markers such as CD138, CD20 and CD56. Levels of cytokines (Interferon (IFN)-γ, Interleukin (IL)-1β, IL-2, IL- 4, IL-6, IL-8, IL12P70, IL-13, and TNF-α) were measured from normalized urine obtained from 18 IC/BPS-HL, 18 IC/BPS-NHL, and 4 UC.ResultsNumbers of CD138+ plasma cells, CD20+ B cells, and CD3+ T cells were significantly increased (50 fold, 30 fold, and an almost 3 fold increase, respectively; p-values: 1.34E-06, 3.26E-04, and 2.52E-6) in the bladders of IC/BPS-HL patients compared to UC. Patients with IC/BPS-HL had significantly elevated urinary levels of IL-6 (p=0.0028) and TNF-α (p=0.009) compared to patients with IC/BPS-NHL and UC. In contrast, IL-12p70 levels were significantly higher in the patients with IC/BPS-NHL than in HL patients (p=0.033). No significant difference in IL-12p70 levels were observed between IC/BPS-HL and UC.ConclusionDifferent cytokines were elevated in the urine of IC/BPS patients with and without HL, suggesting differences in underlying disease processes. Elevated levels of CD138+, CD20+, and CD3+ cells in HL indicate B and T-cell involvement in lesion formation. Determining which cytokines and immunological pathways are present in IC/BPS-HL could elucidate the disease mechanism.

IgG anti-DWEYS antibodies cross-reactive with DNA and the N-methyl-d-aspartate receptor subunits GluN2A and GluN2B are known to be associated with neuropsychiatric systemic lupus erythematosus (NPSLE). IgG anti-DWEYS have not been investigated in demyelinating NPSLE or in another demyelinating disorder, neuromyelitis optica spectrum disorder (NMOSD), which is a disease also found mainly in young women and associated with aquaporin 4 (AQP-4) or myelin oligodendrocyte glycoprotein (MOG) antibodies. This study was undertaken to investigate the frequency of all of these brain-reactive antibodies in patients with NPSLE, those with demyelinating NPSLE, and those with NMOSD.Serum samples from patients with NPSLE (n = 108), patients with SLE without neuropsychiatric manifestations (n = 38), patients with NMOSD (n = 33), and healthy controls (n = 106) were assessed for the frequency of IgG anti-brain antibodies as well as IgG antibodies to AQP-4, MOG, GluN2A/GluN2B, and double-stranded DNA (dsDNA).Sera were positive for IgG anti-AQP-4 antibodies in 27 (82%) of 33 patients with NMOSD and 3 (27%) of 11 patients with demyelinating NPSLE, whereas all sera from patients with non-demyelinating NPSLE, patients with SLE, and healthy controls were negative for IgG anti-AQP-4. IgG anti-MOG were detected at high titers in 3 (50%) of 6 patients with NMOSD who were negative for IgG anti-AQP-4, and at low titers in 2 (18%) of 11 patients with demyelinating NPSLE and 1 (1%) of 97 patients with non-demyelinating NPSLE. IgG antibodies to dsDNA were present in 11 (33%) of 33 patients with NMOSD. Only 4 (12%) of 33 patients with NMOSD were positive for IgG anti-DWEYS, compared to 11 (29%) of 38 patients with SLE and 59 (55%) of 108 patients with NPSLE. IgG anti-DWEYS antibodies were present in 56 (58%) of 97 patients with non-demyelinating NPSLE and 3 (27%) of 11 patients with demyelinating NPSLE. Serum IgG brain-reactive antibodies were present at a similar frequency in patients with non-demyelinating NPSLE (72 [75%] of 96), those with demyelinating NPSLE (9 [82%] of 11), and those with SLE (32 [84%] of 38), but were less frequent in patients with NMOSD (20 [61%] of 33).Patients with demyelinating NPSLE should be tested for IgG antibodies to AQP-4, MOG, and DWEYS. IgG anti-AQP-4 can be considered diagnostic for NMOSD, whereas none of these antibodies appear to be diagnostic for demyelinating NPSLE. Moreover, IgG anti-dsDNA are present in patients with NMOSD but are not cross-reactive with IgG anti-DWEYS, indicating that the antigenic stimulus and mechanisms of tissue damage are potentially different between demyelinating NPSLE and NMOSD.

Samara B Ginzburg, Susan Deutsch, Jaclyn Bellissimo, David E Elkowitz, Joel NH Stern, Robert Lucito Department of Science Education, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA Purpose: The evolution of health care systems in response to societal and financial pressures has changed care delivery models, which presents new challenges for physicians. Leadership training is increasingly being recognized as an essential component of medical education training to prepare physicians to meet these needs. Unfortunately, most medical schools do not include leadership training. It has been suggested that a longitudinal and integrated approach to leadership training should be sought. We hypothesized that integration of leadership training into our hybrid problem-based learning (PBL)/case-based learning (CBL) program, Patient-Centered Explorations in Active Reasoning, Learning and Synthesis (PEARLS), would be an effective way for medical students to develop leadership skills without the addition of curricular time. Methods: We designed a unique leadership program in PEARLS in which 98 medical students participated during each of their six courses throughout the first 2years of school. A program director and trained faculty facilitators educated students and coached them on leadership development throughout this time. Students were assessed by their facilitator at the end of every course on development of leadership skills related to teamwork, meaningful self-assessment, process improvement, and thinking outside the box. Results: Students consistently improved their performance from the first to the final course in all four leadership parameters evaluated. The skills that demonstrated the greatest change were those pertaining to thinking outside the box and process improvement. Conclusion: Incorporation of a longitudinal and integrated approach to leadership training into an existing PBL/CBL program is an effective way for medical students to improve their leadership skills without the addition of curricular time. These results offer a new, time-efficient option for leadership development in schools with existing PBL/CBL programs. Keywords: student-centered, learner-centered, self-directed learning, curricular innovation, higher-order thinking

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. It is characterized by demyelination of neurons and loss of neuronal axons and oligodendrocytes. In MS, auto-reactive T cells and B cells cross the blood-brain barrier (BBB), causing perivenous demyelinating lesions that form multiple discrete inflammatory demyelinated plaques located primarily in the white matter. In chronic MS, cortical demyelination and progressive axonal transections develop. Treatment for MS can be stratified into disease-modifying therapies (DMTs) and symptomatic therapy. DMTs aim to decrease circulating immune cells or to prevent these cells from crossing the BBB and reduce the inflammatory response. There are currently 10 DMTs approved for the relapsing forms of MS; these vary with regard to their efficacy, route and frequency of administration, adverse effects, and toxicity profile. Better drug delivery systems are being developed in order to decrease adverse effects, increase drug efficacy, and increase patient compliance through the direct targeting of pathologic cells. Here, we address the uses and benefits of advanced drug delivery systems, including nanoparticles, microparticles, fusion antibodies, and liposomal formulations. By altering the properties of therapeutic particles and enhancing targeting, breakthrough drug delivery technologies potentially applicable to multiple disease treatments may rapidly emerge.

The prevention and control of Campylobacter colonization of poultry flocks are important public health strategies for the control of human campylobacteriosis. A critical review of the literature on interventions to control Campylobacter in poultry on farms was undertaken using a systematic approach. Although the focus of the review was on aspects appropriate to the United Kingdom poultry industry, the research reviewed was gathered from worldwide literature. Multiple electronic databases were employed to search the literature, in any language, from 1980 to September 2008. A primary set of 4,316 references was identified and scanned, using specific agreed-upon criteria, to select relevant references related to biosecurity-based interventions. The final library comprised 173 references. Identification of the sources of Campylobacter in poultry flocks was required to inform the development of targeted interventions to disrupt transmission routes. The approach used generally involved risk factor-based surveys related to culture-positive or -negative flocks, usually combined with a structured questionnaire. In addition, some studies, either in combination or independently, undertook intervention trials. Many of these studies were compromised by poor design, sampling, and statistical analysis. The evidence for each potential source and route of transmission on the poultry farm was reviewed critically, and the options for intervention were considered. The review concluded that, in most instances, biosecurity on conventional broiler farms can be enhanced and this should contribute to the reduction of flock colonization. However, complementary, non-biosecurity-based approaches will also be required in the future to maximize the reduction of Campylobacter -positive flocks at the farm level.

Summary: Driven by dramatic technological improvements, large-scale characterization of lymphocyte receptor repertoires via high-throughput sequencing is now feasible. Although promising, the high germline and somatic diversity, especially of B-cell immunoglobulin repertoires, presents challenges for analysis requiring the development of specialized computational pipelines. We developed the REpertoire Sequencing TOolkit (pRESTO) for processing reads from high-throughput lymphocyte receptor studies. pRESTO processes raw sequences to produce error-corrected, sorted and annotated sequence sets, along with a wealth of metrics at each step. The toolkit supports multiplexed primer pools, single- or paired-end reads and emerging technologies that use single-molecule identifiers. pRESTO has been tested on data generated from Roche and Illumina platforms. It has a built-in capacity to parallelize the work between available processors and is able to efficiently process millions of sequences generated by typical high-throughput projects. Availability and implementation: pRESTO is freely available for academic use. The software package and detailed tutorials may be downloaded from http://clip.med.yale.edu/presto . Contact: steven.kleinstein@yale.edu Supplementary information: Supplementary data are available at Bioinformatics online.

The benefits of exercise at reducing cardiovascular and all-cause mortality have been well described, but certain cohorts of individuals exist in which the safety of exercise has not been studied and its benefits and harms are thus far unknown. During participation in sports or other forms of exercise, patients with transposition of the great arteries (TGA) with systemic right ventricles (SRVs) may have a higher risk of adverse events, including sudden cardiac death. There is little evidence regarding the exercise tolerance and safety in this cohort of patients and it is unknown if exercise will increase the stress on the SRV and result in diminished function.

The acknowledgments section of this article needs to be updated to include the following: The project was initiated at the Harvard Macy Institute and was funded by a President Award from the Josiah Macy Jr.

Campylobacter jejuni is the most common food borne bacterial pathogen and leading cause of food borne disease in humans in the United States and other industrialized nations. Approximately four million cases of human campylobacteriosis occur each year in the United States. Although the majority of cases consist of limited diarrheal illness, severe sequelae can affect a small portion of patients with campylobacteriosis that may include reactive arthritis and Guillain-Barre syndrome. Animal reservoirs primarily include poultry (C. jejuni) and swine (C. coli). Pathogen reduction during poultry processing and safe handling of raw poultry in the kitchen are needed to prevent illness.

Analyses of somatic hypermutation (SHM) patterns in B cell immunoglobulin (Ig) sequences contribute to our basic understanding of adaptive immunity, and have broad applications not only for understanding the immune response to pathogens, but also to determining the role of SHM in autoimmunity and B cell cancers. Although stochastic, SHM displays intrinsic biases that can confound statistical analysis, especially when combined with the particular codon usage and base composition in Ig sequences. Analysis of B cell clonal expansion, diversification, and selection processes thus critically depends on an accurate background model for SHM micro-sequence targeting (i.e., hot/cold-spots) and nucleotide substitution. Existing models are based on small numbers of sequences/mutations, in part because they depend on data from non-coding regions or non-functional sequences to remove the confounding influences of selection. Here, we combine high-throughput Ig sequencing with new computational analysis methods to produce improved models of SHM targeting and substitution that are based only on synonymous mutations, and are thus independent of selection. The resulting "S5F" models are based on 806,860 Synonymous mutations in 5-mer motifs from 1,145,182 Functional sequences and account for dependencies on the adjacent four nucleotides (two bases upstream and downstream of the mutation). The estimated profiles can explain almost half of the variance in observed mutation patterns, and clearly show that both mutation targeting and substitution are significantly influenced by neighboring bases. While mutability and substitution profiles were highly conserved across individuals, the variability across motifs was found to be much larger than previously estimated. The model and method source code are made available at http://clip.med.yale.edu/SHM.

The most common test to identify latent tuberculosis is the tuberculin skin test that detects T cell responses of delayed type hypersensitivity type IV. Since it produces false negative reactions in active tuberculosis or in high-risk persons exposed to tuberculosis patients as shown in this report, we studied antibody profiles to explain the anergy of such responses in high-risk individuals without active infection. Our results showed that humoral immunity against tuberculin, regardless of the result of the tuberculin skin test is important for protection from active tuberculosis and that the presence of high antibody titers is a more reliable indicator of infection latency suggesting that latency can be based on the levels of antibodies together with in vitro proliferation of peripheral blood mononuclear cells in the presence of the purified protein derivative. Importantly, anti-tuberculin IgG antibody levels mediate the anergy described herein, which could also prevent reactivation of disease in high-risk individuals with high antibody titers. Such anti-tuberculin IgG antibodies were also found associated with blocking and/or stimulation of in vitro cultures of PBMC with tuberculin. In this regard, future studies need to establish if immune responses to Mycobacterium tuberculosis can generate a broad spectrum of reactions either toward Th1 responses favoring stimulation by cytokines or by antibodies and those toward diminished responses by Th2 cytokines or blocking by antibodies; possibly involving mechanisms of antibody dependent protection from Mtb by different subclasses of IgG.

Rituximab is a human/murine chimeric monoclonal antibody primarily used for treating non-Hodgkin's B-cell lymphoma. Recently it has also been used in the treatment of several autoimmune diseases. A literature review was conducted to determine the efficacy of rituximab in the treatment of some of these autoimmune diseases. Multiple mechanisms proposed for the rituximab mediated B cell depletion are also discussed. The efficacy of rituximab is well-established and it is FDA approved for treatment of Rheumatoid arthritis. In this review, data on the use of rituximab is presented from 92 studies involving 1197 patients with the following diseases: systemic lupus erythematosus, idiopathic thrombocytopenic purpura, anti-neutrophil cytoplasmic antibody associated vasculitis, Grave's disease, autoimmune hemolytic anemia, pemphigus vulgaris, hemophilia A, cold agglutinin disease, Sjogren's syndrome, graft vs. host disease, thrombotic thrombocytopenic purpura, cryoglobulinemia, IgM mediated neuropathy, multiple sclerosis, neuromyelitis optica, idiopathic membranous nephropathy, dermatomyositis, and opsoclonus myoclonus. The efficacy varies among different autoimmune diseases. The cumulative data would suggest that in the vast majority of studies in this review, RTX has a beneficial role in their treatment. While rituximab is very effective in the depletion of B cells, current research suggests it may also influence other cells of the immune system by re-establishing immune homeostasis and tolerance. The safety profile of RTX reveals that most reactions are infusion related. In patients with autoimmune diseases the incidence of serious and severe side effects is low. Systemic infection still remains a major concern and may result in death.

Facial nerve neuromas are an unusual cause of facial nerve dysfunction and hearing loss. As clinical manifestations do not accurately reflect tumor extent, imaging techniques can greatly assist the clinician in appropriate diagnostic evaluation and management.

The effect of the ingestion of thyroid extract on normal and myxedematous people has been studied by several observers. The general opinion seems to be that cases of myxedema and cretinism respond readily to thyroid extract by a considerable increase in basal metabolism, and that normal and obese people, while usually affected, respond to a less marked degree. DuBois1reports a case of cretinism whose basal metabolism rose 20 per cent. in three and one-half days under the influence of thyroid extract. The amounts of thyroid extract employed differ greatly in the investigations on normal and obese individuals. A patient with obesity studied by Magnus-Levy2received the largest dose of thyroid extract that we know of— from 3 to 5 gm. daily for nineteen days. Anderson and Bergman3used large doses, but only for one day before observations. Thiele and Nehring4used doses up to 0.9 gm. a day. Observations