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Inheriting genetic risk factors for multiple sclerosis (MS) is not sufficient to cause this demyelinating disease of the central nervous system; exposure to environmental risk factors is also required. MS may be preventable if these unidentified environmental factors can be avoided. MS prevalence increases with decreasing solar radiation, suggesting that sunlight may be protective in MS. Since the vitamin D endocrine system is exquisitely responsive to sunlight, and MS prevalence is highest where environmental supplies of vitamin D are lowest, we have proposed that the hormone, 1, 25-dihydroxycholecalciferol (1,25-(OH)2D3), may protect genetically-susceptible individuals from developing MS. Evidence consistent with this hypothesis comes not only from geographic studies, but also genetic and biological studies. Over-representation of the vitamin D receptor gene b allele was found in Japanese MS patients, suggesting it may confer MS susceptibility. Fish oil is an excellent vitamin D source, and diets rich in fish may lower MS prevalence or severity. Vitamin D deficiency afflicts most MS patients, as demonstrated by their low bone mass and high fracture rates. However, the clearest evidence that vitamin D may be a natural inhibitor of MS comes from experiments with experimental autoimmune encephalomyelitis (EAE), a model of MS. Treatment of mice with 1,25-(OH)2D3 completely inhibited EAE induction and progression. The hormone stimulated the synthesis of two anti-encephalitogenic cytokines, interleukin 4 and transforming growth factor beta-1, and influenced inflammatory cell trafficking or apoptosis. If vitamin D is a natural inhibitor of MS, providing supplemental vitamin D to individuals who are at risk for MS would be advisable. [ABSTRACT FROM AUTHOR]

Microglial cell activation is the earliest biomarker of the inflammatory processes that cause central nervous system (CNS) lesions in multiple sclerosis. We hypothesized that 1,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) production by activated microglia and macrophages in the CNS inhibits these inflammatory processes. To test this hypothesis, we targeted the Cyp27b1 gene specifically in myeloid cells, then analyzed the influence of disrupted myeloid cell 1,25-(OH) 2 D 3 synthesis on vitamin D 3 -mediated resistance to experimental autoimmune encephalomyelitis (EAE). Myeloid cell 1,25-(OH) 2 D 3 synthesis was essential for vitamin D 3 -mediated EAE resistance. Increased CTLA-4 expression in the CNS-infiltrating CD4 + Tconv and Treg cells and decreased splenic B cell CD86 expression correlated with resistance. These new data provide solid support for the view that vitamin D 3 reduces MS risk in part through a mechanism involving myeloid cell 1,25-(OH) 2 D 3 production and CTLA-4 upregulation in CNS-infiltrating CD4 + T cells. We suggest that CTLA-4 serves as a vitamin D 3 -regulated immunological checkpoint in multiple sclerosis prevention., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. We review the two core MS features, myelin instability, fragmentation, and remyelination failure, and dominance of pathogenic CD4 + Th17 cells over protective CD4 + Treg cells. To better understand myelin pathology, we describe myelin biosynthesis, structure, and function, then highlight stearoyl-CoA desaturase (SCD) in nervonic acid biosynthesis and nervonic acid's contribution to myelin stability. Noting that vitamin D deficiency decreases SCD in the periphery, we propose it also decreases SCD in oligodendrocytes, disrupting the nervonic acid supply and causing myelin instability and fragmentation. To better understand the distorted Th17/Treg cell balance, we summarize Th17 cell contributions to MS pathogenesis, then highlight how 1,25-dihydroxyvitamin D 3 signaling from microglia to CD4 + T cells restores Treg cell dominance. This signaling rapidly increases flux through the methionine cycle, removing homocysteine, replenishing S-adenosyl-methionine, and improving epigenetic marking. Noting that DNA hypomethylation and inappropriate DRB1*1501 expression were observed in MS patient CD4 + T cells, we propose that vitamin D deficiency thwarts epigenetic downregulation of DRB1*1501 and Th17 cell signature genes, and upregulation of Treg cell signature genes, causing dysregulation within the CD4 + T cell compartment. We explain how obesity reduces vitamin D status, and how estrogen and vitamin D collaborate to promote Treg cell dominance in females. Finally, we discuss the implications of this new knowledge concerning myelin and the Th17/Treg cell balance, and advocate for efforts to address the global epidemics of obesity and vitamin D deficiency in the expectation of reducing the impact of MS., Competing Interests: CONFLICTS OF INTEREST The authors declare that there is no conflict of interest in relation to this work.

Given the prevalence of skin cancer, sunscreens are recommended by dermatologists including the American Academy of Dermatology to protect skin from harmful ultraviolet rays. Unfortunately, this leads to an estimated 14,000 tons of sunscreen entering waterways each year. Many of the chemicals in sunscreens, such as oxybenzone and benzophenone-2, are indicated to have adverse effects on corals and other aquatic life. As an eco-conscious alternative, physical barrier sunscreens, such as non-nano-titanium dioxide (TiO 2 ), have been suggested as a replacement. This study examines the impact of a non-nano-TiO 2 -based sunscreen over a nationally sold brand of sunscreen containing oxybenzone, on clownfish (Amphiprion ocellaris). Animals were evaluated for mortality, swimming behavior, and feeding behavior. Our data indicate that at an exposure level of 100 mg/L oxybenzone-containing sunscreen had a negative impact on mortality, leading to 25% death by the end of the 97-h testing period. Negative impacts on behavior were even more dramatic for the 100 mg/L oxybenzone-containing sunscreen, with 100% of the animals failing to feed over the first 49 h of testing and 100% of animals demonstrating abnormal swimming behavior over the entire testing period. By comparison, the non-nano-(TiO 2 ) sunscreen at 100 mg/L had little (6.7%) negative impact on mortality and feeding. While swimming behavior was disrupted during the first 25 h of testing (26.7% abnormal movement), animals recovered well over the remainder of the testing period (out to 97 h).

We investigated how one calcitriol dose plus vitamin D 3 reverses experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model. This protocol rapidly increased CD4 + T cell Ikzf2 transcripts, Helios protein, and CD4 + Helios + FoxP3 + T regulatory cells. It also rapidly increased CD4 + T cell Bhmt1 transcripts, betaine:homocysteine methyltransferase-1 (BHMT1) enzyme activity, and global DNA methylation. BHMT1 transmethylates homocysteine to replenish methionine. Targeting the Vdr gene in T cells decreased Ikzf2 and Bhmt1 gene expression, reduced DNA methylation, and elevated systemic homocysteine in mice with EAE. We hypothesize that calcitriol drives a transition from encephalitogenic CD4 + T cell to Treg cell dominance by upregulating Ikzf2 and Bhmt1, recycling homocysteine to methionine, reducing homocysteine toxicity, maintaining DNA methylation, and stabilizing CD4 + Helios + FoxP3 + Tregulatory cells. Conserved vitamin D-responsive element (VDRE)-type sequences in the Bhmt1 and Ikzf2 promoters, the universal need for methionine in epigenetic regulation, and betaine's protective effects in MTHFR-deficiency suggest similar regulatory mechanisms exist in humans., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Pentagonal bipyramidal uranyl (UO2(2+)) complexes of salen ligands, N,N'-bis(3-tert-butyl-(5R)-salicylidene)-1,2-phenylenediamine, in which R = (t)Bu (1a), OMe (1b), and NMe2 (1c), were prepared and the electronic structure of the one-electron oxidized species [1a-c]+ were investigated in solution. The solid-state structures of 1a and 1b were solved by X-ray crystallography, and in the case of 1b an asymmetric UO2(2+) unit was found due to an intermolecular hydrogen bonding interaction. Electrochemical investigation of 1a-c by cyclic voltammetry showed that each complex exhibited at least one quasi-reversible redox process assigned to the oxidation of the phenolate moieties to phenoxyl radicals. The trend in redox potentials matches the electron-donating ability of the para-phenolate substituents. The electron paramagnetic resonance spectra of cations [1a-c]+ exhibited gav values of 1.997, 1.999, and 1.995, respectively, reflecting the ligand radical character of the oxidized forms, and in addition, spin-orbit coupling to the uranium centre. Chemical oxidation as monitored by ultraviolet-visible-near-infrared (UV-vis-NIR) spectroscopy afforded the one-electron oxidized species. Weak low energy intra-ligand charge transfer (CT) transitions were observed for [1a-c]+ indicating localization of the ligand radical to form a phenolate/phenoxyl radical species. Further analysis using density functional theory (DFT) calculations predicted a localized phenoxyl radical for [1a-c]+ with a small but significant contribution of the phenylenediamine unit to the spin density. Time-dependent DFT (TD-DFT) calculations provided further insight into the nature of the low energy transitions, predicting both phenolate to phenoxyl intervalence charge transfer (IVCT) and phenylenediamine to phenoxyl CT character. Overall, [1a-c]+ are determined to be relatively localized ligand radical complexes, in which localization is enhanced as the electron donating ability of the para-phenolate substituents is increased (NMe2 > OMe > (t)Bu).

Background: The Drug Evaluation and Classification Program (DECP) is commonly utilized in driving under the influence (DUI) cases to help determine category(ies) of impairing drug(s) present in drivers. Cannabis, one of the categories, is associated with approximately doubled crash risk. Our objective was to determine the most reliable DECP metrics for identifying cannabis-driving impairment., Methods: We evaluated 302 toxicologically-confirmed (blood Δ(9)-tetrahydrocannabinol [THC] ≥1μg/L) cannabis-only DECP cases, wherein examiners successfully identified cannabis, compared to normative data (302 non-impaired individuals). Physiological measures, pupil size/light reaction, and performance on psychophysical tests (one leg stand [OLS], walk and turn [WAT], finger to nose [FTN], Modified Romberg Balance [MRB]) were included., Results: Cases significantly differed from controls (p<0.05) in pulse (increased), systolic blood pressure (elevated), and pupil size (dilated). Blood collection time after arrest significantly decreased THC concentrations; no significant differences were detected between cases with blood THC <5μg/L versus ≥5μg/L. The FTN best predicted cannabis impairment (sensitivity, specificity, positive/negative predictive value, and efficiency ≥87.1%) utilizing ≥3 misses as the deciding criterion; MRB eyelid tremors produced ≥86.1% for all diagnostic characteristics. Other strong indicators included OLS sway, ≥2 WAT clues, and pupil rebound dilation. Requiring ≥2/4 of: ≥3 FTN misses, MRB eyelid tremors, ≥2 OLS clues, and/or ≥2 WAT clues produced the best results (all characteristics ≥96.7%)., Conclusions: Blood specimens should be collected as early as possible. The frequently-debated 5μg/L blood THC per se cutoff showed limited relevance. Combined observations on psychophysical and eye exams produced the best cannabis-impairment indicators., (Published by Elsevier Ltd.)

Microglia become activated immune cells during infection or disease in the central nervous system (CNS). However, the mechanisms that downregulate activated microglia to prevent immune-mediated damage are not completely understood. Vitamin D3 has been suggested to have immunomodulatory affects, and high levels of vitamin D3 have been correlated with a decreased risk for developing some neurological diseases. Recent studies have demonstrated the synthesis of active vitamin D3, 1,25-dihydroxyvitamin D3, within the CNS, but its cellular source and neuroprotective actions remain unknown. Therefore, we wanted to determine whether microglia can respond to vitamin D3 and whether vitamin D3 alters immune activation of microglia. We have previously shown that microglia become activated by IFNγ or LPS or by infection with virus to express pro-inflammatory cytokines, chemokines, and effector molecules. In this study, activated microglia increased the expression of the vitamin D receptor and Cyp27b1, which encodes the enzyme for converting vitamin D3 into its active form, thereby enhancing their responsiveness to vitamin D3. Most importantly, the activated microglia exposed to vitamin D3 had reduced expression of pro-inflammatory cytokines, IL-6, IL-12, and TNFα, and increased expression of IL-10. The reduction in pro-inflammatory cytokines was dependent on IL-10 induction of suppressor of cytokine signaling-3 (SOCS3). Therefore, vitamin D3 increases the expression of IL-10 creating a feedback loop via SOCS3 that downregulates the pro-inflammatory immune response by activated microglia which would likewise prevent immune mediated damage in the CNS., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Zoonotic diseases are a looming threat to global populations, and nearly 75% of emerging infectious diseases can spread among wildlife, domestic animals and humans. A 'One World, One Health' perspective offers us an ideal framework for understanding and potentially mitigating the spread of zoonoses, and the island of Madagascar serves as a natural laboratory for conducting these studies. Rapid habitat degradation and climate change on the island are contributing to more frequent contact among humans, livestock and wildlife, increasing the potential for pathogen spillover events. Given Madagascar's long geographical isolation, coupled with recent and repeated introduction of agricultural and invasive species, it is likely that a number of circulating pathogens remain uncharacterized in lemur populations. Thus, it is imperative that new approaches be implemented for de novo pathogen discovery. To this end, we used non-targeted deep sequencing of blood transcriptomes from two species of critically endangered wild lemurs (Indri indri and Propithecus diadema) to characterize blood-borne pathogens. Our results show several undescribed vector-borne parasites circulating within lemurs, some of which may cause disease in wildlife, livestock and humans. We anticipate that advanced methods for de novo identification of unknown pathogens will have broad utility for characterizing other complex disease transmission systems., (© 2016 The Author(s).)

A highly selective (>99%) tandem catalytic system for the conversion of ethanol (up to 37%) to n-butanol, through the Guerbet process, has been developed using a bifunctional iridium catalyst coupled with bulky nickel or copper hydroxides. These sterically crowded nickel and copper hydroxides catalyze the key aldol coupling reaction of acetaldehyde to exclusively yield the C4 coupling product, crotonaldehyde. Iridium-mediated dehydrogenation of ethanol to acetaldehyde has led to the development of an ethanol-to-butanol process operated at a lower temperature.

Multiple sclerosis (MS) is a neurodegenerative disease resulting from an autoimmune attack on the axon-myelin unit. A female MS bias becomes evident after puberty and female incidence has tripled in the last half-century, implicating a female sex hormone interacting with a modifiable environmental factor. These aspects of MS suggest that many female MS cases may be preventable. Mechanistic knowledge of this hormone-environment interaction is needed to devise strategies to reduce female MS risk. We previously demonstrated that vitamin D3 (D3) deficiency increases and D3 supplementation decreases experimental autoimmune encephalomyelitis (EAE) risk in a female-biased manner. We also showed that D3 acts in an estrogen (E2)-dependent manner, since ovariectomy eliminated and E2 restored D3-mediated EAE protection. Here we probed the hypothesis that E2 and D3 interact synergistically within CD4(+) T cells to control T cell fate and prevent demyelinating disease. The E2 increased EAE resistance in wild-type (WT) but not T-Vdr(0) mice lacking Vdr gene function in CD4(+) T cells, so E2 action depended entirely on Vdr(+)CD4(+) T cells. The E2 levels were higher in WT than T-Vdr(0) mice, suggesting the Vdr(+)CD4(+) T cells produced E2 or stimulated its production. The E2 decreased Cyp24a1 and increased Vdr transcripts in T cells, prolonging the calcitriol half-life and increasing calcitriol responsiveness. The E2 also increased CD4(+)Helios(+)FoxP3(+) T regulatory (Treg) cells in a Vdr-dependent manner. Thus, CD4(+) T cells have a cooperative amplification loop involving E2 and calcitriol that promotes CD4(+)Helios(+)FoxP3(+) Treg cell development and is disrupted when the D3 pathway is impaired. The global decline in population D3 status may be undermining a similar cooperative E2-D3 interaction controlling Treg cell differentiation in women, causing a breakdown in T cell self tolerance and a rise in MS incidence., (Copyright © 2015 Elsevier B.V. All rights reserved.)

This review summarizes and integrates research on vitamin D and CD4(+) T-lymphocyte biology to develop new mechanistic insights into the molecular etiology of autoimmune disease. A deep understanding of molecular mechanisms relevant to gene-environment interactions is needed to deliver etiology-based autoimmune disease prevention and treatment strategies. Evidence linking sunlight, vitamin D, and the risk of multiple sclerosis and type 1 diabetes is summarized to develop the thesis that vitamin D is the environmental factor that most strongly influences autoimmune disease development. Evidence for CD4(+) T-cell involvement in autoimmune disease pathogenesis and for paracrine calcitriol signaling to CD4(+) T lymphocytes is summarized to support the thesis that calcitriol is sunlight's main protective signal transducer in autoimmune disease risk. Animal modeling and human mechanistic data are summarized to support the view that vitamin D probably influences thymic negative selection, effector Th1 and Th17 pathogenesis and responsiveness to extrinsic cell death signals, FoxP3(+)CD4(+) T-regulatory cell and CD4(+) T-regulatory cell type 1 (Tr1) cell functions, and a Th1-Tr1 switch. The proposed Th1-Tr1 switch appears to bridge two stable, self-reinforcing immune states, pro- and anti-inflammatory, each with a characteristic gene regulatory network. The bi-stable switch would enable T cells to integrate signals from pathogens, hormones, cell-cell interactions, and soluble mediators and respond in a biologically appropriate manner. Finally, unanswered questions and potentially informative future research directions are highlighted to speed delivery of etiology-based strategies to reduce autoimmune disease.

Objective: The objective of this review is to explore how current research measures the effectiveness of inhaled corticosteroids (ICS) in smokers with asthma., Data Sources: PubMed, CINAHL and PsycINFO databases were searched for combinations of terms relating to asthma, tobacco use and ICS effectiveness., Study Selections: The search was limited to articles published between 2004 and 2015, in English language. Studies met inclusion criteria if reporting the use of guideline-based asthma control indicators to measure the therapeutic effects of ICS or ICS combination therapies. This review did not exclude articles based on study design. Data were extracted and summarized to describe how indicators were measured across studies in order to characterize and describe the effects of ICS in smokers., Results: Thirteen studies were included in this review. Six of these 13 studies used only one indicator to measure asthma control in smokers and ICS was found to improve asthma in only one of six of these studies. Of studies evaluating combination therapy, three of four studies reported a therapeutic benefit to smokers. In these studies of combination therapy multiple indicators of control were measured to assess drug effects., Conclusions: To assess the therapeutic benefit of ICS drugs in smokers, multiple indicators should be measured to determine if current therapy is improving asthma control. Asthma therapy should then be adjusted based on the patient's current asthma status. The development of clinical treatment guidelines for asthmatic smokers may help clinicians make best-practice, evidence-based recommendations in order to optimize care for these patients.

Multiple sclerosis (MS) is an incurable inflammatory demyelinating disease. We investigated one calcitriol dose plus vitamin D3 (calcitriol/+D) as a demyelinating disease treatment in experimental autoimmune encephalomyelitis (EAE). Evidence that calcitriol-vitamin D receptor pathway deficits may promote MS, and data showing calcitriol enhancement of autoimmune T cell apoptosis provided the rationale. Whereas vitamin D3 alone was ineffective, calcitriol/+D transiently increased central nervous system (CNS) Helios(+)FoxP3(+) T cells and sustainably decreased CNS T cells, pathology, and neurological deficits in mice with EAE. Calcitriol/+D, which was more effective than methylprednisolone, has potential for reversing inflammatory demyelinating disease safely and cost-effectively., (© 2013.)

Compelling evidence suggests that vitamin D3 insufficiency may contribute causally to multiple sclerosis (MS) risk. Experimental autoimmune encephalomyelitis (EAE) research firmly supports this hypothesis. Vitamin D3 supports 1,25-dihydroxyvitamin D3 (1,25-[OH]2D3) synthesis in the CNS, initiating biological processes that reduce pathogenic CD4+ T cell longevity. MS is prevalent in Sardinia despite high ambient UV irradiation, challenging the vitamin D-MS hypothesis. Sardinian MS patients frequently carry a low Ifng expresser allele, suggesting that inadequate IFN-γ may undermine vitamin D3-mediated inhibition of demyelinating disease. Testing this hypothesis, we found vitamin D3 failed to inhibit EAE in female Ifng knockout (GKO) mice, unlike wild-type mice. The two strains did not differ in Cyp27b1 and Cyp24a1 gene expression, implying equivalent vitamin D3 metabolism in the CNS. The 1,25-(OH)2D3 inhibited EAE in both strains, but 2-fold more 1,25-(OH)2D3 was needed in GKO mice, causing hypercalcemic toxicity. Unexpectedly, GKO mice had very low Vdr gene expression in the CNS. Injecting IFN-γ intracranially into adult mice did not increase Vdr gene expression. Correlating with low Vdr expression, GKO mice had more numerous pathogenic Th1 and Th17 cells in the CNS, and 1,25-(OH)2D3 reduced these cells in GKO and wild-type mice without altering Foxp3+ regulatory T cells. Thus, the Ifng gene was needed for CNS Vdr gene expression and vitamin D3-dependent mechanisms that inhibit EAE. Individuals with inadequate Ifng expression may have increased MS risk despite high ambient UV irradiation because of low Vdr gene expression and a high encephalitogenic T cell burden in the CNS.

Recently, considerable attention has been given to the use of multi-dentate amido ligands in the coordination chemistry of a range of transition metals as a means of accessing novel structural motifs and unusual reactivity. Presented herein is a perspective on transition and f-block metal complexes containing diamido donor ligands of the general form [NDN](2-) (D = NR, O, PR). Particular focus is given to paramagnetic metals, which have in general been studied much less than their diamagnetic counterparts despite their potential to exhibit unique structures and diverse reactivity patterns, in addition to their magnetic properties.

Patients with anti-IFN-γ autoantibodies have impaired IFN-γ signaling, leading to severe disseminated infections with intracellular pathogens, especially nontuberculous mycobacteria. Disease may be severe and progressive, despite aggressive treatment. To address the underlying pathogenic IFN-γ autoantibodies we used the therapeutic monoclonal rituximab (anti-CD20) to target patient B cells. All subjects received between 8 and 12 doses of rituximab within the first year to maintain disease remission. Subsequent doses were given for relapsed infection. We report 4 patients with refractory disease treated with rituximab who had clinical and laboratory evidence of therapeutic response as determined by clearance of infection, resolution of inflammation, reduction of anti-IFN-γ autoantibody levels, and improved IFN-γ signaling.

Purpose: To demonstrate that, when injecting an artificial reference signal for quantitation purposes, the real and artificial signals can be acquired separately, using a single radiofrequency (RF) channel, with no loss of fidelity. Conversion of MR signals to units of concentration can be simplified by injection of a precalibrated, artificial reference signal, or pseudo-signal. In previous implementations, the pseudo-signal was acquired simultaneously with the real signals arising from the sample and this requires a second, integrated RF channel., Materials and Methods: We used in vivo spectroscopy and in vitro imaging measurements to test the validity of the separate acquisition method., Results: There was very strong correlation (r = 0.94; P = 0.02) between the in vivo concentrations determined with separate and simultaneous acquisition methods. The in vitro measurements validated that the separate acquisition method compensates for differences in coil loading conditions as well as the simultaneous acquisition method., Conclusion: Separate acquisition eliminates the need for a second RF channel, which allows easier implementation at sites that have only one channel available, and relaxes the constraints on the number and amplitude of pseudo-signals. This flexibility can be exploited to increase the signal to noise ratio of the pseudo-signal and reduce variability when making the conversion to units of concentration., (Copyright © 2011 Wiley Periodicals, Inc.)

Upper airway MRI can provide a noninvasive assessment of speech and swallowing disorders and sleep apnea. Recent work has demonstrated the value of high-resolution three-dimensional imaging and dynamic two-dimensional imaging and the importance of further improvements in spatio-temporal resolution. The purpose of the study was to describe a novel 16-channel 3 Tesla receive coil that is highly sensitive to the human upper airway and investigate the performance of accelerated upper airway MRI with the coil. In three-dimensional imaging of the upper airway during static posture, 6-fold acceleration is demonstrated using parallel imaging, potentially leading to capturing a whole three-dimensional vocal tract with 1.25 mm isotropic resolution within 9 sec of sustained sound production. Midsagittal spiral parallel imaging of vocal tract dynamics during natural speech production is demonstrated with 2 × 2 mm(2) in-plane spatial and 84 ms temporal resolution., (Copyright © 2010 Wiley-Liss, Inc.)

Multiple sclerosis (MS) is an incurable autoimmune neurodegenerative disease. Environmental factors may be key to MS prevention and treatment. MS prevalence and severity decrease with increasing sunlight exposure and vitamin D(3) supplies, supporting our hypothesis that the sunlight-dependent hormone, 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2) D(3) ), inhibits autoimmune T-cell responses in MS. Moreover, 1,25-(OH)(2) D(3) inhibits and reverses experimental autoimmune encephalomyelitis (EAE), an MS model. Here, we investigated whether 1,25-(OH)(2) D(3) inhibits EAE via the vitamin D receptor (VDR) in T lymphocytes. Using bone marrow chimeric mice with a disrupted VDR only in radio-sensitive hematopoietic cells or radio-resistant non-hematopoietic cells, we found that hematopoietic cell VDR function was necessary for 1,25-(OH)(2) D(3) to inhibit EAE. Furthermore, conditional targeting experiments showed that VDR function in T cells was necessary. Neither 1,25-(OH)(2) D(3) nor T-cell-specific VDR targeting influenced CD4(+) Foxp3(+) T-cell proportions in the periphery or the CNS in these studies. These data support a model wherein 1,25-(OH)(2) D(3) acts directly on pathogenic CD4(+) T cells to inhibit EAE., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Accurate conversion of magnetic resonance spectra to quantitative units of concentration generally requires compensation for differences in coil loading conditions, the gains of the various receiver amplifiers, and rescaling that occurs during post-processing manipulations. This can be efficiently achieved by injecting a precalibrated, artificial reference signal, or pseudo-signal into the data. We have previously demonstrated, using in vitro measurements, that robust pseudo-signal injection can be accomplished using a second coil, called the injector coil, properly designed and oriented so that it couples inductively with the receive coil used to acquire the data. In this work, we acquired nonlocalized phosphorous magnetic resonance spectroscopy measurements from resting human tibialis anterior muscles and used pseudo-signal injection to calculate the Pi, PCr, and ATP concentrations. We compared these results to parallel estimates of concentrations obtained using the more established phantom replacement method. Our results demonstrate that pseudo-signal injection using inductive coupling provides a robust calibration factor that is immune to coil loading conditions and suitable for use in human measurements. Having benefits in terms of ease of use and quantitative accuracy, this method is feasible for clinical use. The protocol we describe could be readily translated for use in patients with mitochondrial disease, where sensitive assessment of metabolite content could improve diagnosis and treatment.

Rat brain models effectively simulate a multitude of human neurological disorders. Improvements in coil design have facilitated the wider utilization of rat brain models by enabling the utilization of clinical MR scanners for image acquisition. In this study, a novel coil design, subsequently referred to as the rat brain coil, is described that exploits and combines the strengths of both solenoids and surface coils into a simple, multichannel, receive-only coil dedicated to whole-brain rat imaging on a 3.0 T clinical MR scanner. Compared with a multiturn solenoid mouse body coil, a 3-cm surface coil, a modified Helmholtz coil, and a phased-array surface coil, the rat brain coil improved signal-to-noise ratio by approximately 72, 61, 78, and 242%, respectively. Effects of the rat brain coil on amplitudes of static field and radiofrequency field uniformity were similar to each of the other coils. In vivo, whole-brain images of an adult male rat were acquired with a T(2)-weighted spin-echo sequence using an isotropic acquisition resolution of 0.25 x 0.25 x 0.25 mm(3) in 60.6 min. Multiplanar images of the in vivo rat brain with identification of anatomic structures are presented. Improvement in signal-to-noise ratio afforded by the rat brain coil may broaden experiments that utilize clinical MR scanners for in vivo image acquisition., (2010 Wiley-Liss, Inc.)

The Human Proteome Organisation Human Disease Glycomics/Proteome Initiative recently coordinated a multi-institutional study that evaluated methodologies that are widely used for defining the N-glycan content in glycoproteins. The study convincingly endorsed mass spectrometry as the technique of choice for glycomic profiling in the discovery phase of diagnostic research. The present study reports the extension of the Human Disease Glycomics/Proteome Initiative's activities to an assessment of the methodologies currently used for O-glycan analysis. Three samples of IgA1 isolated from the serum of patients with multiple myeloma were distributed to 15 laboratories worldwide for O-glycomics analysis. A variety of mass spectrometric and chromatographic procedures representative of current methodologies were used. Similar to the previous N-glycan study, the results convincingly confirmed the pre-eminent performance of MS for O-glycan profiling. Two general strategies were found to give the most reliable data, namely direct MS analysis of mixtures of permethylated reduced glycans in the positive ion mode and analysis of native reduced glycans in the negative ion mode using LC-MS approaches. In addition, mass spectrometric methodologies to analyze O-glycopeptides were also successful.

BAFF-R (B cell-activating factor belonging to the tumor necrosis factor family receptor) regulates B lymphocyte survival, maturation, homeostasis, and self-tolerance through signaling mechanisms that are not completely understood. A spontaneous BAFF-R mutation, Bcmd-1, disrupts BAFF-R signaling. However, it is not clear why the Bcmd-1-encoded BAFF-R fails to adequately support B cell survival, optimal CD21/35 expression, and B-cell tolerance to dsDNA, since it is 95% identical to the wild-type (wt) BAFF-R and retains the only known signaling motif. A retrotransposon insertion in A/WySnJ strain mice generated the Bcmd-1 allele, replacing the eight C-terminal BAFF-R residues with 21 retrotransposon-encoded residues. New data reported here show that the displaced residues, previously thought to have no signaling role, are essential for optimal CD21/35 expression but contribute little to B cell survival signaling. Analysis of wt Baffr or Bcmd-1 homozygous (A/WySnJ X B6.BCL2)F2 mice confirmed that BCL2 complemented Bcmd-1 for B cell survival but not CD21/35 expression. Through in vivo retroviral transduction experiments, we show that Baffr complemented Bcmd-1 for B cell survival but not CD21/35 expression, whereas the BaffrDelta103-175 deletion mutant lacking the BAFF-R cytoplasmic domain failed to support these functions. Importantly, we show that the BaffrDelta168-175 deletion mutant lacking the retrotransposon-displaced residues, and a BaffrT170A mutant lacking a critical threonine, supported B cell survival but failed to support optimal CD21/35 expression. These data provide the first evidence for a possible bifurcation at the receptor level in the BAFF-R signaling pathway. We suggest that discrete BAFF-R cytoplasmic domains may interact with distinct downstream pathways to provide fine control over B cell survival, maturation, and tolerance induction.

The author gives a personal account of the development of the birdcage resonator while he worked at GE Medical Systems. The emphasis is on promoting an intuitive understanding of the underlying principles of RF coil design by recounting the assumptions, misconceptions, and reasoning involved in addressing the challenging problems in a new field of technology. Topics covered include the historic context of early MRI development, the critical role of RF coil technology in high field imaging, the need for an RF shield, the importance of distributed capacitance, the scientific controversies over magnetic field strength for imaging, a comparison of the birdcage design to an earlier Technicare phased coil, the distribution of electric fields in birdcage resonators, and the limitations of birdcages at very high fields. The author often cites less well-known patent literature on RF coil technology.

Multiple sclerosis (MS) is an autoimmune, neurodegenerative disease with a rapidly increasing female gender bias. MS prevalence decreases with increasing sunlight exposure, supporting our hypothesis that the sunlight-dependent hormone 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) is a natural inhibitor of autoimmune T cell responses in MS. We found that vitamin D(3) inhibited experimental autoimmune encephalomyelitis (EAE) in intact female mice, but not in ovariectomized females or males. To learn whether 17beta-estradiol (E(2)) is essential for vitamin D(3)-mediated protection, ovariectomized female mice were given E(2) or placebo and evaluated for vitamin D(3)-mediated EAE resistance. Diestrus-level E(2) implants alone provided no benefit, but they restored vitamin D(3)-mediated EAE resistance in the ovariectomized females. Synergy between E(2) and vitamin D(3) occurred through vitamin D(3)-mediated enhancement of E(2) synthesis, as well as E(2)-mediated enhancement of vitamin D receptor expression in the inflamed CNS. In males, E(2) implants did not enable vitamin D(3) to inhibit EAE. The finding that vitamin D(3)-mediated protection in EAE is female-specific and E(2)-dependent suggests that declining vitamin D(3) supplies due to sun avoidance might be contributing to the rapidly increasing female gender bias in MS. Moreover, declining E(2) synthesis and vitamin D(3)-mediated protection with increasing age might be contributing to MS disease progression in older women.

Systemic lupus erythematosus pathology reflects autoantibody-mediated damage due to a failure of B-lymphocyte tolerance. We previously reported that B-lymphopenic A/WySnJ mice develop a lupus-like syndrome and linked this syndrome to the B-cell maturation defect-1 (Bcmd-1) mutant allele of the B-cell-activating factor belonging to the TNF family-receptor (Baffr) gene. Here, we further evaluate the genetic basis for autoimmunity in A/WySnJ mice. We produced B6.Bcmd-1 and AW.Baffr(-/-) congenic mice (N5), and compared them with B6.Baffr(-/-) and A/WySnJ mice with respect to B-lymphocyte development. Bcmd-1-expressing mice had more B cells with greater maturity than Baffr(-/-) mice regardless of genetic background, indicating that Bcmd-1 encodes a partially functional BAFF-R. We also compared these mice for lupus phenotypes to determine whether Bcmd-1 is necessary and sufficient for disease, or whether the Baffr(-/-) (-) allele can also cause autoimmunity. The Baffr(-/-) allele did not lead to autoimmunity on either genetic background. In contrast, the Bcmd-1 allele was necessary and sufficient for development of low levels of IgM autoantibodies in B6.Bcmd-1 mice. However, Bcmd-1 plus unidentified A/WySnJ modifier genes were necessary for development of IgG autoantibodies and renal pathology. We propose that in A/WySnJ mice an excess of BAFF per B cell rescues self-reactive B cells through a partially functional BAFF-R in a B-lymphopenic environment.

Conversion of MR signals into units of metabolite concentration requires a very high level of diligence to account for the numerous parameters and transformations that affect the proportionality between the quantity of excited nuclei in the acquisition volume and the integrated area of the corresponding peak in the spectrum. We describe a method that eases this burden with respect to the transformations that occur during and following data acquisition. The conceptual approach is similar to the ERETIC method, which uses a pre-calibrated, artificial reference signal as a calibration factor to accomplish the conversion. The distinguishing feature of our method is that the artificial signal is introduced strictly via induction, rather than radiation. We tested a prototype probe that includes a second RF coil rigidly positioned close to the receive coil so that there was constant mutual inductance between them. The artificial signal was transmitted through the second RF coil and acquired by the receive coil in parallel with the real signal. Our results demonstrate that the calibration factor is immune to changes in sample resistance. This is a key advantage because it removes the cumbersome requirement that coil loading conditions be the same for the calibration sample as for experimental samples. The method should be adaptable to human studies and could allow more practical and accurate quantification of metabolite content.

Systemic lupus erythematosis is an autoimmune disease of unknown etiology. Lupus pathology is thought to reflect autoantibody-mediated damage due to a failure of B lymphocyte tolerance. Since excessive B cell-activating factor belonging to the TNF family (BAFF) expression correlates with human and murine lupus, and BAFF signals B cell survival through BAFF-R, it is believed that excessive BAFF-R signaling can subvert B cell tolerance and facilitate lupus development. Here we report the unexpected finding that BAFF-R-mutant A/WySnJ mice develop a lupus-like syndrome. These mice carry the B cell maturation defect-1 (Bcmd-1) mutant allele of the Baffr gene. Bcmd-1 causes premature B cell death and profound B cell deficiency. Despite having 90% fewer splenic B cells than normal mice, A/WySnJ mice had an 18-fold increased frequency of splenocytes secreting IgM antibodies to dsDNA, and increased amounts of circulating IgM and IgG to dsDNA by 9 months of age. By age 11 months, most A/WySnJ mice displayed renal pathology characteristic of lupus, including proteinuria as well as periodic acid-Schiff-positive deposits and glomerular capillary bed destruction. Importantly, we genetically linked this autoimmunity to Bcmd-1, since congenic AW.Baffr(+/+) mice carrying a wild-type allele developed none of these phenotypes. Our data provide the first evidence linking altered BAFF-R signaling to the development of B cell-mediated autoimmunity.

Multiple sclerosis (MS) is a neurodegenerative disease of uncertain etiology. In MS, neurodegeneration is thought to be secondary to autoimmune-mediated damage. However, no cohesive explanation yet exists as to how environmental factors interact to induce a neurodegenerative autoimmune response. Insufficient sunlight exposure and chronic viral infections have been proposed as unrelated environmental risk factors for MS. We suggest that these risk factors may act synergistically to enable the pathogenic autoimmune response. Low ultraviolet light (UVL) exposure depletes vitamin D3 stores, and low vitamin D3 levels correlate strongly with high MS risk. The central nervous system converts vitamin D3 into 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3), a biologically active hormone with anti-inflammatory and neuro-protective functions that depend on IL-10-producing regulatory lymphocytes. Herpesvirus infection also correlates with MS risk. Some herpesviruses like Epstein-Barr virus produce an IL-10-like cytokine termed vIL-10. We hypothesize that vIL-10 may induce a dysfunction of IL-10-producing regulatory lymphocytes, thereby undermining the protective functions of sunlight, vitamin D3, and 1,25-(OH)2 D3. The vIL-10 could elicit a host immune response capable of neutralizing or depleting IL-10, or the vIL-10 could compete with IL-10 but fail to perform an essential IL-10 function. In either case, the lack of sunlight exposure and the herpes virus infection might synergize to induce a defect in IL-10-producing regulatory lymphocyte function that undermines self-tolerance mechanisms and enables a pathogenic autoimmune response to neural proteins.

Multiple sclerosis (MS) is a complex neurodegenerative disease whose pathogenesis involves genetic and environmental risk factors leading to an aberrant, neuroantigen-specific, CD4+ T cell-mediated autoimmune response. In support of the hypothesis that vitamin D3 may reduce MS risk and severity, we found that vitamin D3 and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) inhibited induction of experimental autoimmune encephalomyelitis (EAE), an MS model. To investigate how 1,25-(OH)2D3 could carry out anti-inflammatory functions, we administered 1,25-(OH)2D3 or a placebo to mice with EAE, and subsequently analyzed clinical disease, chemokines, inducible nitric oxide synthase (iNOS), and recruitment of dye-labeled monocytes. The 1,25-(OH)2D3 treatment significantly reduced clinical EAE severity within 3 days. Sharp declines in chemokines, inducible iNOS, and CD11b+ monocyte recruitment into the central nervous system (CNS) preceded this clinical disease abatement in the 1,25-(OH)2D3-treated animals. The 1,25-(OH)2D3 did not directly and rapidly inhibit chemokine synthesis in vivo or in vitro. Rather, the 1,25-(OH)2D3 rapidly stimulated activated CD4+ T cell apoptosis in the CNS and spleen. Collectively, these results support a model wherein inflammation stimulates a natural anti-inflammatory feedback loop. The activated inflammatory cells produce 1,25-(OH)2D3, and this hormone subsequently enhances the apoptotic death of inflammatory CD4+ T cells, removing the driving force for continued inflammation. In this way, the sunlight-derived hormone could reduce the risk of chronic CNS inflammation and autoimmune-mediated neurodegenerative disease., (Copyright 2007 Wiley-Liss, Inc.)

Purpose: To evaluate the platform and reader reproducibility of quantitative carotid plaque measurements., Materials and Methods: A total of 32 individuals with >or=15% carotid stenosis by duplex ultrasound were each imaged once by a 1.5T General Electric (GE) whole body scanner and twice by either a 1.5T Philips scanner or a 1.5T Siemens scanner. A standardized multisequence protocol and identical phased-array carotid coils were used. Expert readers, blinded to subject information, scanner type, and time point, measured the lumen, wall, and total vessel areas and determined the modified American Heart Association lesion type (AHA-LT) on the cross-sectional images., Results: AHA-LT was consistently identified across the same (kappa = 0.75) and different scan platforms (kappa = 0.75). Furthermore, scan-rescan coefficients of variation (CV) of wall area measurements on Siemens and Philips scanners ranged from 6.3% to 7.5%. However, wall area measurements differed between Philips and GE (P = 0.003) and between Siemens and GE (P = 0.05). In general, intrareader reproducibility was higher than interreader reproducibility for AHA-LT identification as well as for quantitative measurements., Conclusion: All three scanners produced images that allowed AHA-LT to be consistently identified. Reproducibility of quantitative measurements by Siemens and Philips scanners were comparable to previous studies using 1.5T GE scanners. However, bias was introduced with each scanner and the use of different readers substantially increased variability. We therefore recommend using the same platform and the same reader for scans of individual subjects undergoing serial assessment of carotid atherosclerosis., ((c) 2007 Wiley-Liss, Inc.)

Multiple sclerosis (MS) results from an aberrant, neuroantigen-specific, T cell-mediated autoimmune response. Because MS prevalence and severity decrease sharply with increasing sunlight exposure, and sunlight supports vitamin D(3) synthesis, we proposed that vitamin D(3) and 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) may protect against MS. In support of this hypothesis, 1,25-(OH)(2)D(3) strongly inhibited experimental autoimmune encephalomyelitis (EAE). This inhibition required lymphocytes other than the encephalitogenic T cells. In this study, we tested the hypothesis that 1,25-(OH)(2)D(3) might inhibit EAE through the action of IL-10-producing regulatory lymphocytes. We report that vitamin D(3) and 1,25-(OH)(2)D(3) strongly inhibited myelin oligodendrocyte peptide (MOG(35-55))-induced EAE in C57BL/6 mice, but completely failed to inhibit EAE in mice with a disrupted IL-10 or IL-10R gene. Thus, a functional IL-10-IL-10R pathway was essential for 1,25-(OH)(2)D(3) to inhibit EAE. The 1,25-(OH)(2)D(3) also failed to inhibit EAE in reciprocal, mixed bone marrow chimeras constructed by transferring IL-10-deficient bone marrow into irradiated wild-type mice and vice versa. Thus, 1,25-(OH)(2)D(3) may be enhancing an anti-inflammatory loop involving hemopoietic cell-produced IL-10 acting on brain parenchymal cells and vice versa. If this interpretation is correct, and humans have a similar bidirectional IL-10-dependent loop, then an IL-10-IL-10R pathway defect could abrogate the anti-inflammatory and neuro-protective functions of sunlight and vitamin D(3). In this way, a genetic IL-10-IL-10R pathway defect could interact with an environmental risk factor, vitamin D(3) insufficiency, to increase MS risk and severity.

Purpose: To compare black-blood multicontrast carotid imaging at 3T and 1.5T and assess compatibility between morphological measurements of carotid arteries at 1.5T and 3T., Materials and Methods: Five healthy subjects and two atherosclerosis patients were scanned in 1.5T and 3T scanners with a similar protocol providing transverse T1-, T2-, and proton density (PD)-weighted black-blood images using a fast spin-echo sequence with single- (T1-weighted) or multislice (PD-/T2-weighted) double inversion recovery (DIR) preparation. Wall and lumen signal-to-noise ratio (SNR) and wall/lumen contrast-to-noise ratio (CNR) were compared in 44 artery cross-sections by paired t-test. Interscanner variability of the lumen area (LA), wall area (WA), and mean wall thickness (MWT) was assessed using Bland-Altman analysis., Results: Wall SNR and lumen/wall CNR significantly increased (P < 0.0001) at 3T with a 1.5-fold gain for T1-weighted images and a 1.7/1.8-fold gain for PD-/T2-weighted images. Lumen SNR did not differ for single-slice DIR T1-weighted images (P = 0.2), but was larger at 3T for multislice DIR PD-/T2-weighted images (P = 0.01/0.03). The LA, WA, and MWT demonstrated good agreement with no significant bias (P 0.5), a coefficient of variation (CV) of < 10%, and intraclass correlation coefficient (ICC) of > 0.95., Conclusion: This study demonstrated significant improvement in SNR, CNR, and image quality for high- resolution black-blood imaging of carotid arteries at 3T. Morphologic measurements are compatible between 1.5T and 3T., (Copyright 2006 Wiley-Liss, Inc.)

The prevalence of multiple sclerosis (MS) increases significantly with decreasing UV B light exposure, possibly reflecting a protective effect of vitamin D(3). Consistent with this theory, previous research has shown a strong protective effect 1,25-dihydroxyvitamin D(3) in experimental autoimmune encephalomyelitis (EAE), an MS model. However, it is not known whether the hormone precursor, vitamin D(3), has protective effects in EAE. To address this question, B10.PL mice were fed a diet with or without vitamin D(3), immunized with myelin basic protein, and studied for signs of EAE and for metabolites and transcripts of the vitamin D(3) endocrine system. The intact, vitamin D(3)-fed female mice had significantly less clinical, histopathological, and immunological signs of EAE than ovariectomized females or intact or castrated males. Correlating with reduced EAE, the intact, vitamin D(3)-fed female mice had significantly more 1,25-dihydroxyvitamin D(3) and fewer CYP24A1 transcripts, encoding the 1,25-dihydroxyvitamin D(3)-inactivating enzyme, in the spinal cord than the other groups of mice. Thus, there was an unexpected synergy between vitamin D(3) and ovarian tissue with regard to EAE inhibition. We hypothesize that an ovarian hormone inhibited CYP24A1 gene expression in the spinal cord, so the locally-produced 1,25-dihydroxyvitamin D(3) accumulated and resolved the inflammation before severe EAE developed. If humans have a similar gender difference in vitamin D(3) metabolism in the CNS, then sunlight deprivation would increase the MS risk more significantly in women than in men, which may contribute to the unexplained higher MS incidence in women than in men.

Multiple sclerosis (MS) is a debilitating autoimmune disease of the central nervous system (CNS) that develops in genetically susceptible individuals who are exposed to undefined environmental risk factors. Epidemiological, genetic, and biological evidence suggests that insufficient vitamin D may be an MS risk factor. However, little is known about how vitamin D might be protective in MS. We hypothesized that 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] might regulate gene expression patterns in a manner that would resolve inflammation. To test this hypothesis, experimental autoimmune encephalomyelitis (EAE) was induced in mice, 1,25-(OH)2D3 or a placebo was administered, and 6 h later, DNA microarray hybridization was performed with spinal cord RNA to analyze the gene expression patterns. At this time, clinical, histopathological, and biological studies showed that the two groups did not differ in EAE disease, but changes in several 1,25-(OH)2D3-responsive genes indicated that the 1,25-(OH)2D3 had reached the CNS. Compared with normal mice, placebo-treated mice with EAE showed increased expression of many immune system genes, confirming the acute inflammation. When 1,25-(OH)2D3 was administered, several genes like glial fibrillary acidic protein and eukaryotic initiation factor 2alpha kinase 4, whose expression increased or decreased with EAE, returned to homeostatic levels. Also, two genes with pro-apoptotic functions, calpain-2 and caspase-8-associated protein, increased significantly. A terminal deoxynucleotidyl transferase-mediated dUTP nicked end labeling study detected increased nuclear fragmentation in the 1,25-(OH)2D3-treated samples, confirming increased apoptosis. Together, these results suggest that sensitization of inflammatory cells to apoptotic signals may be one mechanism by which the 1,25-(OH)2D3 resolved EAE.

Constitutive NF-kappaB activity has emerged as an important cell survival component of physiological and pathological processes, including B-cell development. In B cells, constitutive NF-kappaB activity includes p50/c-Rel and p52/RelB heterodimers, both of which are critical for proper B-cell development. We previously reported that WEHI-231 B cells maintain constitutive p50/c-Rel activity via selective degradation of IkappaBalpha that is mediated by a proteasome inhibitor-resistant, now termed PIR, pathway. Here, we examined the mechanisms of PIR degradation by comparing it to the canonical pathway that involves IkappaB kinase-dependent phosphorylation and beta-TrCP-dependent ubiquitylation of the N-terminal signal response domain of IkappaBalpha. We found a distinct consensus sequence within this domain of IkappaBalpha for PIR degradation. Chimeric analyses of IkappaBalpha and IkappaBbeta further revealed that the ankyrin repeats of IkappaBalpha, but not IkappaBbeta, contained information necessary for PIR degradation, thereby explaining IkappaBalpha selectivity for the PIR pathway. Moreover, we found that PIR degradation of IkappaBalpha and constitutive p50/c-Rel activity in primary murine B cells were maintained in a manner different from B-cell-activating-factor-dependent p52/RelB regulation. Thus, our findings suggest that nonconventional PIR degradation of IkappaBalpha may play a physiological role in the development of B cells in vivo.

Objective: Noninvasive observation of degenerating and regenerating peripheral nerves could improve the diagnosis and treatment of nerve injuries. We constructed a novel phased-array radiofrequency coil to permit magnetic resonance imaging (MRI) observation of the sciatic nerve and its target muscles in rats after injury., Methods: Adult male Lewis rats underwent either crushing (n = 18) or cutting and capping (n = 17) of their right sciatic nerves and then underwent serial MRI. Serial gait track analysis was performed to assess behavioral recovery. Animals from both groups were killed at several time points for histological evaluation of the nerves, with axon counting., Results: Crushed sciatic nerves demonstrated increased T2-weighted signals, followed by signal normalization as axonal regeneration and behavioral recovery occurred. Cut sciatic nerves prevented from regenerating displayed a prolonged phase of increased signal intensity. Acutely denervated muscles exhibited hyperintense T2-weighted signals, which normalized with reinnervation and behavioral recovery. Chronically denervated muscles demonstrated persistently increased T2-weighted signals and atrophy., Conclusion: In this study, we demonstrated the ability of MRI to noninvasively monitor injury and recovery in the peripheral nervous system, by demonstrating changes in nerve and muscle that correlated with histological and behavioral evidence of axonal degeneration and regeneration. This study demonstrates the potential of MRI to distinguish traumatic peripheral nerve injuries that recover through axonal regeneration (i.e., axonotmetic grade) from those that do not and therefore require surgical repair (i.e., neurotmetic grade). This diagnostic modality could improve treatment by providing earlier and more accurate diagnoses of nerve damage, as well as reducing the need for exploratory surgery.

The TNFR family member BAFF-R facilitates peripheral B cell development, although it is unclear whether it promotes survival of B cells, or also initiates a differentiation program. We show that disruption of the BAFF-R encoding gene Tnfrsf13c in strain A/WySnJ mice causes a progressive decline in peripheral B cell numbers, beginning at the transitional 1 developmental stage and continuing through the mature peripheral B cell stage. Bcl-x(L) overexpression in A/WySnJ B cells decreased the turnover of transitional B cells, as determined by 5-bromo-2'-deoxyuridine labeling, and restored follicular B cell development. We conclude that the mutant A/WySnJ allele of Tnfrsf13c can be complemented through the survival signal provided by Bcl-x(L).

The discoveries that activated macrophages produce 1alpha25-dihydroxyvitamin D3 (1alpha,25-(OH)2D3), and that immune system cells express the vitamin D receptor (VDR), suggested that the vitamin D endocrine system influences immune system function. In this review, we compare and contrast how 1alpha,25-(OH)2D3 synthesis and degradation is regulated in kidney cells and activated macrophages, summarize data on hormone receptor function and expression in lymphocytes and myeloid lineage cells, and discuss how locally-produced 1alpha,25-(OH)2D3 may activate a negative feed-back loop at sites of inflammation. Studies of immunity in humans and animals lacking VDR function, or lacking vitamin D, are viewed to gain insight into the immunological functions of the vitamin D endocrine system. The strong associations between poor vitamin D nutrition, particular VDR alleles, and susceptibility to chronic mycobacterial infections, together with evidence that 1alpha,25-(OH)2D3 served as a vaccine adjuvant enhancing antibody-mediated immunity, suggest a model wherein high levels of 1alpha,25-(OH)2D3-liganded VDR transcriptional activity may promote the CD4+ T helper 2 (Th2) cell-mediated and mucosal antibody responses to cutaneous antigens in vivo. We also review a diverse and rapidly growing body of epidemiological, climatological, genetic, nutritional and biological evidence indicating that the vitamin D endocrine system functions in the establishment and/or maintenance of immunological self tolerance. Studies done in animal models of multiple sclerosis (MS), insulin-dependent diabetes mellitus (IDDM), inflammatory bowel disease (IBD), and transplantation support a model wherein the 1alpha,25-(OH)2D3 may augment the function of suppressor T cells that maintain self tolerance to organ-specific self antigens. The recent progress in infectious disease, autoimmunity and transplantation has stimulated a gratifying renaissance of interest in the vitamin D endocrine system and its role in immunological health.