E1 ΔBR mutants were grown in media amended with 25 μg mL−1 kanamycin. Dietzia sp. E1 cells were cultivated in 100-mL Erlenmeyer flasks containing 50 mL of MNPS minimal medium [0.1 M sodium-phosphate

buffer, 5 g L−1 (NH4)2SO4, 5 g L−1 KCl, 0.2 g L−1 MgSO4·7H2O, 0.05 g L−1 CaCl2·2H2O, 10 mL L−1 trace element solution SL-4 (http://www.dsmz.de/microorganisms/media_list.php, see Medium 14 and 27), pH 8.0] supplemented with 1 g L−1 of different individual n-alkanes or 2.9 g L−1 sodium acetate. Solid n-alkanes were weighed in Erlenmeyer flasks before autoclaving, while presterilized liquid n-alkanes were pipetted in the inoculated selleck chemicals media. For the inoculation, overnight GPY-grown E1 starter cultures were applied. The centrifuged (16 000g, 5 min) cells were resuspended in MNPS minimal broth and were diluted to a starting cell number of 106 mL−1. Flasks were incubated at 37 °C at 200 r.p.m. for 16–60 h. Microbial growth was monitored via the increases in OD600 nm and microscopically counted total cell number. All measurements were performed in triplicate. Plasmid DNA was isolated with the EZ-10 Spin Column Plasmid DNA MiniPreps Kit (Bio Basic Inc.). Chromosomal DNA from Dietzia Selleck 17-AAG spp. was prepared as described previously (Szvetnik et al., 2010). Southern blot analysis was performed on genomic DNA digested with various restriction enzymes (BamHI, NotI, PstI, SalI

and SacI), using a 518-bp SacI/PstI Dietzia sp. E1 alkB fragment probe (Bihari et al., 2010). Nonradioactive DNA probe labelling, Southern hybridization and detection

were performed according to the manufacturer’s instructions (DIG DNA Labeling and Detection Kit, Roche). Plasmid pKAlkB518 was constructed by cloning the 518-bp SacI/PstI alkB fragment into pK18 (Pridmore, 1987). The construct was maintained in E. coli DH5α and introduced into competent Dietzia sp. E1 cells by electroporation (Szvetnik et al., 2010). Integration of the plasmid resulted in a kanamycin-resistant disruption mutant designated Dietzia sp. E1 ΔBR. The genomic DNA of this mutant strain was purified, digested with Tangeritin NotI or MunI and self-ligated. After propagation in DH5α, the two rescue plasmids obtained were sequenced partially by a combination of subcloning and walking primers. On the basis of the sequence data, outer alkBPromF and rubCFLAG oligonucleotides priming to the 5′ and 3′ flanking regions of the 518-bp alkB fragment were designed (Table 1). PCR reactions were carried out using these primers on the genomic DNA template of the ΔBR mutant and also that of each wild-type Dietzia strain. For this purpose, KOD Hot Start DNA Polymerase (Novagen) was applied according to the manufacturer’s instructions, except that long initial denaturation was performed and 10% dimethyl sulphoxide was present in all reactions. For PCRs, the following program was used: 10 min at 95 °C; 35 cycles of 0.5 min at 95 °C, 0.5 min at 55 °C and 2.5 min at 70 °C; and 5 min at 70 °C.

9 μg L−1 for hexadecane (C16) and is equivalent to 0.03–0.009 p.p.m. The very low water solubility of these compounds selleck products would have made their utilization

by the 12 field isolates difficult. However, although not at high levels, growth was observed through changes in the OD600 nm measurements. Some microbial organisms, such as some Pseudomonas, Acinetobacter, and Rhodococcus species, produce biosurfactants, which effectively make the hydrocarbons more available for microbial utilization (Beal & Betts, 2000; Chang et al., 2009; Henry & Abazinge, 2009). Pseudomonas and Rhodococcus species, in particular, are well known for their production of biosurfactants. In the current study, both achieved relatively high growth on all of the alkane substrates, and principally the mid-chain length alkanes. In summary, results suggest that members of the same community showed preference for specific carbon sources shown through their ability to utilize various diesel constituents, potentially leading to a cooperative hypothesis within the community. Some are likely to be competitive in a broader range of scenarios, while others may be more suited to specific conditions and habitats. The site isolates could be categorized into two classes of microorganisms,

which Selleckchem Alectinib have previously been identified in terms of their survival strategy: the K-strategists and the r-strategists (Winogradsky, 1924; Kuznetsov et al., 1979; Andrews & Harris, 1985). The r-strategists exist mostly in a resting phase demonstrating brief periods of activity stimulated by the appearance Gemcitabine ic50 of an available substrate. Examples in the present study could be R. erythropolis, Pseudomonas sp. 1, and A. xylosoxidans 1. In contrast, the K-strategists are continually

and slowly active: for example Pseudomonas sp. 2 and 3, and Psychrobacter sp. 3. It was observed that, in general, organisms that were particularly good at degrading diesel were likely to fall into the r-strategists. Previous studies of communities utilizing a mixed hydrocarbon source have observed either antagonism and competition between the organisms or cometabolism (Bouchez et al., 1999; Mariano et al., 2008). The investigation demonstrated that high community diversity may allow for the coexistence of both K- and r-strategists and the compartmentalization of functions among key organisms resulting in the utilization of the whole spectrum of diesel fuel components. This work was supported by the Natural Environment Research Council and Napier University, Edinburgh. We would like to thank CORUS UK for the GC-MS analysis of the site diesel fuel and ERS Ltd (http://www.ersremediation.com/index.php) for access to the study site.

A more complex analysis of the virological response to HIV treatment is used by the US Food and Drug Administration (FDA) for clinical trials

comparing the outcomes of two different treatment regimens [6]. There has, however, been little discussion in the literature about how best to measure virological response as a quality indicator, because the main use to date for this variable has been to compare the efficacies of different antiretroviral regimens. If an outcome Selleck Enzalutamide indicator is to be useful for a measure of quality in clinical practice, it should fulfil a number of requirements in addition to correlating well with the patients’ future prognosis [4]. These characteristics include the ease and feasibility of collection and the degree to which the outcomes are predicted by differences in the provider characteristics rather than differences among individual patients. Our aim in this study was to describe the HIV virological response for a single health service using three different definitions of treatment failure and to discuss their relationship

to the requirements of a quality outcome measure. We included three measures of virological response, including the definition recommended by the US FDA, called IDH inhibitor the ‘time to loss of virologic response’ (TLOVR) algorithm [6]. The clinical data for this study were obtained for HIV-infected patients attending the Melbourne Sexual Health Centre between January 2000 and December 2008. During this period, 310 HIV-positive patients commenced antiretroviral Metalloexopeptidase treatment for the first time (i.e. were antiretroviral naïve). The electronic medical record data, including laboratory measures and HIV treatment histories for each patient, were examined. Clinical files were reviewed to determine the reason for any change in HIV treatment. The outcomes of treatment were assessed using a number of different definitions of treatment failure. In the first analysis (definition 1), we used

the TLOVR algorithm, where an individual is deemed to have failed if a plasma HIV-1 RNA level <400 copies/mL was never achieved, or they had confirmed virological rebound from <400 copies/mL on two consecutive readings, or they had discontinued their first treatment regimen for any reason [6]. In the second analysis (definition 2), an individual was deemed to have failed if the plasma HIV-1 RNA was never below 400 copies/mL, or their viral load rebounded above 400 copies/mL (on two consecutive readings) while on any treatment. They were permitted to change treatment so long as their viral load remained below 400 copies/mL and were also permitted to stop treatment as long as their last viral load on treatment was below 400 copies/mL.

e., 48% Europe, 20% America, 15% Africa, 8.5% in Asia-Oceania,

and 6.6% in the Near and Middle East).7 The repatriation of French patients from foreign hospitals, but also health care provided to foreigners traveling in France, whatever their nationality, then expose the French population to highly resistant bacteria acquired in high resistance prevalent areas. The risk of the emergence and spread of highly resistant bacteria from migration has been recently evaluated in France because sporadic or limited epidemic situations have occurred in the recent past with pathogens such as Clostridium difficile ribotype 027,8,9 carbapenemase-producing Enterobacteriaceae (CPE),10–12 vancomycin-resistant Enterococcus (VRE),13,14 or multidrug-resistant Acinetobacter baumannii.15 French guidelines buy LY2109761 to control the hospital spread of CPE and VRE from patients repatriated and travelers hospitalized in French hospitals were published in August 2010.16 They are so far available in French only but an official translation into English is under consideration. This article reviews the highly resistant bacteria at risk of importation from high prevalence foreign countries, having only spread to France GSK126 clinical trial on sporadic or limited epidemic situations, and describes the recent French guidelines to control their

spread. The emergence of CPE since the early 1990s is alarming, and carries the risk for therapeutic failures.17 The carbapenems are now often used for the treatment of severe infections caused by Enterobacteriaceae producing extended-spectrum β-lactamases (ESBL). The large increase of ESBL prevalence and the exposure Interleukin-3 receptor of hospitalized population

to carbapenems appear to be a major factor favoring the emergence of carbapenem-resistant bacteria via selective pressure, particularly in Klebsiella pneumoniae species, also in other species such as Escherichia coli.18 Resistance is due to carbapenemases, of which there are three types: K pneumoniae carbapenemases (KPC), metallo-β-lactamases, and oxacillinases.19 The production of metallo-β-lactamases has mostly been associated with Pseudomonas aeruginosa and Acinetobacter spp. and is rare in Enterobacteriaceae, except in isolates from Mediterranean Europe.20 New Delhi metallo-β-lactamase (NDM) 1 was identified in K pneumoniae and E coli recovered from a Swedish patient who was admitted in a hospital in New Delhi, India.21 The first CPE strain described was a Klebsiella isolate recovered in North Carolina, United States in 1996, and the enzyme was called KPC-1.22 Subsequently, other KPC-type enzymes have been described throughout the United States (KPC-2 to KPC-7) by sporadic or epidemic spread.23 The first outbreak of KPC outside the United States was reported in Israel, from passengers and/or patients having traveled between the two countries.24 Since then, many continents, such as South America and Asia, have reported the emergence of CPE.

A31627) according to the manufacturer’s protocol. After washing three times with PBS, the immunostained coverslips were viewed using a Zeiss LSM 510 Meta

confocal microscope with a Plan Apochromat × 63/1.0 water-dipping objective lens. For the uptake experiment of recombinant SpHtp1 proteins, RTG-2 cells were washed three times with HBSS before a 20–30-min incubation with 20 μM recombinant SpHtp124-198(His)6 protein in L-15 medium containing 10% FCS. After washing cells three times with PBS, they were fixed as described above. Fixed cells were washed three times with PBS, permeabilized for 15 min with PBS containing 0.1% Triton-X 100 and washed again three times before incubation with the primary penta-His antibody at 37 °C for 1 h (Qiagen, No. 34660; titre 1 : 300). AZD2281 Subsequently, the samples were washed three times with PBS, and incubated Selleckchem Etoposide at 37 °C for 1 h with the secondary antibody [fluorescein

isothiocyanate (FITC) 488-conjugated goat-anti-mouse immunoglobulin G; Jackson ImmunoResearch] according to the manufacturer’s protocol. The immunostained coverslips were washed again three times with PBS and mounted onto microscope slides. Microscopy was carried out using a Zeiss LSM 510 META confocal microscope (Fluor 488/FITC: excitation is 488 nm, filter settings BP 505-530; detector gain 750. Iodide: excitation is 633 nm, filter settings LP 650; detector gain 540, all Casein kinase 1 1 μm slices). In order to identify and investigate genes of S. parasitica that are expressed in the preinfection and early infection

stages, we set up a cDNA library from RNA isolated from zoospores, cysts and germinated cysts of S. parasitica and generated ESTs. End-sequencing of the cloned cDNA library and subsequent preliminary bioinformatic analysis resulted in the identification of a putative secreted protein with an RxLR motif located within the first 40 aa after the predicted signal peptide cleavage site. The ORF, SpHtp1 (S. parasitica host targeting protein 1), encodes a putative protein, SpHtp1, of 198 aa, of which the first 23 aa encode a signal peptide (Fig. 1a). The RxLR motif is located 22 aa downstream of the predicted signal peptide cleavage site, which is comparable to all known and characterized oomycete RxLR effector proteins (Fig. 1b, Fig. S1). Genome sequencing confirmed that the ORF is present in the genome and revealed an intron of 55 nt long, ranging from 74 nt up to 129 nt. Also, the oomycete conserved sequence motif in the promoter region of SpHtp1 was identified 35 nt upstream of the start codon (Pieterse et al., 1994; McCleod et al., 2004) (Fig. S2). blastp analysis of SpHtp1 yielded sequence similarity only to regions of low complexity in other proteins such as the elicitin 6 precursor proteins of Phytophthora medicaginis, Phytophthora ramorum and Phytophthora sojae (E-values 9e-19, 2e-16, 3e-16 and 52%, 68% and 51% identity, respectively).

A31627) according to the manufacturer’s protocol. After washing three times with PBS, the immunostained coverslips were viewed using a Zeiss LSM 510 Meta

confocal microscope with a Plan Apochromat × 63/1.0 water-dipping objective lens. For the uptake experiment of recombinant SpHtp1 proteins, RTG-2 cells were washed three times with HBSS before a 20–30-min incubation with 20 μM recombinant SpHtp124-198(His)6 protein in L-15 medium containing 10% FCS. After washing cells three times with PBS, they were fixed as described above. Fixed cells were washed three times with PBS, permeabilized for 15 min with PBS containing 0.1% Triton-X 100 and washed again three times before incubation with the primary penta-His antibody at 37 °C for 1 h (Qiagen, No. 34660; titre 1 : 300). this website Subsequently, the samples were washed three times with PBS, and incubated IBET762 at 37 °C for 1 h with the secondary antibody [fluorescein

isothiocyanate (FITC) 488-conjugated goat-anti-mouse immunoglobulin G; Jackson ImmunoResearch] according to the manufacturer’s protocol. The immunostained coverslips were washed again three times with PBS and mounted onto microscope slides. Microscopy was carried out using a Zeiss LSM 510 META confocal microscope (Fluor 488/FITC: excitation is 488 nm, filter settings BP 505-530; detector gain 750. Iodide: excitation is 633 nm, filter settings LP 650; detector gain 540, all GBA3 1 μm slices). In order to identify and investigate genes of S. parasitica that are expressed in the preinfection and early infection

stages, we set up a cDNA library from RNA isolated from zoospores, cysts and germinated cysts of S. parasitica and generated ESTs. End-sequencing of the cloned cDNA library and subsequent preliminary bioinformatic analysis resulted in the identification of a putative secreted protein with an RxLR motif located within the first 40 aa after the predicted signal peptide cleavage site. The ORF, SpHtp1 (S. parasitica host targeting protein 1), encodes a putative protein, SpHtp1, of 198 aa, of which the first 23 aa encode a signal peptide (Fig. 1a). The RxLR motif is located 22 aa downstream of the predicted signal peptide cleavage site, which is comparable to all known and characterized oomycete RxLR effector proteins (Fig. 1b, Fig. S1). Genome sequencing confirmed that the ORF is present in the genome and revealed an intron of 55 nt long, ranging from 74 nt up to 129 nt. Also, the oomycete conserved sequence motif in the promoter region of SpHtp1 was identified 35 nt upstream of the start codon (Pieterse et al., 1994; McCleod et al., 2004) (Fig. S2). blastp analysis of SpHtp1 yielded sequence similarity only to regions of low complexity in other proteins such as the elicitin 6 precursor proteins of Phytophthora medicaginis, Phytophthora ramorum and Phytophthora sojae (E-values 9e-19, 2e-16, 3e-16 and 52%, 68% and 51% identity, respectively).

, 2002; Nakasone et al., 2007), which is the most abundantly secreted protein in both pathogens. The RPLA test is more sensitive (detection limit: 1 ng mL−1) than the IC test (detection limit: 4 ng mL−1), but requires overnight incubation. Although Dulbecco’s modified Eagle’s medium (DMEM) is commonly used to detect EspB from EPEC or STEC, we noticed

that some strains grew poorly and sometimes did not grow at all in the medium, even though they were shown to possess the eae gene by PCR. Therefore, using DMEM may GSK J4 research buy produce false-negative results due to small amounts of or no EspB being produced. To resolve this problem, a medium in which bacteria can grow and produce EspB is required. If a growth medium that enhances both bacterial growth and EspB production could be created, the sensitivity of the RPLA and/or the IC test for detecting EPEC and/or STEC might be increased. Although various media and/or culture conditions have been considered for the enhancement of the

proteins secreted by EPEC and STEC (Haigh et al., 1995; Kenny et al., 1997; Beltrametti et al., 1999; Yoh et al., 2003), a medium that works equally well for both pathogens has been identified. Considering the environmental conditions found in the human body, bacterial growth and the secretion of Esp proteins might be affected by bile acid or detergents. In this report, we considered a medium supplemented with various detergents and examined its beta-catenin inhibitor effects on EspB production. Our results suggested that the detergent-supplemented medium enhanced EspB production in the EPEC and STEC strains and that this new medium is a convenient tool for promoting the expression of EspB. E2348/69 (O127:H6) and EDL933 (O157:H7) were used as standard EPEC and STEC strains, respectively. The other strains used in this study were isolated

from patients with diarrhea in a variety of countries, as described previously (Lu et al., 2002). The strain of each isolate was determined using a standard biochemical test Palmatine and the PCR method described by Toma et al. (2003). The characteristics of the organisms used in this study are listed in Table 1. To elucidate the optimal concentrations of the detergents for EspB detection, each detergent was serially diluted from 1.5% (w/v) with Luria–Bertani (LB) broth and incubated with the reference strains at 37 °C for 15 h. After incubation, the OD at 600 nm was adjusted to 0.7 (c. 1 × 108 CFU mL−1) with LB broth. The culture was then centrifuged at 5000 g for 15 min, and the supernatant proteins were precipitated by the addition of trichloroacetic acid at 10%, as described by Yoh et al. (2003). The resultant pellet was resuspended in 50 μL of 1 M Tris-HCl buffer (pH 7.6), and EspB was detected using Western blotting, the RPLA test, or the enzyme-linked immunosorbent assay (ELISA). The RPLA test was carried out as described elsewhere (Lu et al., 2002).

Patients receiving 24 weeks of early cART more often reported tingling in the hands or feet (P = 0.02) and a numb feeling in the fingers or toes (P = 0.01) than patients receiving 60 weeks of early cART or no treatment. Patients receiving no treatment more often reported itchiness (P = 0.001) and skin changes (P = 0.04)

than patients receiving 24 or 60 weeks of early cART. At week 8, patients receiving 24 or 60 weeks of early cART more often reported nausea (P = 0.002), diarrhoea (P < 0.001), abdominal pain (P = 0.02), stomach pain (P = 0.049) and dizziness (P = 0.01) than patients receiving no treatment (Fig. 2). These differences had disappeared at week 24. No differences in patient characteristics and HRQL at baseline Anticancer Compound Library Rapamycin in vitro and during follow-up were seen between the randomized (n = 16) and nonrandomized (n = 12) untreated patients, except that the randomized patients were more often born in the Netherlands [15 of 16 (94%) versus seven of 12 (58%); P = 0.02]. When we repeated the mixed linear models including only the RCT patients, the significant differences in HRQL among the three groups

disappeared for cognitive functioning and mental health, although the trend remained similar. The differences in pain, physical functioning, role functioning and the PHS score remained significant. For these scales, patients receiving 60 weeks of early cART had a significantly better HRQL than patients ID-8 receiving 24 weeks of early cART. The differences seen in reported symptoms remained the same. The present study was set up as a substudy of the Primo-SHM RCT, which demonstrated a clinical benefit of 24 and 60 weeks of cART initiated during PHI [1]. This substudy provides the first data on the effects on HRQL of temporary treatment during PHI. Early cART did not have a negative impact on patients’ HRQL over a study period of 96 weeks as compared with no treatment. Overall, patients receiving 60 weeks of cART showed a better HRQL than patients in whom treatment was deferred. Although the patients on early cART initially suffered more from physical symptoms,

which were probably related to drug toxicity, this seemed to have minor effects on their HRQL perception. This is in agreement with a previous study in which persons with chronic HIV infection on cART made distinctions between symptoms caused by HIV itself and those caused by drug toxicity when evaluating HRQL. Disease-related symptoms, but not side effects, were related to perceptions of general health [14]. Regardless of cART intervention, social functioning, health distress, overall quality of life, energy/fatigue and the MHS score improved significantly during the 96 weeks of follow-up in all groups. This might be explained by initial psychological distress as a consequence of being diagnosed with PHI and its acceptance over time. In addition, the symptoms occurring during PHI will also diminish without early treatment over time.

GHSR KO mice, however, did not show these alterations despite having normal glucocorticoid responses to stress. In parallel with these changes, chronic unpredictable Panobinostat mouse stress caused changes in norepinephrine, dopamine and serotonin in a number of brain regions. Of these, norepinephrine neurotransmission in the arcuate nucleus and prefrontal cortex was differentially altered

in GHSR KO mice. Within the nucleus acumbens, dopamine utilization was increased in WT mice but not in GHSR KO mice. Finally, there were strain differences in serotonin neurotransmission that may explain interstrain body weight and adiposity differences. These results suggest that the metabolic changes necessary to deal with the energetic challenge presented by repeated exposure to stressors do not occur in GHSR KO mice, and they are discussed within the context of the potential vulnerability to

stress-induced pathology. “
“Department of Neurology & Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA Brain-derived neurotrophic factor (BDNF) plays a critical role in plasticity at glutamate synapses and in the effects of repeated cocaine exposure. We recently showed that intracranial injection of BDNF into the rat nucleus accumbens (NAc), a key region for cocaine addiction, rapidly increases α-amino-3-hyroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) surface expression. To further characterize DZNeP chemical structure BDNF’s role in both rapid AMPAR trafficking and slower, homeostatic changes in AMPAR surface expression, we investigated the effects of acute (30 min) and long-term (24 h) treatment with BDNF on AMPAR distribution in NAc medium spiny neurons from postnatal rats co-cultured with mouse prefrontal cortex neurons to restore excitatory inputs. Immunocytochemical

studies showed that acute BDNF treatment increased cell surface GluA1 and GluA2 levels, as well as their co-localization, on NAc neurons. This effect of BDNF, confirmed Phospholipase D1 using a protein crosslinking assay, was dependent on ERK but not AKT signaling. In contrast, long-term BDNF treatment decreased AMPAR surface expression on NAc neurons. Based on this latter result, we tested the hypothesis that BDNF plays a role in AMPAR ‘scaling down’ in response to a prolonged increase in neuronal activity produced by bicuculline (24 h). Supporting this hypothesis, decreasing BDNF signaling with the extracellular BDNF scavenger TrkB-Fc prevented the scaling down of GluA1 and GluA2 surface levels in NAc neurons normally produced by bicuculline. In conclusion, BDNF exerts bidirectional effects on NAc AMPAR surface expression, depending on duration of exposure. Furthermore, BDNF’s involvement in synaptic scaling in the NAc differs from its previously described role in the visual cortex.

One other nutrient that has generated heaps of literature, including many controversies in rheumatology is vitamin D. Emerging evidence and consensus regarding its function have established it as a popular and economic therapeutic agent prescribed by many physicians and rheumatologists for a spectrum of disorders, but not without criticism. Careful and critical appraisal of such confusing and contradicting literature is needed to reach any cautious conclusion. There are also differing views on the cut-off value of vitamin D to label insufficiency and deficiency, but most agree on a value that keeps parathhormone (PTH) levels in the normal range. Keeping

click here this in mind, 25(OH)D levels more than 30 ng/mL (75 nmol/L) is considered normal, levels between 20 and 30 ng/mL (50–75 nmol/L) is defined as insufficiency and level less than 20 ng/mL (50 nmol/L) is called deficiency.[1] Vitamin D insufficiency and deficiency are global phenomena and sun exposure alone may not be the sole determinant for this. In spite of good sun exposure, vitamin D deficiency is prevalent from sub-Saharan Africa to south Asia and affects half the population

in this region, similar to that in Western countries with temperate climates.[2, 3] The fascinating molecule of vitamin D belongs to the class of secosteroids. It is different from other steroids by unfolding of two of its four rings. Its role as an anti-inflammatory, immunomodulatory and antineoplastic agent, as well as its GSK-3 inhibitor review role in preventing cardiovascular Alanine-glyoxylate transaminase morbidity and mortality, are well known. It interacts with a large array of molecules, including vitamin D receptor (VDR), and much of it depends on vitamin D binding proteins. The role of VDR polymorphisms in the pathogenesis of autoimmune diseases has also been extensively studied.[4] As expected of a steroid, vitamin D’s anti-inflammatory actions are mediated by down regulation of dendritic cells, Th1 cells and B cells, many pro-inflammatory cytokines, and inhibition of micro-RNAs like MiRNA-155, and by inducing apoptosis.[5] Vitamin D is also capable of neutralizing interleukin (IL)-17A and IL-22 which are not achieved even by tumor necrosis factor (TNF) blockade; this action has far-reaching implications

in many systemic autoimmune diseases.[6] There are now studies showing enriched gene expression of vitamin D response elements (VDRE) in non-major histocompatibility loci associated with rheumatoid arthritis (RA) as well as modest association of variants of loci controlling vitamin D levels with RA.[7] These findings strongly support the theory that vitamin D plays an important role in the pathogenesis of RA. Prevalence of low vitamin D states in RA is reported from most populations,[8] including publications associating low vitamin D state with disease activity.[9, 10] Indeed, a recent meta-analysis of 215 757 participants proves these points beyond doubt.[11] Relatively fewer studies found no correlation between disease activity and low vitamin D state in RA.