Defective Induction of IL-27-Mediated Immunoregulation by Myeloid DCs in Multiple Sclerosis.

The purpose of this study was to examine whether myeloid dendritic cells (mDCs) from patients with multiple sclerosis (MS) and healthy controls (HCs) become similarly tolerogenic when exposed to IL-27 as this may represent a potential mechanism of autoimmune dysregulation. Our study focused on natural mDCs that were isolated from HCs and MS patient peripheral blood mononuclear cells (PBMCs). After a 24-h treatment with IL-27 ± lipopolysaccharide (LPS), the mDCs were either harvested to identify IL-27-regulated gene expression or co-cultured with naive T-cells to measure how the treated DC affected T-cell proliferation and cytokine secretion. mDCs isolated from HCs but not untreated MS patients became functionally tolerogenic after IL-27 treatment. Although IL-27 induced both HC and untreated MS mDCs to produce similar amounts of IL-10, the tolerogenic HC mDCs expressed PD-L2, IDO1, and SOCS1, while the non-tolerogenic untreated MS mDCs expressed IDO1 and IL-6R. Cytokine and RNA analyses identified two signature blocks: the first identified genes associated with mDC tolerizing responses to IL-27, while the second was associated with the presence of MS. In contrast to mDCs from untreated MS patients, mDCs from HCs and IFNb-treated MS patients became tolerogenic in response to IL-27. The genes differentially expressed in the different donor IL-27-treated mDCs may contain targets that regulate mDC tolerogenic responses.

Neuropathy and primary headaches affect different subgroups of inflammatory bowel disease patients.

BACKGROUND: Peripheral neuropathies (PN) and primary headaches (PH) are common comorbidities in inflammatory bowel disease (IBD) patients. We aimed to evaluate whether PN and PH affect the same subgroups of IBD patients. METHODS: Since 2004, we established a cohort study to evaluate neurological diseases in IBD patients. Over 2 years, all consecutive (N = 155) IBD patients (either Crohn's disease (CD) or ulcerative colitis (UC) were evaluated for the presence of PN and PH. PH were also evaluated in dyspeptic patients (N = 84) and IBD relatives (controls, N = 101). After neurological evaluation, symptomatic patients underwent skin wrinkling test to evaluate small fiber function and/or electromyography. RESULTS: Headaches and migraine were more prevalent in IBD than control patients: 52.3 and 34.2% vs. 40.6 and 20.8% (P < 0.05). Migraine was 2.6 times more common in CD patients than controls (CI = 1.34-5.129) and 8.6 times (13.3 times in the CD group) more common in men with IBD (P < 0.05). Headache and migraine were also more common in dyspeptic patients (P < 0.05). Chi-square, univariate, and multivariate regression analysis did not disclose any association between PN, headache, or PH (P > 0.05). Multivariate regression analysis disclosed that headaches were more prevalent in women, co-existing psychiatric disease, IBD, CD, and UC. After age, gender distribution, and prevalence of hypertension and psychiatric diseases were matched among the groups, there were still differences in the prevalence of headaches and migraine among IBD, CD, and UC versus control patients. CONCLUSION: In summary, PH and PN are common in IBD and do not affect the same subgroups of patients.

c.9253-6T>c REV3L: A novel marker of poor prognosis in Myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by dysplasias, ineffective hematopoiesis and risk of acute myeloid leukemia transformation. Approximately 90% of MDS patients present mutations in genes involved in various cell signaling pathways. Specialized DNA polymerases, such as POLN, POLI, POLK, POLQ, POLH, POLL and REV3L, insert a nucleotide opposite replication-blocking DNA lesions in an error-prone manner and, in this way, sometimes can actively promote the generation of mutation. For the best of our knowledge, has not been described the mutations of these genes in MDS. DNA target sequencing CDS regions of the REV3L gene was performed in a 58-year-old man diagnosed as High Risk Myelodysplastic Syndrome. The patient presented very low hemoglobin, increased number of blasts, karyotype:47,XY,+8[6]/47,XY,del(7)(q32),+8[7], no response to hypomethylating therapy (decitabine), all markers of poor prognosis. Target sequencing identified a mutation c.9253-6T>C REV3L (Substitution - intronic) with VAF (variant allele frequency)=16% considered pathogenic according to Functional Analysis through. Hidden Markov Models (FATHMM). This is the first evidence of REV3L mutation in MDS and, of utmost importance, associated with poor prognosis.

Epilepsy surgery in Panama: Establishment of a successful hybrid program as a model for small middle-income countries.

OBJECTIVE: The majority of the 65 million people worldwide with epilepsy live in low- and middle-income countries. Many of these countries have inadequate resources to serve the large patient population affected by epilepsy. Panama is a middle-income country that currently has only 2 facilities that can provide basic epilepsy services and no epilepsy surgery services. To address this need, a group of Panamanian physicians partnered with U.S. epilepsy health care providers to test a hybrid epilepsy surgery program, combining resources and expertise. METHODS: From 2011 to 2017, a multidisciplinary team of neurologists, neurosurgeons, and an electroencephalography (EEG) technician from the United States traveled to Panama 6 times and, in collaboration with the local team, performed surgical procedures for intractable epilepsy at the national children's hospital. Resective surgeries were performed with intraoperative electrocorticography and/or implantation of subdural and depth electrodes and extra-operative monitoring. Cost was calculated using Panama government data. RESULTS: Twenty-seven children with intractable epilepsy were surgically treated. Fifteen children are seizure-free (Engle class I), 11 children are Engel II, and one child is Engel III. No major morbidity or mortality occurred, with only one postoperative infection. The average cost of treatment was calculated at $9850 per patient. SIGNIFICANCE: This program is a model for creating a multinational and multi-institutional collaboration to provide surgical epilepsy treatment in a middle-income country without an adequate infrastructure. To be successful, this collaboration needed to address medical, technical, and cultural challenges. This partnership helps to alleviate some of the present need for surgical epilepsy services while laying the groundwork for the development of a future local independent epilepsy surgery program.

National Trends (2009-2013) for Palliative Care Utilization for Patients Receiving Prolonged Mechanical Ventilation.

OBJECTIVES: Patients requiring mechanical ventilation have high morbidity and mortality. Providing palliative care services has been suggested as a way to improve comprehensive management of critically ill patients. We examined the trend in the utilization of palliative care among adults who require prolonged mechanical ventilation. Primary objectives were to determine the trend in palliative care utilization over time, predictors for palliative care utilization, and palliative care impact on hospital length of stay. DESIGN: Retrospective, cross-sectional study. SETTING: The National Inpatient Sample data between 2009 and 2013 was used for this study. PATIENTS: Adults (age ≥ 18 yr) who underwent prolonged mechanical ventilation (≥ 96 consecutive hr) were studied. MEASUREMENTS AND MAIN RESULTS: Palliative care and mechanical ventilation were identified using the corresponding International Classification of Diseases, 9th revision, Clinical Modification, codes. A total of 1,751,870 hospitalizations with prolonged mechanical ventilation were identified between 2009 and 2013. The utilization of palliative care increased yearly from 6.5% in 2009 to 13.1% in 2013 (p < 0.001). Among the mechanically ventilated patients who died, palliative care increased from 15.9% in 2009 to 33.3% in 2013 (p < 0.001). Median hospital length of stay for patients with and without palliative care was 13 and 17 days, respectively (p < 0.001). Patients discharged to either short- or long-term care facilities had a shorter length of stay if palliative care was provided (15 vs 19 d; p < 0.001). The factors associated with a higher palliative care utilization included older age, malignancy, larger hospitals in urban areas, and teaching hospitals. Non-Caucasian race was associated with lower palliative care utilization. CONCLUSIONS: Among patients who undergo prolonged mechanical ventilation, palliative care utilization is increasing, particularly in patients who die during hospitalization. Using palliative care for mechanically ventilated patients who are discharged to either short- or long-term care facilities is associated with a shorter hospital length of stay.

DNA repair gene expressions are related to bone marrow cellularity in myelodysplastic syndrome.

OBJECTIVE: To evaluate the expression of genes related to nuclear excision (ERCC8, XPA and XPC), homologous recombination and non-homologous end-joining (ATM, BRCA1, BRCA2 and LIG4) repair mechanisms, using quantitative PCR methodologies, and it relation with bone marrow cellularity in myelodysplastic syndrome (MDS). METHODS AND RESULTS: A total of 51 adult de novo patients with MDS (3 refractory anaemia (RA), 11 refractory anaemia with ringed sideroblasts (RARS), 28 refractory cytopenia with multilineage dysplasia (RCMD), 3 refractory anaemia with excess blasts type I (RAEB-I), 5 refractory anaemia with excess blasts type II (RAEB-II), and 1 chronic myelomonocytic leukaemia (CMML) were evaluated. For karyotype, 16.2% patients were defined as very low prognosis, 59.5% low risk, 8.1% intermediate risk, 5.4% high risk and 10.8% very high risk. For bone marrow cellularity, 17.6%, 17.6% and 64.7% presented as hypocellular, normocellular and hypercellular, respectively. Patients with hypocellular MDS had significantly decreased expression of ATM (p=0.000), BRCA1 (p=0.014), BRCA2 (p=0.003), LIG4 (p=0.004) and ERCC8 (p=0.000) than those with normocellular/hypercellular bone marrow, whereas XPA (p=0.049) and XPC (p=0.000) genes were increased. In patients with hypoplastic MDS, a low expression of ATM (p=0.0268), LIG4 (p=0.0199) and ERCC8 (p=0.0493) was significantly associated with the presence of chromosomal abnormalities. We detected positive correlations between BRCA1 and BRCA2 (r=0.416; p=0.007), ATM and LIG4 (r=0.472; p=0.001), LIG4 and BRCA1 (r=0.333; p=0.026), LIG4 and BRCA2 (r=0.334; p=0.025), ATM and XPA (r=0.377; p=0.008), ATM and XPC (r=0.287; p=0.046), LIG4 and XPC (r=0.371; p=0.007) and XPA and XPC genes (r=0.895; p=0.0000). We also found among all patients evaluated that correlation with LIG4 occurred most often. CONCLUSIONS: These correlations demonstrate the important intrinsic relations between single and double DNA strand breaks genes in MDS, emphasising that these genes are related to MDS pathogenesis.

Effect of Puerperal Infections on Early Neonatal Mortality: A Secondary Analysis of Six Demographic and Health Surveys.

BACKGROUND: Around 1.5 million annual neonatal deaths occur in the first week of life, and infections represent one of the major causes in developing countries. Neonatal sepsis is often strictly connected to infection of the maternal genital tract during labour. METHODS: The association between signs suggestive of puerperal infection and early neonatal mortality (<7 days of life) was performed using Demographic and Health Surveys (DHS) data of six countries, conducted between 2010 and 2013. The population attributable fraction (PAF) was generated using the estimates on early neonatal mortality of a 1990-2013 systematic analysis for the Global Burden of Disease Study. RESULTS: Signs of puerperal infection ranged from 0.7% in the Philippines to 16.4% in Honduras. Infection was associated with a 2.1 adjusted Risk Ratio (95% CI: 1.4-3.2) of early neonatal mortality. Around five percent of all deaths in the first week of life were attributable to signs suggestive of puerperal infections and varied from 13.9% (95% CI: 1.0-26.6) in Honduras to 3.6% (95% CI: 1.0-8.5) in Indonesia. CONCLUSIONS: Targeted interventions should be addressed to contain the burden of puerperal infections on early neonatal mortality. Consideration of the PAF will help in the discussion of the benefits of antenatal and perinatal measures.

Cryptic diversity in Black rats Rattus rattus of the Galápagos Islands, Ecuador.

Human activity has facilitated the introduction of a number of alien mammal species to the Galápagos Archipelago. Understanding the phylogeographic history and population genetics of invasive species on the Archipelago is an important step in predicting future spread and designing effective management strategies. In this study, we describe the invasion pathway of Rattus rattus across the Galápagos using microsatellite data, coupled with historical knowledge. Microsatellite genotypes were generated for 581 R. rattus sampled from 15 islands in the archipelago. The genetic data suggest that there are at least three genetic lineages of R. rattus present on the Galápagos Islands. The spatial distributions of these lineages correspond to the main centers of human settlement in the archipelago. There was limited admixture among these three lineages, and these finding coupled with low rates of gene flow among island populations suggests that interisland movement of R. rattus is rare. The low migration among islands recorded for the species will have a positive impact on future eradication efforts.

Metabolic Correction in Patients Sample with Diabetes: Clinical Outcomes and Costs Reductions.

Diabetes is a leading cause of mortality and morbidity worldwide. Diabetes complications produce profound impact on patient's quality of life and represent very significant economic cost to patients, their family, the government and society as a whole. Metabolic correction has been proposed as an efficient method to improve clinical outcomes and reduce costs in diabetes. Metabolic correction is a concept that supports health maintenance and promotes the healing processes by improving the body's biochemical-physiological mechanisms. This is done by helping activate the metabolic enzymes necessary to facilitate key physiological pathways. A group of 50 patients followed a simple metabolic correction strategy based on hydration, diet, and magnesium supplementation during a 6 months period. Outcomes measures included laboratory testing, anthropometric measures and medication use including its related costs. Patients had an average weight loss of 9.4 lbs (↓5.0%) from baseline at month 3 and 12 lbs (↓6.4%) at month 6. Waist circumference decreased on average 3.7 inches (↓9.0%) from baseline at month 3 and had further decrease to 5.5 inches (↓13.4%) from baseline at month 6. Laboratory testing of average triglycerides decreased from a baseline of 156.9 to 116.7 (↓25.6%) at month 3 and maintained a reduction of ↓24.2% by month 6. Total cholesterol concentration decreased from a baseline of 181.1 mg/dL to 173.9 (↓4.0%) in month 3 and to 171.1 (↓5.5%) at month 6. Average HgA1c decreased from baseline of 7.17 to 6.52 (↓9.1%) at month 3 and maintained 6.52 at months 6. The atherogenic index decreased from 4.18 at baseline to 3.85 at month 3 (↓7.9%) and then 3.47 (17.0%) at month 6. Medication use and cost was quantified in various ways. The average baseline monthly diabetes medication cost per patient of $124.10 was reduced to $ 78.23 (↓36.7% reduction) at month 3 and to $62.80 (↓49.4% reduction) at month 6. A simple and well structured metabolic correction program that includes a significant educational component, dietary modifications and dietary supplement intake was able to maintain or improve vital signs, anthopometric and laboratory measurements that correlate with improved clinical diabetes and cardiovascular health. This outcome was achieved while decreasing the use medications at month 3 and 6 at significant cost savings.

23 y/o female with dysphagia--Evaluation, intervention and resolution of symptoms in the Psychiatry consultation setting.

Dysphagia is a symptom shared by many medical and psychiatric conditions. A thorough Psychiatric evaluation could rule in a functional or psychological etiology. If a Psychological etiology is identified, a psychodynamic formulation could help the consultation psychiatrist clarify the origin of the symptom and provide a better explanation to the patient and medical team, resulting in improved care by prevention of unnecessary medical interventions, improvement of symptoms and individualization of the treatment.

Pharmacogenomic assessment of Mexican and Peruvian populations.

BACKGROUND: Clinically relevant polymorphisms often demonstrate population-specific allele frequencies. Central and South America remain largely uncategorized in the context of pharmacogenomics. MATERIALS & METHODS: We assessed 15 polymorphisms from 12 genes (ABCB1 3435C>T, ABCG2 Q141K, CYP1B1*3, CYP2C19*2, CYP3A4*1B, CYP3A5*3C, ERCC1 N118N, ERCC2 K751Q, GSTP1 I105V, TPMT 238G>C, TPMT 460G>A, TPMT 719A>G, TYMS TSER, UGT1A1*28 and UGT1A1 -3156G>A) in 81 Peruvian and 95 Mexican individuals. RESULTS: Six polymorphism frequencies differed significantly between the two populations: ABCB1 3435C>T, CYP1B1*3, GSTP1 I105V, TPMT 460G>A, UGT1A1*28 and UGT1A1 -3156G>A. The pattern of observed allele frequencies for all polymorphisms could not be accurately estimated from any single previously studied population. CONCLUSION: This highlights the need to expand the scope of geographic data for use in pharmacogenomics studies.

Exploring the distribution of genetic markers of pharmacogenomics relevance in Brazilian and Mexican populations.

Studies of pharmacogenomics-related traits are increasingly being performed to identify loci that affect either drug response or susceptibility to adverse drug reactions. However, the effect of the polymorphisms can differ in magnitude or be absent depending on the population being assessed. We used the Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array to characterize the distribution of polymorphisms of pharmacogenetics and pharmacogenomics (PGx) relevance in two samples from the most populous Latin American countries, Brazil and Mexico. The sample from Brazil included 268 individuals from the southeastern state of Rio de Janeiro, and was stratified into census categories. The sample from Mexico comprised 45 Native American Zapotecas and 224 self-identified Mestizo individuals from 5 states located in geographically distant regions in Mexico. We evaluated the admixture proportions in the Brazilian and Mexican samples using a panel of Ancestry Informative Markers extracted from the DMET array, which was validated with genome-wide data. A substantial variation in ancestral proportions across census categories in Brazil, and geographic regions in Mexico was identified. We evaluated the extent of genetic differentiation (measured as FST values) of the genetic markers of the DMET Plus array between the relevant parental populations. Although the average levels of genetic differentiation are low, there is a long tail of markers showing large frequency differences, including markers located in genes belonging to the Cytochrome P450, Solute Carrier (SLC) and UDP-glucuronyltransferase (UGT) families as well as other genes of PGx relevance such as ABCC8, ADH1A, CHST3, PON1, PPARD, PPARG, and VKORC1. We show how differences in admixture history may have an important impact in the distribution of allele and genotype frequencies at the population level.

RBC transfusion in pediatric patients supported with extracorporeal membrane oxygenation: is there an impact on tissue oxygenation?

OBJECTIVE: To examine first the RBC transfusion practice in pediatric patients supported with extracorporeal membrane oxygenation and second the relationship between transfusion of RBCs and changes in mixed venous saturation (SvO2) and cerebral regional tissue oxygenation, as measured by near-infrared spectroscopy in patients supported with extracorporeal membrane oxygenation. DESIGN: Retrospective observational study. SETTING: Pediatric, cardiovascular, and neonatal ICUs of a tertiary care children's hospital. PATIENTS: All pediatric patients supported with extracorporeal membrane oxygenation between January 1, 2010, and December 31, 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 45 patients supported with extracorporeal membrane oxygenation. The median (interquartile range) phlebotomy during extracorporeal membrane oxygenation was 75 mL/kg (33, 149 mL/kg). A total of 617 transfusions were administered (median, 9 per patient; range = 1-57). RBC volumes transfused during extracorporeal membrane oxygenation support were 254 mL/kg (136, 557) and 267 mL/kg (187, 393; p = 0.82) for cardiac and noncardiac patients, respectively. Subtracting the volume of RBCs used for extracorporeal membrane oxygenation circuit priming, median RBC transfusion volumes were 131 and 80 mL/kg for cardiac and noncardiac patients, respectively (p = 0.26). The cardiac surgical patients received the most RBCs (529 vs 74 mL/kg for nonsurgical cardiac patients). The median hematocrit maintained during extracorporeal membrane oxygenation support was 37%, with no difference between cardiac and noncardiac patients. Patients supported with extracorporeal membrane oxygenation were exposed to a median of 10.9 (range, 3-43) individual donor RBC units. Most transfusions resulted in no significant change in either SvO2 or cerebral near-infrared spectroscopy. Only 5% of transfusions administered (31/617) resulted in an increase in SvO2 of more than 5%, whereas an increase in cerebral near-infrared spectroscopy of more than 5 was only observed in 9% of transfusions (53/617). Most transfusions (73%) were administered at a time when the pretransfusion SvO2 was more than 70%. CONCLUSIONS: Patients supported with extracorporeal membrane oxygenation were exposed to large RBC transfusion volumes for treatment of mild anemia resulting from blood loss, particularly phlebotomy. In the majority of events, RBC transfusion did not significantly alter global tissue oxygenation, as assessed by changes in SvO2 and cerebral near-infrared spectroscopy. Most transfusions were administered at a time at which the patient did not appear to be oxygen delivery dependent according to global measures of tissue oxygenation.

Marine and inland fishes of St. Croix, U. S. Virgin Islands: an annotated checklist.

An historical account is given for the ichthyological research at St. Croix, U. S. Virgin Islands, followed by an annotated list of 544 species of mostly marine shore fishes known or reported from the island to depths of 200 m. Color photographs are included for 103 of these species. Collections made at Buck Island Reef National Monument with the ichthyocide rotenone in 2001 and 2005 increased the known ichthyofauna by about 80 species. The rational for inclusion of each species in the checklist is given, with remarks for those species for which additional documentation or voucher specimens are needed. Reports of species known or presumed to have been based on misidentifications are discussed. Of the total marine fish fauna of the island, 404 species (75%) are restricted to the western Atlantic Ocean, (223 of these species are essentially Caribbean endemics that do not occur south of the Amazon River outflow), and no St. Croix endemic species are known. An additional 17 species (3.2%) also occur at mid-Atlantic islands, 57 species (10.6 %) are limited to both sides of the Atlantic Ocean, and 40 species (7.4%) have circumtropical distributions. The four most species-rich families are the Gobiidae (47 species), Serranidae (groupers and sea basses, 41), Labridae (wrasses and parrotfishes, 31), and Labrisomidae (scaly blennies, 27). Literature reports of Mosquitofish, Gambusia sp., from St. Croix apparently were based on misidentifications of a different introduced poeciliid genus. Four species of the amphidromus goby genus Sicydium occur in St. Croix inland waters, together with three established introduced species (one cichlid and two poeciliids). Also included are one catfish (Ictaluridae) and three sunfishes (Centrarchidae) known only from ponds. The Lionfish, Pterois volitans, the only introduced marine species, was first reported from St. Croix in 2008 and is now common despite control efforts.

Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk.

BACKGROUND: The Selenium and Vitamin E Cancer Prevention Trial found no effect of selenium supplementation on prostate cancer (PCa) risk but a 17% increased risk from vitamin E supplementation. This case-cohort study investigates effects of selenium and vitamin E supplementation conditional upon baseline selenium status. METHODS: There were 1739 total and 489 high-grade (Gleason 7-10) PCa cases and 3117 men in the randomly selected cohort. Proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for effects of supplementation within quintiles of baseline toenail selenium. Cox proportional hazards models were used to estimate hazard ratios, and all statistical tests are two-sided. RESULTS: Toenail selenium, in the absence of supplementation, was not associated with PCa risk. Selenium supplementation (combined selenium only and selenium + vitamin E arms) had no effect among men with low selenium status (<60th percentile of toenail selenium) but increased the risk of high-grade PCa among men with higher selenium status by 91% (P = .007). Vitamin E supplementation (alone) had no effect among men with high selenium status (≥40th percentile of toenail selenium) but increased the risks of total, low-grade, and high-grade PCa among men with lower selenium status (63%, P = .02; 46%, P = .09; 111%, P = .008, respectively). CONCLUSIONS: Selenium supplementation did not benefit men with low selenium status but increased the risk of high-grade PCa among men with high selenium status. Vitamin E increased the risk of PCa among men with low selenium status. Men should avoid selenium or vitamin E supplementation at doses that exceed recommended dietary intakes.

Hsp65-producing Lactococcus lactis prevents experimental autoimmune encephalomyelitis in mice by inducing CD4+LAP+ regulatory T cells.

Heat shock proteins (Hsps) participate in the cellular response to stress and they are hiperexpressed in inflammatory conditions. They are also known to play a major role in immune modulation, controlling, for instance, autoimmune responses. In this study, we showed that oral administration of a recombinant Lactococcus lactis strain that produces and releases LPS-free Hsp65 prevented the development of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. This was confirmed by the reduced inflammatory cell infiltrate and absence of injury signs in the spinal cord. The effect was associated with reduced IL-17 and increased IL-10 production in mesenteric lymph node and spleen cell cultures. Hsp65-producing-L. lactis-fed mice had a remarkable increase in the number of natural and inducible CD4+Foxp3+ regulatory T (Treg) cells and CD4+LAP+ (Latency-associated peptide) Tregs - which express the membrane-bound TGF-ß - in spleen, inguinal and mesenteric lymph nodes as well as in spinal cord. Moreover, many Tregs co-expressed Foxp3 and LAP. In vivo depletion of LAP+ cells abrogated the effect of Hsp65-producing L. lactis in EAE prevention and worsened disease in medium-fed mice. Thus, Hsp65-L.lactis seems to boost this critical regulatory circuit involved in controlling EAE development in mice.

Aging correlates with reduction in regulatory-type cytokines and T cells in the gut mucosa.

Aging is reported to be associated with decline in oral tolerance induction, which is initiated at the intestinal mucosal surface. Herein, we examined the effect of aging in T cells and cytokines at the intestinal mucosa that might be involved in oral tolerance induction. Frequencies of regulatory-type IEL subsets such as TCRγδ(+) and TCRαß(+)CD8αα(+) were lower in aged mice. Mucosal CD4(+)CD25(+)Foxp3(+) and CD4(+)LAP(+) T cells increased with aging but activated CD44(+)CD4(+) mucosal T cells also augmented. Production of TGF-ß and IL-10 in the small intestine of old mice was reduced. Moreover, the ability of mucosal dendritic cells of aged mice to stimulate TGF-ß secretion and differentiation of CD4(+)LAP(+) T cells in co-culture studies also declined with aging. Reduction in these regulatory-type cytokines and T cells may help to explain the decline in susceptibility to oral induction during aging. However, not all mucosal regulatory elements were altered by aging and CD4(+)CD25(+)Foxp3(+) T cells were especially resistant to changes. Persistence of some mechanisms of regulation may play a critical role in maintaining mucosal homeostasis during aging.

Oral tolerance reduces Th17 cells as well as the overall inflammation in the central nervous system of EAE mice.

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory immune response directed against myelin antigens of the central nervous system. In its murine model, EAE, Th17 cells play an important role in disease pathogenesis. These cells can induce blood-brain barrier disruption and CNS immune cells activation, due to the capacity to secrete high levels of IL-17 and IL-22 in an IL-6+TGF-ß dependent manner. Thus, using the oral tolerance model, by which 200 µg of MOG 35-55 is given orally to C57BL/6 mice prior to immunization, we showed that the percentage of Th17 cells as well as IL-17 secretion is reduced both in the periphery and also in the CNS of orally tolerated animals. Altogether, our data corroborates with the pathogenic role of IL-17 and IFN-γ in EAE, as its reduction after oral tolerance, leads to an overall reduction of pro-inflammatory cytokines, such as IL-1α, IL-6, IL-9, IL-12p70 and the chemokines MIP-1ß, RANTES, Eotaxin and KC in the CNS. It is noteworthy that this was associated to an increase in IL-10 levels. Thus, our data clearly show that disease suppression after oral tolerance induction, correlates with reduction in target organ inflammation, that may be caused by a reduced Th1/Th17 response.