Toward a better understanding of T cell dysregulation in autism: An integrative review.

Autism spectrum disorder (ASD) is a highly heterogeneous disorder characterized by impairments in social, communicative, and restrictive behaviors. Over the past 20 years, research has highlighted the role of the immune system in regulating neurodevelopment and behavior. In ASD, immune abnormalities are frequently observed, such as elevations in pro-inflammatory cytokines, alterations in immune cell frequencies, and dysregulated mechanisms of immune suppression. The adaptive immune system - the branch of the immune system conferring cellular immunity - may be involved in the etiology of ASD. Specifically, dysregulated T cell activity, characterized by altered cellular function and increased cytokine release, presence of inflammatory phenotypes and altered cellular signaling, has been consistently observed in several studies across multiple laboratories and geographic regions. Similarly, mechanisms regulating their activation are also disrupted. T cells at homeostasis coordinate the healthy development of the central nervous system (CNS) during early prenatal and postnatal development, and aid in CNS maintenance into adulthood. Thus, T cell dysregulation may play a role in neurodevelopment and the behavioral and cognitive manifestations observed in ASD. Outside of the CNS, aberrant T cell activity may also be responsible for the increased frequency of immune based conditions in the ASD population, such as allergies, gut inflammation and autoimmunity. In this review, we will discuss the current understanding of T cell biology in ASD and speculate on mechanisms behind their dysregulation. This review also evaluates how aberrant T cell biology affects gastrointestinal issues and behavior in the context of ASD.

Atypical Presentation of Gout: A Case Report.

Gout is the most common inflammatory arthritis which is caused by the buildup of uric acid crystals in the joints, that leads to severe pain, swelling, and stiffness. The condition typically affects the first metatarsophalangeal joint but it can impact other joints in the body. We present a case in which a 43-year-old male with a past medical history of obesity, hypertension, osteoarthritis, and gout presented with bilateral leg pain and the inability to walk for the last two years. Labs showed persistent leukocytosis, elevated ESR (erythrocyte sedimentation rate), normal uric acid levels, with physical exam findings of bilateral tender nodular leg lesions. Chest X-ray, head CT without contrast, left hip X-ray and ultrasound of left lower extremity were performed which were all negative. Biopsy of the tender skin nodules confirmed the diagnosis of tophaceous gout. Acute and prophylactic treatment of tophaceous gout resulted in resolved inflammation and leukocytosis without any complications.

Patient preferences in Italy: health state utilities associated with attributes of weekly injection devices for treatment of type 2 diabetes.

OBJECTIVES: Several glucagon-like peptide-1 receptor agonists are administered as weekly injections for treatment of type 2 diabetes (T2D). These medications vary in their injection processes, and a recent study in the UK found that these differences had an impact on patient preference and health state utilities. The purpose of this study was to replicate the UK study in Italy to examine preferences of an Italian patient sample, while allowing for comparison between utilities in the UK and Italy. MATERIALS AND METHODS: Participants with T2D in Italy valued health states in time trade-off interviews. All health states had the same description of T2D, but differed in description of the treatment process. As in the original UK study, the first health state described an oral treatment regimen, while additional health states added a weekly injection. The injection health states differed in three injection-related attributes: requirements for reconstituting the medication, waiting during medication preparation, and needle handling. RESULTS: Interviews were completed by 238 patients (58.8% male; mean age = 60.2 years; 118 from Milan, 120 from Rome). The oral treatment health state had a mean (SD) utility of 0.90 (0.10). The injection health states had significantly (p < 0.0001) lower utilities, which ranged from 0.87 (requirements for reconstitution, waiting, and handling) to 0.89 (weekly injection with none of these requirements). Differences in health state utility scores suggest that each administration requirement was associated with a disutility (ie, negative utility difference): -0.006 (reconstitution), -0.006 (needle handling), -0.011 (reconstitution, needle handling), and -0.022 (reconstitution, waiting, needle handling). CONCLUSION: Disutilities associated with the injection device characteristics were similar to those reported with the UK sample. Results suggest that injection device attributes may be important to some patients with T2D, and it may be useful for clinicians to consider these attributes when choosing medication for patients initiating these weekly treatments.

The rectal mucosa and condomless receptive anal intercourse in HIV-negative MSM: implications for HIV transmission and prevention.

Most HIV transmissions among men who have sex with men (MSM), the group that accounted for 67% of new US infections in 2014, occur via exposure to the rectal mucosa. However, it is unclear how the act of condomless receptive anal intercourse (CRAI) may alter the mucosal immune environment in HIV-negative MSM. Here, we performed a comprehensive characterization of the rectal mucosal immune environment for the phenotype and production of pro-inflammatory cytokines by CD4 and CD8 T cells, global transcriptomic analyses, and the composition of microbiota in HIV-negative MSM. Our results show that compared with men who had never engaged in anal intercourse, the rectal mucosa of MSM engaging in CRAI has a distinct phenotype characterized by higher levels of Th17 cells, greater CD8+ T cell proliferation and production of pro-inflammatory cytokines, molecular signatures associated with mucosal injury and repair likely mediated by innate immune cells, and a microbiota enriched for the Prevotellaceae family. These data provide a high-resolution model of the immunological, molecular, and microbiological perturbations induced by CRAI, will have direct utility in understanding rectal HIV transmission among MSM, and will enhance the design of future biomedical prevention interventions, including candidate HIV vaccines.

Insights on stock structure of round sardinella Sardinella aurita off north-west Africa based on otolith shape analysis.

This study examines the geographic variability in otolith shape of round sardinella Sardinella aurita as a tool for stock discrimination. Fish were analysed from six sampling locations from Senegal to the Mediterranean coast of Morocco. A combination of otolith shape indices and elliptic Fourier descriptors was investigated by multivariate statistical procedures. Within the studied area, three distinct groups were identified with an overall correct classification of 78%. Group A: Nador (Alboran Sea), group B: Casablanca (northern Morocco) and group C: Senegalese-Mauritanian. The results of this study confirm the absence of an Atlantic Ocean-Mediterranean Sea transition for this species, the Gibraltar Strait acting as an efficient barrier for S. aurita population separation. Off north-west Africa, fish from northern Morocco form a single group which is clearly isolated from Senegalese-Mauritanian waters, confirming the existence of a distinct stock in this area. Among group C, some discontinuity exists and suggests the existence of a sedentary fraction of S. aurita in northern Mauritania (Arguin Bank). The results are discussed in relation to oceanographic features and physical barriers to dispersal and fish management strategy in the study area.

Interactions of Phytophthora capsici with Resistant and Susceptible Pepper Roots and Stems.

Using host resistance is an important strategy for managing pepper root and crown rot caused by Phytophthora capsici. An isolate of P. capsici constitutively expressing a gene for green fluorescent protein was used to investigate pathogen interactions with roots, crowns, and stems of Phytophthora-susceptible bell pepper 'Red Knight', Phytophthora-resistant bell pepper 'Paladin', and Phytophthora-resistant landrace Criollos de Morelos 334 (CM-334). In this study, the same number of zoospores attached to and germinated on roots of all cultivars 30 and 120 min postinoculation (pi), respectively. At 3 days pi, significantly more secondary roots had necrotic lesions on Red Knight than on Paladin and CM-334 plants. By 4 days pi, necrotic lesions had formed on the taproot of Red Knight but not Paladin or CM-334 plants. Although hyphae were visible in the crowns and stems of all Red Knight plants observed at 4 days pi, hyphae were observed in crowns of only a few Paladin and in no CM-334 plants, and never in stems of either resistant cultivar at 4 days pi. These results improve our understanding of how P. capsici infects plants and may contribute to the use of resistant pepper cultivars for disease management and the development of new cultivars.

Effects of chemical stress and food limitation on the energy reserves and growth of turbot, Scophthalmus maximus.

The objective of the present study is to examine the growth and energetic performance of juvenile turbot after exposure to contaminated sediment and during the subsequent recovery period with or without food limitation. We designed a two-step experiment by first exposing juvenile turbot to harbour sediment for 26 days and then transferring them to clean sea water with different frequencies of feeding for 35 days. Without food limitation, fish previously exposed to contaminated sediment compensated for weight, length and lipid reserve losses; we did not record any differences in size, Fulton's K condition index and triacylglycerol/sterol (TAG/ST) ratio after the 35-day depuration period compared to the reference fish. This result could be related to the compensatory growth mechanism observed in a wide range of fish species following a period of growth depression. With food limitation during the 35-day depuration period, recovery growth was not sufficient to restore length and weight values similar to the reference fish. Moreover, turbot previously exposed to contaminated sediment and subsequently fed twice or once a week exhibited extremely low TAG/ST ratios, but the reference fish submitted to the same restrictive feeding conditions did not. This study indicates that juvenile fish affected by chemical pollution can improve their biological performance if pollution events are followed by a period of abundant food. However, if pollution events occur during periods of food scarcity, e.g. in winter, storage of energy reserves will be compromised.

Evolution of an Experimental Population of Phytophthora capsici in the Field.

Populations of the vegetable pathogen Phytophthora capsici are often highly diverse, with limited gene flow between fields. To investigate the structure of a newly established, experimental population, an uninfested research field was inoculated with two single-zoospore isolates of P. capsici in September 2008. From 2009 through 2012, ≈50 isolates of P. capsici were collected from the field each year and genotyped using five microsatellite loci. The same two isolates were also crossed in the lab. High levels of diversity were detected in the research field, with 26 to 37 unique multilocus genotypes detected each year. Through 2012, genotypic diversity did not decline and no evidence of genetic drift was observed. However, during the 2011 and 2012 growing seasons, four new alleles not present in either parental isolate were observed in the field. Selfing (but not apomixis) was observed at low frequency among in vitro progeny. In addition, evidence for loss of heterozygosity was observed in half of the in vitro progeny. These results suggest that recombination, mutation, and loss of heterozygosity can affect the genetic structure observed in P. capsici populations.

A combined measurement of metal bioaccumulation and condition indices in juvenile European flounder, Platichthys flesus, from European estuaries.

Condition indices and metal bioaccumulation of early life stages of juvenile flounder (5-10 cm) were determined in three anthropogenic estuaries (the Scheldt, Seine and Loire) and compared to a reference site (the Canche). Significant correlations were found between metal concentrations in sediment and (i) fish liver for Cd, Cu, Ni, Pb, V and Zn and (ii) fish gills for Cd and Mn. Metal accumulation in juvenile flounder from the three anthropogenic estuaries coincided with significantly lower Fulton's K indices (from 0.99 ± 0.03 to 1.06 ± 0.01 mg mm(-3)) compared to those from the Canche estuary (from 1.02 ± 0.01 to 1.13 ± 0.01 mg mm(-3)). This discrepancy in fish condition index increased with fish size and therefore, strongly depends on the time juvenile spend in estuary. Muscle lipid contents and Triacylglycerol to Sterol ratios were significantly lower in fish collected in the Scheldt (lipid content: 21.3 ± 3.6%), Seine (17.9 ± 19.8%) and Loire (19.5 ± 2.4%) estuaries compared to those originating from the Canche (38.3 ± 4.6%). This study highlights that combined measures of both fish metal contents and condition indices gives a relevant assessment of juvenile fish health growing in anthropogenic estuaries.

Metal concentrations, growth and condition indices in European juvenile flounder (Platichthys flesus) relative to sediment contamination levels in four Eastern English Channel estuaries.

The aim of the present study was to evaluate the effects of metal contamination on the biological responses of 0-group juvenile European flounder and to assess and compare the quality of four estuarine habitats located in the Eastern English Channel. Fish otolith growth and condition indices (RNA : DNA ratio, Fulton's K condition index) were measured and found to be significantly lower in individuals from the Seine estuary compared to those of the Canche, Authie and Somme estuaries. No obvious effects of hydrological condition or food availability on the flounder biological responses were observed. Sediments from the Seine showed the highest metal concentrations, bioavailable proportion and enrichment factors. Higher metal concentrations were observed in fish from the Seine compared to the other ones caught in less polluted estuaries. These results suggest that contaminants may have a negative impact on the early life history stage of flounder.

A multibiomarker approach in juvenile turbot, Scophthalmus maximus, exposed to contaminated sediments.

Juvenile turbot were exposed in laboratory conditions to a mixture of chemical contaminants associated with harbour and estuarine sediments for seven and 21 days. Several molecular biomarkers of exposure were then measured in fish liver: two biotransformation parameters [ethoxyresorufin-O-deethylase (EROD) and phase II glutathione S-transferase (GST) activities] and an antioxidant enzyme activity [catalase (CAT)]. Modifications at the histological level were analysed by the measurement of the number and size of melanomacrophage centres (MMCs) and disturbances to the immune function by the measurement of cytokine transforming growth factor-beta (TGF-ß) and development of the thymus. The responses of these molecular and immunological biomarkers were correlated with metal and PAH concentrations measured in sediments and with the physiological performance of turbot analysed in a previous study on the same fish (growth rates, condition factor K, RNA:DNA ratio and lipid index). While no difference was found in thymus analysis, some molecular and immunological responses were observed in fish exposed to contaminated sediments. Weak relationships between molecular biomarkers' responses and PAH concentrations were recorded, while their responses were significantly correlated with some metals. MMC and aggregates were weakly related to chemical contaminants whereas some significant correlations were found between TGF-b1 responses and some metal concentrations. However, molecular and immunological biomarkers were weakly related to fish physiological damages since low responses were observed in the condition which led to the lowest growth and condition indices. These data suggest the complexity of cause-effect relationships between exposure to pollutants, metabolisms and health damages. Precautions should be considered in the use of molecular and immunological biomarkers alone in biomonitoring programs. Their complementary use with physiological biomarkers, such as fish growth and condition indices, could improve their utilisation.

Responses of juvenile sea bass, Dicentrarchus labrax, exposed to acute concentrations of crude oil, as assessed by molecular and physiological biomarkers.

In the present study, juvenile sea bass were exposed for 48 and 96 h to an Arabian light crude oil and their responses were assessed at the molecular and physiological levels. The aim of the study was therefore to assess (i) the short term effects of crude oil exposure by the measurement of several molecular biomarkers, (ii) the consequences of this short term exposure on fish health by using growth and condition indices measured after a decontamination period of 28 and 26 d in seawater. Hydrocarbon petroleum concentrations was monitored during the 96 h experiments and an increase of PAH concentrations were found in fish following both exposure times. An 7-ethoxyresorufin-O-deethylase (EROD) induction was observed after 48 h of exposure, while a significant decrease in the sea bass specific growth rate in length and for the RNA:DNA ratio was observed 28 d after that exposure ceased. The EROD induction doubled after the 96 h exposure, and a significant increase in GST activities was observed. A significant decrease in the specific growth rates, the otolith recent growth, the RNA:DNA ratio and the Fulton's K condition index were then observed in sea bass 26 d after the 96 h exposure to mechanically dispersed crude oil compared to the control. The present study shows that growth and condition indices can prove useful in assessing fish health status following an oil spill. Their complementary analysis with sensitive molecular biomarkers as EROD could improve the determination of oil spill impact on fish populations.

Growth and condition indices of juvenile turbot, Scophthalmus maximus, exposed to contaminated sediments: effects of metallic and organic compounds.

Since sediments have the potential to form associations with several classes of pollutants, they have been recognized as a possible and significant source of contamination for the benthic environment. Flatfish maintain a close association with sediments for food and cover, and are therefore more likely to be exposed to contaminated sediments, especially in coastal areas (e.g. nursery grounds). The assessment of these potential biological effects involves the use of adapted biomonitoring tools. The main objective of this study was to assess and compare the response of several physiological biomarkers measured on juvenile turbot (Scophthalmus maximus) exposed to contaminated sediments. Sediments were collected from three stations in a harbour in northern France (Boulogne-sur-Mer), in an anthropogenic French estuary (the Seine), and in a reference site (exposed sandy beach of Wimereux). Unexposed lab-reared juvenile turbots were exposed to sediments for 7 and 21 days in laboratory conditions. Sediments were analysed for metals, PAH and PCB contamination. Several fish growth and condition indices were individually analysed in fish according to the chemical contaminant availability in sediment, the metal concentrations in gills and the estimation of PAH metabolites in their bile. Significant decreases in growth rates, morphometric index, RNA:DNA ratio and the lipid storage index, based on the ratio of the quantity of triacylglycerols on sterols (TAG:ST), were observed with increasing level of chemical contamination. This decrease in the fish's physiological status could be related to the significant increase of several metal concentrations in contaminated fish gills and the significant increase of PAH metabolites in bile. In a field situation, such a reduction in growth and energetic status of juvenile fish could dramatically decrease their over-winter survival in contaminated nursery grounds.

Are biochemical biomarker responses related to physiological performance of juvenile sea bass (Dicentrarchus labrax) and turbot (Scophthalmus maximus) caged in a polluted harbour?

Biomarker responses to toxic exposure have been used for decades to indicate stress in aquatic organisms, or the magnitude of environmental pollution. However, little has been done to compare the simultaneous responses of both biochemical and physiological biomarkers. The purpose of this study was twofold. Firstly to analyse the responses of several biochemical biomarkers measured on juvenile sea bass and turbot caged in a northern France harbour at a reference and contaminated stations. Several biotransformation parameters (Ethoxyresorufin-O-deethylase - EROD - and Glutathione S-transferase -GST) and an antioxidant enzyme (Catalase -CAT) were analysed. Secondly, to compare their responses to several growth and condition indices, measured on the same fish. In the contaminated station, EROD and GST activities were found to be significantly higher, and a decrease of CAT activity was observed for both species. For individual sea bass, biochemical biomarkers showed numerous significant correlations with growth and condition indices, such as the Fulton's K condition index, the RNA:DNA ratio and the lipid storage index. On the contrary, there were only a few significant correlations for turbot, suggesting a species-specific response. Our study indicates that the analysis of the simultaneous responses of both biochemical and physiological biomarkers can be useful for monitoring complex exposure and to assess habitat quality.

Adenovirus type 5 induces vitamin A-metabolizing enzymes in dendritic cells and enhances priming of gut-homing CD8 T cells.

Protective immunity at the gut-associated mucosal tissue is induced primarily by oral/rectal immunization owing to the need for targeting antigen to the gut-resident dendritic cells (DCs). In this study we show that an adenovirus type 5 (Ad5)-based human immunodeficiency virus type 1 vaccine can prime a durable antigen-specific CD8 T-cell response in the gut following intramuscular (IM) immunization in mice. The ability of Ad5 to prime gut-homing CD8 T cells in vivo was associated with Ad5-induced expression of retinal dehydrogenase (RALDH) enzymes in conventional DCs. The Ad5-mediated induction of RALDH did not require signaling through Toll-like receptors, DNA-dependent activator of interferon regulatory factors and several mitogen-activated protein kinases, or replication capacity of the virus, but was dependent on nuclear factor-κB and granulocyte-macrophage colony-stimulating factor. These results provide an innate mechanism through which Ad5-stimulated DCs prime gut-homing CD8 T cells and have implications for the development of novel mucosal adjuvants for subunit vaccines administered via the IM route.

Excellent safety and tolerability of the human immunodeficiency virus type 1 pGA2/JS2 plasmid DNA priming vector vaccine in HIV type 1 uninfected adults.

A vaccine consisting of DNA priming followed by recombinant modified vaccinia Ankara (rMVA) boosting has achieved long-term control of a pathogenic challenge with a chimera of simian and human immunodeficiency viruses (SHIV-89.6P) in rhesus macaques. Based on these results, clade B HIV-1 DNA and rMVA immunogens have been developed for trials in humans. We conducted a first-time in humans phase I safety trial using the pGA2/JS2 (JS2) HIV-1 DNA priming vector expressing Gag, Pol, Env, Tat, Rev, and Vpu. Thirty HIV-uninfected adults were vaccinated with 0.3 or 3 mg of JS2 DNA, or a saline placebo, by intramuscular injection at months 0 and 2. Both doses of DNA were safe and well-tolerated with no differences between the control, 0.3 mg, or 3 mg groups (n = 6, 12, and 12, respectively) through 12 months of postvaccination follow- up. A chromium-release assay using fresh peripheral blood mononuclear cells (PBMCs) and a validated IFN-gamma ELISpot assay with frozen PBMCs failed to detect CD4(+) or CD8(+) HIV-1-specific T cell responses. HIV-specific neutralizing antibodies were also not detected. The vaccine is being further developed as a priming vector for a combined DNA plus rMVA prime/boost HIV vaccination regimen.

Heavy metals in four fish species from the French coast of the Eastern English Channel and Southern Bight of the North Sea.

Shallow coastal waters act as nurseries for various fish species and have been recognized as essential fish habitat. We studied heavy metal concentrations in four fish species (plaice, dab, flounder and cod) as an indicator of large-scale habitat quality. The study took place along the French coasts between the Eastern English Channel and the Southern Bight of the North Sea. All species show different concentrations of measured metals (e.g., Cd, Cu, Mn and Pb) in liver but not in muscle. The highest concentrations are found for the flounder and the lowest for cod which is consistent with their habitat and diet. Although our results do not highlight levels of appreciable pollution within the study area, inter-site differences are mainly observed in the muscle tissues and are generally in agreement with the known environmental data (e.g., anthropogenic pressure). However, in the Bay of Seine, one of the most contaminated estuaries in Europe, metal concentrations are in the same range or even lower than those found in fish collected from areas distant from any anthropogenic pressures. At one site, the comparisons of the Cd, Cu and Pb concentrations between healthy and diseased dabs have been carried out on the muscle and liver tissues. The results of this preliminary study show a relationship between metal concentrations and the pathological status of the fish. The use of fish health as indicator of habitat quality is discussed.

Apoptosis-mediated enhancement of DNA-raised immune responses by mutant caspases.

Apoptotic bodies can be used to target delivery of DNA-expressed immunogens into professional antigen-presenting cells (APCs). Here we show that antigen-laden apoptotic bodies created by vectors co-expressing influenza virus hemagglutinin (HA) or nucleoprotein (NP) genes and mutant caspase genes markedly increased T-cell responses. Both CD8 and CD4 T-cell responses were affected. The adjuvant activity was restricted to partially inactivated caspases that allowed immunogen expression before the generation of apoptotic bodies. Active-site mutants of murine caspase 2 and an autocatalytic chimera of murine caspase 2 prodomain and human caspase 3 induced apoptosis that did not interfere with immunogen expression. The adjuvant activity also enhanced B-cell responses, but to a lesser extent than T-cell responses. The large increases in T-cell responses represent one of the strongest effects to date of a DNA adjuvant on cellular immunity.

Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine.

Heterologous prime/boost regimens have the potential for raising high levels of immune responses. Here we report that DNA priming followed by a recombinant modified vaccinia Ankara (rMVA) booster controlled a highly pathogenic immunodeficiency virus challenge in a rhesus macaque model. Both the DNA and rMVA components of the vaccine expressed multiple immunodeficiency virus proteins. Two DNA inoculations at 0 and 8 weeks and a single rMVA booster at 24 weeks effectively controlled an intrarectal challenge administered 7 months after the booster. These findings provide hope that a relatively simple multiprotein DNA/MVA vaccine can help to control the acquired immune deficiency syndrome epidemic.