Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Doyne lecture 2016:intraocular health and the many faces of inflammation

Dogma for reasons of immune privilege including sequestration (sic) of ocular antigen, lack of lymphatic and immune competent cells in the vital tissues of the eye has long evaporated. Maintaining tissue and cellular health to preserve vision requires active immune responses to prevent damage and respond to danger. A priori the eye must contain immune competent cells, undergo immune surveillance to ensure homoeostasis as well as an ability to promote inflammation. By interrogating immune responses in non-infectious uveitis and compare with age-related macular degeneration (AMD), new concepts of intraocular immune health emerge. The role of macrophage polarisation in the two disorders is a tractable start. TNF-alpha regulation of macrophage responses in uveitis has a pivotal role, supported via experimental evidence and validated by recent trial data. Contrast this with the slow, insidious degeneration in atrophic AMD or in neovasular AMD, with the compelling genetic association with innate immunity and complement, highlights an ability to attenuate pathogenic immune responses and despite known inflammasome activation. Yolk sac-derived microglia maintains tissue immune health. The result of immune cell activation is environmentally dependent, for example, on retinal cell bioenergetics status, autophagy and oxidative stress, and alterations that skew interaction between macrophages and retinal pigment epithelium (RPE). For example, dead RPE eliciting macrophage VEGF secretion but exogenous IL-4 liberates an anti-angiogenic macrophage sFLT-1 response. Impaired autophagy or oxidative stress drives inflammasome activation, increases cytotoxicity, and accentuation of neovascular responses, yet exogenous inflammasome-derived cytokines, such as IL-18 and IL-33, attenuate responses

Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk

Large cell neuroendocrine lung carcinoma: consensus statement from The British Thoracic Oncology Group and the Association of Pulmonary Pathologists

Over the past 10 years, lung cancer clinical and translational research has been characterised by exponential progress, exemplified by the introduction of molecularly targeted therapies, immunotherapy and chemo-immunotherapy combinations to stage III and IV non-small cell lung cancer. Along with squamous and small cell lung cancers, large cell neuroendocrine carcinoma (LCNEC) now represents an area of unmet need, particularly hampered by the lack of an encompassing pathological definition that can facilitate real-world and clinical trial progress. The steps we have proposed in this article represent an iterative and rational path forward towards clinical breakthroughs that can be modelled on success in other lung cancer pathologies

Lipid and fatty acid composition, and persistent organic pollutant levels in tissues of migrating Atlantic bluefin tuna (Thunnus thynnus, L.) broodstock

Lipid class, fatty acid and POP levels were measured in migrating Atlantic bluefin tuna (ABT) tissues caught off the Barbate coast, Spain. Tissue lipids were largely characterized by triacylglycerol, reflecting large energy reserves accumulated prior to reproductive migration. Fatty acid compositions of muscle, liver and adipose exhibited similar profiles, whereas gonads showed a higher affinity for docosahex- aenoic acid. Tissue POP concentrations correlated positively with percentage triacylglycerol and nega- tively with polar lipids. Highest POP concentrations were in adipose and lowest in gonads, reflecting lipid content. DL-PCBs contributed most to total PCDD/F þ DL-PCB levels, with mono-ortho concentrations higher in tissues, whereas non-ortho PCBs contributed greater WHO-TEQs due to differences in TEFs. PBDE47 was the most prominent BDE congener in tissues, probably through biotransformation of BDE99 and other higher brominated congeners. The perceived POP risk from ABT consumption should be balanced by the well-established beneficial effects on human health of omega-3 fatty acids

Factors affecting phage D29 infection: a tool to investigate different growth states of mycobacteria

Bacteriophages D29 and TM4 are able to infect a wide range of mycobacteria, including pathogenic and non pathogenic species. Successful phage infection of both fast- and slow-growing mycobacteria can be rapidly detected using the phage amplification assay. Using this method, the effect of oxygen limitation during culture of mycobacteria on the success of phage infection was studied. Both D29 and TM4 were able to infect cultures of M. smegmatis and Mycobacterium avium subspecies paratuberculosis (MAP) grown in liquid with aeration. However when cultures were grown under oxygen limiting conditions, only TM4 could productively infect the cells. Cell attachment assays showed that D29 could bind to the cells surface but did not complete the lytic cycle. The ability of D29 to productively infect the cells was rapidly recovered (within 1 day) when the cultures were returned to an aerobic environment and this recovery required de novo RNA synthesis. These results indicated that under oxygen limiting conditions the cells are entering a growth state which inhibits phage D29 replication, and this change in host cell biology which can be detected by using both phage D29 and TM4 in the phage amplification assay

Exploring the Mode of Action of Bioactive Compounds by Microfluidic Transcriptional Profiling in Mycobacteria

10.1371/journal.pone.0069191PLoS ONE87-POLN

Dental and prosthodontic status of an over 40 year-old population in Shandong Province, China

Contains fulltext : 97791.pdf (postprint version ) (Open Access)BACKGROUND: This study aims to (1) describe the dental status using DMFT for the whole dentition and the anterior, premolar and molar regions; (2) determine associations of demographic variables and socio-economic status (SES) with DMFT and tooth replacement; (3) analyze to what extent the goal as proposed by the WHO -'the retention of not less than 20 teeth throughout life' is achieved. METHODS: DMFT and tooth replacement data of 1588 subjects over 40 years from urban and rural sites in Qingdao (Shandong Province, China) were collected. Relative D, M, and F scores per dental region were calculated and compared by paired T-tests. Multivariable logistic regression was used to determine relationships with age, gender, place of residence, and SES. RESULTS: Mean numbers of D and F were low (1.36 respectively 0.27) at all ages. Molars had highest chance for D and M. For the molar region every additional year of age gave significantly lower chance for D and higher chance for M (OR: 0.98 and 1.02 respectively; both p </= 0.01). Mean number of M was associated with age (approximately 1.5 in each jaw at 40 years and 6 at 80 years). Females had higher chance for D (OR: 1.34; p </= 0.05) and F (OR: 1.69; p </= 0.01), and lower chance for M (OR: 0.60; p </= 0.01). Urban and rural subjects had similar chance for D; urban subjects had approximately 5 times more chance for F (p </= 0.01). SES had no relationship with D and M, however SES low was associated with F (OR: 0.45; p </= 0.01). Replacements were significantly associated with age (all dental regions except anterior region), gender (all dental regions), place of residence (whole dentition and molar region), and SES (whole dentition and premolar and molar regions). CONCLUSIONS: The majority of subjects presented a reduced dentition. Molars were most frequently affected by D and M. D, M, F and replaced teeth were associated with the background variables, however differently for different dental regions. Above the age of 70 years, only 64% of the subjects presented 'not less than 20 natural teeth'

Vetufebrus ovatus n. gen., n. sp. (Haemospororida: Plasmodiidae) vectored by a streblid bat fly (Diptera: Streblidae) in Dominican amber

This is the publisher’s final pdf. The published article is copyrighted by BioMed Central Ltd. and can be found at: http://www.parasitesandvectors.com/.Background: Both sexes of bat flies in the families Nycteribiidae and Streblidae (Diptera: Hippoboscoidea) reside in\ud the hair or on the wing membranes of bats and feed on blood. Members of the Nycteribiidae transmit bat malaria\ud globally however extant streblids have never been implemented as vectors of bat malaria. The present study\ud shows that during the Tertiary, streblids also were vectors of bat malaria.\ud Results: A new haemospororidan, Vetufebrus ovatus, n. gen., n. sp., (Haemospororida: Plasmodiidae) is described\ud from two oocysts attached to the midgut wall and sporozoites in salivary glands and ducts of a fossil bat fly\ud (Diptera: Streblidae) in Dominican amber. The new genus is characterized by ovoid oocysts, short, stubby\ud sporozoites with rounded ends and its occurrence in a fossil streblid. This is the first haemosporidian reported from\ud a streblid bat fly and shows that representatives of the Hippoboscoidea were vectoring bat malaria in the New\ud World by the mid-Tertiary.\ud Conclusions: This report is the first evidence of an extant or extinct streblid bat fly transmitting malaria.\ud Discovering a mid-tertiary malarial parasite in a fossil streblid that closely resembles members of a malarial genus\ud found in nycteribiid bat flies today shows how little we know about the vector associations of streblids. While no\ud malaria parasites have been found in extant streblids, they probably occur and it is possible that streblids were the\ud earliest lineage of flies that transmitted bat malaria to Chiroptera

Effects of the noradrenergic agonist clonidine on temporal and spatial attention

Rationale: Recent theories posit an important role for the noradrenergic system in attentional selection in the temporal domain. In contrast, the spatially diffuse topographical projections of the noradrenergic system are inconsistent with a direct role in spatial selection. Objectives: To test the hypotheses that pharmacological attenuation of central noradrenergic activity should (1) impair performance on the attentional blink task, a task requiring the selection of targets in a rapid serial visual stream of stimuli; and (2) leave intact the efficiency of the search for a target in a two-dimensional visuospatial stimulus array. Materials and methods: Thirty-two healthy adult human subjects performed an attentional blink task and a visual search task in a double-blind, placebo-controlled, between-subject study investigating the effects of the α2 adrenoceptor agonist clonidine (150 μg, oral dose). Results: No differential effects of clonidine vs placebo were found on the attentional blink performance. Clonidine slowed overall reaction times in the visual search task but did not impair the efficiency of the visual search. Conclusions: The attentional blink results are inconsistent with recent theories about the role of the noradrenergic system in temporal filtering and in mediating the attentional blink. This discrepancy between theory and data is discussed in detail. The visual search results, in combination with previous findings, suggest that the noradrenergic system is not directly involved in spatial attention processes but instead can modulate these processes in an indirect fashion. © 2007 Springer-Verlag