Innate immunity in ocular Chlamydia trachomatis infection: contribution of IL8 and CSF2 gene variants to risk of trachomatous scarring in Gambians

BACKGROUND: Trachoma, a chronic keratoconjunctivitis caused by Chlamydia trachomatis, is the world's commonest infectious cause of blindness. Blindness is due to progressive scarring of the conjunctiva (trachomatous scarring) leading to in-turning of eyelashes (trichiasis) and corneal opacification. We evaluated the contribution of genetic variation across the chemokine and cytokine clusters in chromosomes 4q and 5q31 respectively to risk of scarring trachoma and trichiasis in a large case-control association study in a Gambian population. METHODS: Linkage disequilibrium (LD) mapping was used to investigate risk effects across the 4q and 5q31 cytokine clusters in relation to the risk of scarring sequelae of ocular Ct infection. Disease association and epistatic effects were assessed in a population based study of 651 case-control pairs by conditional logistic regression (CLR) analyses. RESULTS: LD mapping suggested that genetic effects on risk within these regions mapped to the pro-inflammatory innate immune genes interleukin 8 (IL8) and granulocyte-macrophage colony stimulatory factor (CSF2) loci. The IL8-251 rare allele (IL8-251 TT) was associated with protection from scarring trachoma (OR = 0.29 p = 0.027). The intronic CSF2_27348 A allele in chromosome 5q31 was associated with dose dependent protection from trichiasis, with each copy of the allele reducing risk by 37% (p = 0.005). There was evidence of epistasis, with effects at IL8 and CSF2 loci interacting with those previously reported at the MMP9 locus, a gene acting downstream to IL8 and CSF2 in the inflammatory cascade. CONCLUSION: innate immune response SNP-haplotypes are linked to ocular Ct sequelae. This work illustrates the first example of epistatic effects of two genes on trachoma

The Development of an Age-Structured Model for Trachoma Transmission Dynamics, Pathogenesis and Control

Trachoma is the worldwide leading infectious cause of blindness and is due to repeated conjunctival infection with Chlamydia trachomatis bacteria. The effects of control interventions on population levels of infection and active disease can be promptly measured, but the effects on severe ocular disease outcomes require long-term monitoring. We present a mathematical model of trachoma transmission and disease to predict the impact of interventions on blinding trachoma. The model is based on the concept of multiple re-infections leading to progressive scarring of the eye and the potentially blinding disease sequelae. It includes aspects of trachoma natural history such as an increasing rate of recovery from infection, and a decreasing chlamydial load with subsequent infections. The model reproduces key features of trachoma epidemiology such as the age-profile of infection prevalence; a shift in the prevalence peak toward younger ages in higher-transmission environments; and a rising profile of the prevalence of the severe sequelae (scarring, trichiasis), as well as estimates of the number of infections experienced before these sequelae appear. The model can be used to examine the outcomes of various control strategies on infection and disease and can help to plan treatment interventions for different endemic settings

Identification of Novel Single Nucleotide Polymorphisms in Inflammatory Genes as Risk Factors Associated with Trachomatous Trichiasis

infection, the primary cause of trachoma. Despite control programs that include mass antibiotic treatment, reinfection and recurrence of trachoma are common after treatment cessation. Furthermore, a subset of infected individuals develop inflammation and are at greater risk for developing the severe sequela of trachoma known as trachomatous trichiasis (TT). While there are a number of environmental and behavioral risk factors for trachoma, genetic factors that influence inflammation and TT risk remain ill defined. = 0.001] with the combination of TNFA (-308A), LTA (252A), VCAM1 (-1594C), SCYA 11 (23T) minor allele, and the combination of TNFA (-308A), IL9 (113M), IL1B (5′UTR-T), and VCAM1 (-1594C). However, TT risk increased 13.5 times [odds ratio = 13.5 (95% confidence interval 3.3–22), p = 0.001] with the combination of TNFA (-308G), VDR (intron G), IL4R (50V), and ICAM1 (56M) minor allele.Evaluating genetic risk factors for trachoma will advance our understanding of disease pathogenesis, and should be considered in the context of designing global control programs

Haptoglobin and Sickle Cell Polymorphisms and Risk of Active Trachoma in Gambian Children

BACKGROUND: Susceptibility and resistance to trachoma, the leading infectious cause of blindness, have been associated with a range of host genetic factors. In vitro studies of the causative organism, Chlamydia trachomatis, demonstrate that iron availability regulates its growth, suggesting that host genes involved in regulating iron status and/or availability may modulate the risk of trachoma. The objective was to investigate whether haptoglobin (Hp) haplotypes constructed from the functional polymorphism (Hp1/Hp2) plus the functional promoter SNPs -61A-C (rs5471) and -101C-G (rs5470), or sickle cell trait (HbAS, rs334) were associated with risk of active trachoma when stratified by age and sex, in rural Gambian children. METHODOLOGY AND PRINCIPAL FINDINGS: In two cross sectional surveys of children aged 6-78 months (n = 836), the prevalence of the clinical signs of active trachoma was 21.4%. Within boys, haplotype E (-101G, -61A, Hp1), containing the variant allele of the -101C-G promoter SNP, was associated with a two-fold increased risk of active trachoma (OR = 2.0 [1.17-3.44]). Within girls, an opposite association was non-significant (OR = 0.58 [0.32-1.04]; P = 0.07) and the interaction by sex was statistically significant (P = 0.001). There was no association between trachoma and HbAS. CONCLUSIONS: These data indicate that genetic variation in Hp may affect susceptibility to active trachoma differentially by sex in The Gambia

Understanding Interorganizational Learning Based on Social Spaces and Learning Episodes

Different organizational settings have been gaining ground in the world economy, resulting in a proliferation of different forms of strategic alliances that translate into a growth in the number of organizations that have started to deal with interorganizational relationships with different actors. These circumstances reinforce Crossan, Lane, White and Djurfeldt (1995) and Crossan, Mauer and White (2011) in exploring what authors refer to as the fourth, interorganizational, level of learning. These authors, amongst others, suggest that the process of interorganizational learning (IOL) warrants investigation, as its scope of analysis needs widening and deepening. Therefore, this theoretical essay is an attempt to understand IOL as a dynamic process found in interorganizational cooperative relationships that can take place in different structured and unstructured social spaces and that can generate learning episodes. According to this view, IOL is understood as part of an organizational learning continuum and is analyzed within the framework of practical rationality in an approach that is less cognitive and more social-behavioral

Alle origini dell'arbitrato commerciale internazionale. L'arbitrato a Venezia tra Medioevo ed Età moderna

L'opera si distingue in due parti, di cui la prima costituisce presentazione ed analisi complessiva di materiali documentari poi ordinati e pubblicati nella seconda. I documenti pubblicati sono il frutto di ricerche effettuate direttamente presso l’Archivio storico di Venezia e costituiscono, nella loro grande maggioranza, degli inediti di importanza fondamentale per la comprensione delle radici dell’istituto arbitrale. I documenti pubblicati, che vanno dalla fine del 1200 agli inizi del 1600, ma che sono essenzialmente concentrati fra il 1300 ed il 1400, sono ripartiti a seconda delle fonti: fonti consiliari, fonti notarili e fonti giudiziarie. Data la inesistenza di un sistema di ripartizione dei poteri in Venezia in quel periodo, nelle fonti consiliari sono ricompresi sia atti legislativi in tema di arbitrato che decisioni arbitrali e decisioni giudiziarie in tema di arbitrato. Le fonti notarili sono quelle che danno atto della stipulazione di compromessi, o di contratti con clausole compromissorie, o di decisioni arbitrali che risolvono le controversie. Le fonti giudiziarie, essenzialmente le decisioni dei Giudici di Petizione, attengono all'esecuzione dei lodi e, talvolta, alla loro validità. Oltre ad alcuni riferimenti relativi all’arbitrato internazionale che la Repubblica Serenissima utilizzava nei rapporti tra Stati, la maggior parte del lavoro è dedicata all’arbitrato nei rapporti interindividuali. Fra i tanti punti messi in evidenza occorre menzionare dapprima la distinzione fra arbiter e arbitrator essendo quest'ultimo un amichevole compositore della lite fra le parti senza obbligo di applicare norme di diritto. Va poi ricordata la possibilità di collegi arbitrali composti di due arbitri, con possibile nomina di un terzo arbitro in caso di disaccordo fra i due (legge del Maggior Consiglio del 1 settembre 1437), così anticipando di gran tempo soluzioni per le quali è oggi noto l'arbitrato nel Regno Unito con la figura dell' umpire. In alcuni casi la scelta del terzo era rimessa agli stessi arbitri, in altri il terzo – sempre in assenza di accordo dei primi due sulla decisione da adottare – era da individuare nell'ambito dei Giudici di Petizione; con l'ulteriore utile conseguenza di una sicura facilità di exequatur in caso di successivo ricorso a questo organo giudiziario per ottenere l'esecuzione forzata del lodo. Quanto alle materie arbitrabili, viene messo in luce come tali materie fossero molto più numerose di quelle oggi possibili oggetto di arbitrato, anche nei paesi più liberali al riguardo. L'arbitrato era previsto nelle liti fra coniugi, fra genitori e figli e fra parenti fino ad un certo grado. Questo anche allo scopo di evitare che questioni personali venissero trattate e decise senza la necessaria giustizia e riservatezza che le relative dispute necessitavano. Pure arbitrabili erano le controversie in materia di contratti di lavoro, sia collettive fra categorie di datori di lavoro e di lavoratori (Arte della Lana e Corporazione dei Cimadori, sia fra singolo lavoratore e datore di lavoro. Sono infine di rilievo le considerazioni raggiunte in tema di esecuzione dei lodi. La loro efficacia di giudicato si era andata consolidando nel tempo con l'attribuzione al lodo della caratteristica dell'inappellabilità. L'intervento del Giudice di Petizion era essenzialmente limitato a fornire forza esecutiva al lodo stesso. Speciale attenzione è rivolta alle clausole penali contenute nei compromessi e per le quali una penale avrebbe dovuto essere versata – in favore di un'autorità pubblica o dell'altra parte – da quella parte che avesse causato il ricorso all'autorità giudiziaria per l'esecuzione del lodo

Long-term record of Barents Sea Ice Sheet advance to the shelf edge from a 140,000 year record

The full-glacial extent and deglacial behaviour of marine-based ice sheets, such as the Barents Sea Ice Sheet, is well documented since the Last Glacial Maximum about 20,000 years ago. However, reworking of older sea-floor sediments and landforms during repeated Quaternary advances across the shelf typically obscures their longer-term behaviour, which hampers our understanding. Here, we provide the first detailed long-term record of Barents Sea Ice Sheet advances, using the timing of debris-flows on the Bear Island Trough-Mouth Fan. Ice advanced to the shelf edge during four distinct periods over the last 140,000 years. By far the largest sediment volumes were delivered during the oldest advance more than 128,000 years ago. Later advances occurred from 68,000 to 60,000, 39,400 to 36,000 and 26,000 to 20,900 years before present. The debris-flows indicate that the dynamics of the Saalian and the Weichselian Barents Sea Ice Sheet were very different. The repeated ice advance and retreat cycles during the Weichselian were shorter lived than those seen in the Saalian. Sediment composition shows the configuration of the ice sheet was also different between the two glacial periods, implying that the ice feeding the Bear Island Ice stream came predominantly from Scandinavia during the Saalian, whilst it drained more ice from east of Svalbard during the Weichselian

Chapter E1 Integrated stratigraphy of the middle to upper miocene pelagic sequence of the cönero riviera (Marche region, Italy)

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