Resident tissue macrophages within the normal rat iris lack immunosuppressive activity and are effective antigen-presenting cells

Despite extensive study of the numerous immunoregulatory mechanisms that contribute to the immune-privileged nature of the anterior chamber (AC) of the eye, little is known of the functional nature of antigen-presenting cells (APC) present in the tissues adjoining the AC. In the present study, we have compared the antigen-presenting capacity of dendritic cells (DC) and macrophages isolated from the normal rat iris. Whereas iris DC exhibited a potent ability to stimulate resting allogeneic T cells in MLR cultures (an in-vitro correlate of the ability to induce primary T cell responses), resident iris macrophages displayed negligible MLR-stimulatory capacity. Significantly, iris macrophages could efficiently elicit proliferation of primed antigen-specific T cells (an in-vitro correlate of the ability to act as local APC in secondary responses). This antigen-presenting activity was approximately half that of fully mature iris DC and considerably greater than that of freshly isolated iris DC. A key contributor to the effectiveness of resident iris macrophage antigen presentation was considered to be the absence of lymphocytostatic control of T cell proliferation exerted by these cells. The results indicate dichotomous but complementary roles for DC (immune surveillance) and macrophages (local antigen presentation in secondary responses) in this tissue.

The Mesozoic and Cenozoic motion of Adria (central Mediterranean): a review of constraints and limitations

This paper presents kinematic analysis on the motion of Adria, which is the continental mass that bridges Africa and Europe in the central Mediterranean. Palaeomagnetic data show a general coherence between the motion of Adria and Africa since the Late Paleozoic. This mutual motion, for the period from 120 Ma and the present, is verified by comparing inferred palaeolatitudes from relatively stable parts of Adria (Apulia, Gargano, Istria, and the Southern Alps) and the Hyblean Plateau, with latitudinal changes that are calculated from the motion of Africa with respect to hotspots. Additional constraints on the motion of Adria are provided from the Late Paleozoic-Early Mesozoic passive margin of Adria in the Ionian Sea. The seismic structure of the floor of the Ionian Sea resembles the structure of the oceanic crust in marginal back-arc basins, suggesting that it formed as a small ocean basin. Furthermore, the Ionian lithosphere in the Calabrian arc has been subjected to rapid rollback, which commonly occurs only when the subducting slab is made of oceanic lithosphere. This oceanic domain marks the Pennian-Triassic to Jurassic plate boundary between Adria and Africa, suggesting that a small amount of independent motion between Adria and Africa took place at that time. Since the Jurassic, Adria and Africa have shared a relatively coherent motion path. (C) 2004 Lavoisier SAS. All rights reserved.

The Western Alps from the Jurassic to Oligocene: spatio-temporal constraints and evolutionary reconstructions

Despite extensive research in the last 150 years, the regional tectonic reconstruction of the Western Alps has remained controversial. The curved orogenic belt consists of several ribbon-like continental terranes (Sesia/Austroalpine, Internal Crystalline Massifs, Brianconnais), which are separated by two or more ophiolitic sutures (Piemonte, Valais, Antrona?, Lanzo/ Canavese?). High-pressure (HP) metamorphism of each terrane occurred during distinct orogenic episodes: at similar to65 Ma in the Sesia/Austroalpine, at similar to45 Ma in the Piemonte zone and at similar to35 Ma in the Internal Crystalline Massifs. It is suggested that these events reflect individual accretionary episodes, which together with kinematic indicators and the speed and direction of plate motions, provide constraints for the discussed reconstruction model. The model involves a prolonged orogenic history that took place during relative convergence of Europe and Adria (here considered as a promontory of the African plate). The first accretionary event involved the Sesia/Austroalpine terrane. Final closure of the Piemonte Ocean occurred during the Eocene (similar to45 Ma) and involved ultra-high-pressure (UHP) metamorphism of the Piemonte oceanic crust. Incorporation of the Brianconnais terrane in the accretionary wedge occurred thereafter, possibly during or after subduction of the Valais Ocean in the late Eocene (45-35 Ma). This subduction was terminated at ca. 35 Ma, when the Internal Crystalline Massifs (i.e. the assumed internal parts of the Brianconnais terrane) were buried into great depths and underwent HP and UHP metamorphism. (C) 2004 Elsevier B.V. All rights reserved.

Thought and picture in the Tractatus Logico-Philosophicus

When an elementary proposition is instituted, the pictorial relations establish a contact between the proposition and the fact. This seems to commit the Tractarian project with a psychological view, but this is not the case because the point of view of the Tractatus Logico-Philosophicus is concerned with the conditions of possibility of the representation. In this paper my objective is twofold. First, I show that the thought plays a basic function in the institution of a picture. Second, I show that the fact that the thought plays an important role in the institution of a picture does not commit the Tractarian project with an inquiry of psychological nature.

Improvement in Insulin Sensitivity and B-Cell Function Following Ileal Interposition with Sleeve Gastrectomy in Type 2 Diabetic Patients: Potential Mechanisms

Bariatric surgery in morbidly obese type 2 diabetic (T2DM) patients is associated with high rates of diabetes remission. We investigated the mechanisms of the anti-diabetic effect of the laparoscopic ileal interposition with sleeve gastrectomy (LII-SG) in normal weight (NW), overweight (OW) and obese (OB) T2DM patients. Ninety-four patients (aged 54 +/- 8 years) with long-standing (median 10 years), treated diabetes (median HbA(1c) = 8.6%), who were NW (15), OW (64) or OB (15) based on BMI, underwent LII-SG. Insulin sensitivity and parameters of -cell function were measured from an Oral Glycaemic Tolerance Test pre- and post-operatively. At a median of 13.4 months post-operatively, weight loss averaged 9.4 +/- 1.3, 16.8 +/- 0.8 and 23.2 +/- 1.7 kg in NW, OW and OB subjects, respectively (p < 0.0001). Insulin sensitivity was fully restored (395 [108] vs 208 [99] ml min(-1) m(-2)), fasting insulin secretion rate decreased (68 [52] vs 146 [120] pmol min(-1) m(-2)) and total insulin output increased (52 [26] vs 39 [28] nmol m(-2), all p a parts per thousand currency signaEuro parts per thousand 0.001). -cell glucose sensitivity doubled (37 [33] vs 18 [24] mol min(-1) m(-2) mM(-1), p < 0.0001). The only parameter predicting remission of diabetes was a lower baseline insulin sensitivity (p = 0.005). LII-SG induced changes on T2DM by mechanisms in part distinct from weight loss, principally involving restoration of insulin sensitivity and improvement of -cell function.

Short-term and long-term cardiovascular actions of different doses of perindopril in the rabbit

Short-term (one week) and chronic (six week) cardiovascular effects of orally administered perindopril were examined in the rabbit to demonstrate if short-term results can predict chronic outcomes. In short-term treatment, five doses of perindopril were examined in random order separated by a one week recovery period in each of six rabbits. Two doses of perindopril which resulted in a moderate hypotensive effect (-14 mmHg) and no hypotensive effect, respectively, were then selected for long-term treatment. Each rabbit in the short-term study received perindopril in doses of 0.01, 0.06, 0.32, 1.8 and 10 mg kg(-1) day(-1) for a week at a time. Rabbits on long-term treatment received either 0.3 or 0.01 mg kg(-1) day(-1) perindopril for six weeks. All rabbits had their mean arterial blood pressure (MAP) and heart rate recorded throughout treatment. Plasma angiotensin I (AngI), perindoprilat, angiotensin converting enzyme (ACE) inhibition were also assayed. Perindopril treatment for one week produced a dose-dependent hypotensive effect with the threshold dose, 0.06 mg kg(-1) day(-1), producing a 6.5+/-1.8 mmHg fall in MAP. The highest dose (10.0 mg kg(-1) day(-1)) produced a large fall in blood pressure of -29.6+/-4.2 mmHg. The 0.01 and 0.06 mg kg(-1) day(-1) doses of perindopril produced an average 2.65 fold increase in plasma AngI levels compared to the initial control. The three higher doses (0.32-10.0 mg kg(-1) day(-1)) of perindopril produced an equivalent 5.7 fold increase in plasma AngI levels compared to the initial controls. However, over six weeks 0.01 mg kg(-1) day(-1) perindopril induced a similar decrease in MAP as the 30 fold higher dose (-9.3 mmHg compared to -11.7 mmHg,). This was in spite of a 3 fold difference in plasma perindoprilat concentrations between the high and low dose perindopril groups. Plasma ACE inhibition was >80% with both doses of perindopril. The results indicate that while perindopril decreases MAP in a dose-dependent manner in short-term (one week) periods, over longer treatment times (six weeks) low concentrations of perindopril, non-hypotensive with shortterm treatment, may be as anti-hypertensive as considerably higher doses. (C) 1996 The Italian Pharmacological Society.

Body mass index and risk of head and neck cancer in a pooled analysis of case-control studies in the International Head and Neck Cancer Epidemiology (INHANCE) Consortium

Methods We pooled data from 17 case-control studies including 12 716 cases and the 17 438 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for associations between body mass index (BMI) at different ages and HNC risk, adjusted for age, sex, centre, race, education, tobacco smoking and alcohol consumption. Results Adjusted ORs (95% CIs) were elevated for people with BMI at reference (date of diagnosis for cases and date of selection for controls) < 18.5 kg/m(2) (2.13, 1.75-2.58) and reduced for BMI > 25.0-30.0 kg/m(2) (0.52, 0.44-0.60) and BMI >= 30 kg/m(2) (0.43, 0.33-0.57), compared with BMI > 18.5-25.0 kg/m(2). These associations did not differ by age, sex, tumour site or control source. Although the increased risk among people with BMI < 18.5 kg/m(2) was not modified by tobacco smoking or alcohol drinking, the inverse association for people with BMI > 25 kg/m(2) was present only in smokers and drinkers. Conclusions In our large pooled analysis, leanness was associated with increased HNC risk regardless of smoking and drinking status, although reverse causality cannot be excluded. The reduced risk among overweight or obese people may indicate body size is a modifier of the risk associated with smoking and drinking. Further clarification may be provided by analyses of prospective cohort and mechanistic studies.

Interaction between Tobacco and Alcohol Use and the Risk of Head and Neck Cancer: Pooled Analysis in the International Head and Neck Cancer Epidemiology Consortium

Background: The magnitude of risk conferred by the interaction between tobacco and alcohol use on the risk of head and neck cancers is not clear because studies have used various methods to quantify the excess head and neck cancer burden. Methods: We analyzed individual-level pooled data from 17 European and American case-control studies (11,221 cases and 16,168 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We estimated the multiplicative interaction parameter (psi) and population attributable risks (PAR). Results: A greater than multiplicative joint effect between ever tobacco and alcohol use was observed for head and neck cancer risk (psi = 2.15; 95% confidence interval, 1.53-3.04). The PAR for tobacco or alcohol was 72% (95% confidence interval, 61-79%) for head and neck cancer, of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to tobacco and alcohol combined. The total PAR differed by subsite (64% for oral cavity cancer, 72% for pharyngeal cancer, 89% for laryngeal cancer), by sex (74% for men, 57% for women), by age (33% for cases < 45 years, 73% for cases > 60 years), and by region (84% in Europe, 51% in North America, 83% in Latin America). Conclusions: Our results confirm that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk. However, a substantial proportion of head and neck cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head and neck cancer among women and among young-onset cases. (Cancer Epidemiol Biomarkers Prev 2009;18(2):541-50)

ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency

Adenosine deaminase (ADA) deficiency is a disorder of the purine metabolism leading to combined immunodeficiency and systemic alterations, including skeletal abnormalities. We report that ADA deficiency in mice causes a specific bone phenotype characterized by alterations of structural properties and impaired mechanical competence. These alterations are the combined result of an imbalanced receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin axis, causing decreased osteoclastogenesis and an intrinsic defect of osteoblast function with subsequent low bone formation. In vitro, osteoblasts lacking ADA displayed an altered transcriptional profile and growth reduction. Furthermore, the bone marrow microenvironment of ADA-deficient mice showed a reduced capacity to support in vitro and in vivo hematopoiesis. Treatment of ADA-deficient neonatal mice with enzyme replacement therapy, bone marrow transplantation, or gene therapy resulted in full recovery of the altered bone parameters. Remarkably, untreated ADA-severe combined immunodeficiency patients showed a similar imbalance in RANKL/osteoprotegerin levels alongside severe growth retardation. Gene therapy with ADA-transduced hematopoietic stem cells increased serum RANKL levels and children`s growth. Our results indicate that the ADA metabolism represents a crucial modulatory factor of bone cell activities and remodeling. The trials were registered at www.clinicaltrials.gov as #NCT00598481 and #NCT00599781. (Blood. 2009; 114: 3216-3226)

Molecular Epidemiology of Avian Infectious Bronchitis in Brazil from 2007 to 2008 in Breeders, Broilers, and Layers

Multiple lineages of Brazilian strains from 2007 to 2008 of avian infectious bronchitis virus (IBV) were detected in flocks of breeders, broilers, and layers. Organs samples from 20 IBV-positive flocks with variable clinical signs were submitted to the partial amplification of S gene (nucleotides 726-1071) of IBV. Fifteen of the 20 sequenced strains segregated in a unique Brazilian cluster subdivided in three subclusters (Brazil 01, 02, and 03). Whereas three strains could be classified as Massachusetts (Mass) genotype, the remaining two strains, originating from flocks with reproductive and respiratory disorders, grouped within the 4/91-793B genotype, a genotype that has not been detected before in Brazil. The potential relevance of the findings to the poultry industry is discussed because the low level of identity of the sequenced part of the S gene from 17 of 20 detected field strains and the vaccines of the Massachusetts serotype used suggest that the level of cross-protection by the Massachusetts vaccines might be low.

Blink startle modulation during anticipation of pleasant and unpleasant stimuli

The present research investigated blink startle modulation during the anticipation of pleasant, unpleasant, or neutral pictures. In Experiment 1 (N = 18), participants were presented with three different tone-picture pairings. Tones differed in pitch and were followed by pleasant, neutral or unpleasant pictures. Acoustic blink reflexes were elicited during some tones and during stimulus free intervals. Blink facilitation during tones that preceded pleasant and unpleasant pictures was larger than during the tone that preceded neutral pictures. Experiment 2 (N = 10) assessed whether this difference was due to a difference in the presentation frequency of the three conditions. No difference in blink facilitation between the conditions was found when pictures of flowers and mushrooms replaced the pleasant and unpleasant pictures, indicating that picture content was instrumental in causing the differential blink facilitation in Experiment 1. The results from Experiment 1 seem to indicate that startle modulation during the anticipation of pictorial material reflects the interest in or the arousal associated with the pictures rather than picture valence.

Quantitative analysis of the speed and accuracy of tongue movements in dysarthria subsequent to traumatic brain injury using electromagnetic articulography

It has been recognised that in order to study the displacement, timing and co-ordination of articulatory components (i.e., tongue. lips, jaw) in speech production it is desirable to obtain high-resolution movement data on multiple structures inside and outside the vocal tract. Until recently, with the exception of X-ray techniques such as cineradiography, the study 0. speech movements has been hindered by the inaccessibility of the oral cavity during speech. X-ray techniques are generally not used because of unacceptable radiation exposure. The aim of the present study was to demonstrate the use of a new physiological device, the electromagnetic articulograph, for assessing articulatory dysfunction subsequent to traumatic brain injury. The components of the device together with the measuring principle are described and data collected from a single case presented. A 19 year-old male who exhibited dysarthria subsequent to a traumatic brain injury was fitted wit 2 the electromagnetic articulograph (Carstens AG-100) and a kinematic analysis of his tongue movements during production of the lingual consonants it, s, k/ within single syllable words was performed. Examination of kinematic parameters including movemmt trajectories, velocity, and acceleration revealed differences in the speed and accuracy of his tongue movements compared to those produced by a non-neurologically impaired adult male. It was concluded that the articulograph is a useful device for diagnosing speed and accuracy disorders in tongue movements during speech and that the device has potential for incorporation into physiologically based rehabilitation programs as a real-time biofeedback instrument.

Familial corticosteroid-binding globulin deficiency due to a noval null mutation: Association with fatigue and relative hypotension

Corticosteroid-binding globulin is a 383-amino acid glycoprotein that serves a hormone transport role and may have functions related to the stress response and inflammation. We describe a 39-member Italian-Australian family with a novel complete loss of function (null) mutation of the corticosteroid-binding globulin gene. A second, previously described, mutation (Lyon) segregated independently in the same kindred. The novel exon 2 mutation led to a premature termination codon corresponding to residue -12 of the procorticosteroid-binding globulin molecule (c.121G->A). Among 32 family members there were 3 null homozygotes, 19 null heterozygotes, 2 compound heterozygotes, 3 Lyon heterozygotes, and 5 individuals without corticosteroid-binding globulin mutations. Plasma immunoreactive corticosteroid-binding globulin was undetectable in null homozygotes, and mean corticosteroid-binding globulin levels were reduced by approximately 50% at 18.7 ± 1.3 µg/ml (reference range, 30–52 µg/ml) in null heterozygotes. Morning total plasma cortisol levels were less than 1.8 µg/dl in homozygotes and were positively correlated to the plasma corticosteroid-binding globulin level in heterozygotes. Homozygotes and heterozygote null mutation subjects had a high prevalence of hypotension and fatigue. Among 19 adults with the null mutation, the systolic blood pressure z-score was 12.1 ± 3.5; 11 of 19 subjects (54%) had a systolic blood pressure below the third percentile. The mean diastolic blood pressure z-score was 18.1 ± 3.4; 8 of 19 subjects (42%) had a diastolic blood pressure z-score below 10. Idiopathic chronic fatigue was present in 12 of 14 adult null heterozygote subjects (86%) and in 2 of 3 null homozygotes. Five cases met the Centers for Disease Control criteria for chronic fatigue syndrome. Fatigue questionnaires revealed scores of 25.1 ± 2.5 in 18 adults with the mutation vs. 4.2 ± 1.5 in 23 healthy controls (P < 0.0001). Compound heterozygosity for both mutations resulted in plasma cortisol levels comparable to those in null homozygotes. Abnormal corticosteroid-binding globulin concentrations or binding affinity may lead to the misdiagnosis of isolated ACTH deficiency. The mechanism of the association between fatigue and relative hypotension is not established by these studies. As idiopathic fatigue disorders are associated with relatively low plasma cortisol, abnormalities of corticosteroid-binding globulin may be pathogenic.