Regulation of human CD4(+) alphabeta T-cell-receptor-positive (TCR(+)) and gammadelta TCR(+) T-cell responses to Mycobacterium tuberculosis by interleukin-10 and transforming growth factor beta.

Mycobacterium tuberculosis is the etiologic agent of human tuberculosis and is estimated to infect one-third of the world's population. Control of M. tuberculosis requires T cells and macrophages. T-cell function is modulated by the cytokine environment, which in mycobacterial infection is a balance of proinflammatory (interleukin-1 [IL-1], IL-6, IL-8, IL-12, and tumor necrosis factor alpha) and inhibitory (IL-10 and transforming growth factor beta [TGF-beta]) cytokines. IL-10 and TGF-beta are produced by M. tuberculosis-infected macrophages. The effect of IL-10 and TGF-beta on M. tuberculosis-reactive human CD4(+) and gammadelta T cells, the two major human T-cell subsets activated by M. tuberculosis, was investigated. Both IL-10 and TGF-beta inhibited proliferation and gamma interferon production by CD4(+) and gammadelta T cells. IL-10 was a more potent inhibitor than TGF-beta for both T-cell subsets. Combinations of IL-10 and TGF-beta did not result in additive or synergistic inhibition. IL-10 inhibited gammadelta and CD4(+) T cells directly and inhibited monocyte antigen-presenting cell (APC) function for CD4(+) T cells and, to a lesser extent, for gammadelta T cells. TGF-beta inhibited both CD4(+) and gammadelta T cells directly and had little effect on APC function for gammadelta and CD4(+) T cells. IL-10 down-regulated major histocompatibility complex (MHC) class I, MHC class II, CD40, B7-1, and B7-2 expression on M. tuberculosis-infected monocytes to a greater extent than TGF-beta. Neither cytokine affected the uptake of M. tuberculosis by monocytes. Thus, IL-10 and TGF-beta both inhibited CD4(+) and gammadelta T cells but differed in the mechanism used to inhibit T-cell responses to M. tuberculosis.

High P-T granulite relicts from the Imjingang belt, South Korea:Tectonic significance

This study presents a detailed description on crustal metamorphic signatures of garnet-clinopyroxene-quartz-rutile-bearing high P-T granulites, Samgot unit, Imajingang belt, northwestern Korean Peninsula that formed during Permo-Triassic regional metamorphism related to the amalgamation of East Asian continental fragments. Lenses and blocks of high P-T granulites and garnet-bearing leucosomes occur within mafic metamorphic rocks (mainly amphibolites). The mafic blocks comprise relicts of granoblastic garnet and clinopyroxene with medium-grained quartz and rutile. These relict mineral assemblages are confined to local micro-domains and constitute remnants of peak metamorphism. Plagioclase and amphibole form only as retrograde phases in medium ton coarse-grained moats that rim grain boundaries between relict peak mineral assemblages. This microstructure represents the reaction between garnet, clinopyroxene, quartz and rutile in the presence of melt to form amphibole, plagioclase and titanite with minor biotite. The leucosome domains consist of euhedral garnets within the quartz-K feldspar-plagioclase (granitic) matrix, probably representing peritectic garnet growth along with melting. The rare earth element (REE) composition of minerals also support the peritectic garnet growth with a positive Eu/Eu* (positive Eu anomaly), while the relict garnet shows a slight negative anomaly typical for high-grade granulites. The peak-metamorphic conditions calculated from thermodynamic modeling and compositional isopleths indicate a temperature around c. 900 degrees C at a pressure around c. 20 kbar. The present P-T path indicates a clear multi-stage decompression history with initial decompression and cooling followed by a stage of decompression during hydration possibly during Late Triassic exhumation. The results from this study together with the presence of eclogites from the Hongsung area suggest that the Imjingang area and the western Gyeonggi massif likely resided at crustal levels deeper than those of the eastern and southern part of the Gyeonggi massif. (C) 2009 International Association for Gondwana Research. Published by Elsevier B.V. All rights reserved.

High-pressure Raman and infrared spectroscopic studies of ZrP2O7

High-pressure Raman and mid-infrared spectroscopic studies were carried out on ZrP2O7 to 23.2 and 13 GPa respectively. In the pressure range 0.7-4.3 GPa the lattice mode at 248 cm(-1) disappears, new modes appear around 380 and 1111 cm(-1) and the strong symmetric stretching mode at 476 cm(-1) softens, possibly indicating a subtle phase transition. Above 8 GPa all the modes broaden, and all of the Raman modes disappear beyond 18 GPa. On decompression from the highest pressure, 23.2, to 0 GPa all of the modes reappear but with larger full width at half maximum. Lattice dynamics of the high temperature phase of ZrP2O7 were studied using first principles method and compared with experimental values. (C) 2009 Elsevier Ltd. All rights reserved.

Free-volume dependent pressure sensitivity of Zr-based bulk metallic glass

Instrumented indentation experiments on a Zr-based bulk metallic glass (BMG) in as-cast, shot-peened and structurally relaxed conditions were conducted to examine the dependence of plastic deformation on its structural state. Results show significant differences in hardness, H, with structural relaxation increasing it and shot peening markedly reducing it, and slightly changed morphology of shear bands around the indents. This is in contrast to uniaxial compressive yield strength, sigma(y), which remains invariant with the change in the structural state of the alloys investigated. The plastic constraint factor, C = H/sigma(y), of the relaxed BMG increases compared with that of the as-cast glass, indicating enhanced pressure sensitivity upon annealing. In contrast, C of the shot-peened layer was found to be similar to that observed in crystalline metals, indicating that severe plastic deformation could eliminate pressure sensitivity. Microscopic origins for this result, in terms of shear transformation zones and free volume, are discussed.

Topical tacrolimus in atopic dermatitis : Effects of long-term treatment on skin and respiratory symptoms

Objective: Patients with atopic dermatitis often have a poor long-term response to conventional topical or systemic treatments. Staphylococcal superinfections, skin atrophy due to corticosteroid use, and asthma and allergic rhinitis are common. Only a few, usually short-term, studies have addressed the effects of different treatments on these problems. Tacrolimus ointment is the first topical compound suitable for long-term treatment. The aim of this thesis was to evaluate the effects of long-term topical tacrolimus treatment on cutaneous staphylococcal colonization, collagen synthesis, and symptoms and signs of asthma and allergic rhinitis. Methods: Patients with moderate-to-severe atopic dermatitis were treated with intermittent 0.1% tacrolimus ointment in prospective, open studies lasting for 6 to 48 months. In Study I, cutaneous staphylococcal colonization was followed for 6 to 12 months. In Study II, skin thickness and collagen synthesis were followed by skin ultrasound and procollagen I and III propeptide concentrations of suction blister fluid samples for 12 to 24 months and compared with a group of corticosteroid-treated atopic dermatitis patients and with a group of healthy subjects. Study III was a cross-sectional study of the occurrence of respiratory symptoms, bronchial hyper-responsiveness, and sputum eosinophilia in atopic dermatitis patients and healthy controls. In Study V, the same parameters as in Study III were assessed in atopic dermatitis patients before and after 12 to 48 months of topical tacrolimus treatment. Study IV was a retrospective follow-up of the effect of tacrolimus 0.03% ointment on severe atopic blepharoconjunctivitis and conjunctival cytology. Results: The clinical response to topical tacrolimus was very good in all studies (p≤0.008). Staphylococcal colonization decreased significantly, and the effect was sustained throughout the study (p=0.01). Skin thickness (p<0.001) and markers of collagen synthesis (p<0.001) increased in the tacrolimus-treated patients significantly, whereas they decreased or remained unchanged in the corticosteroid-treated controls. Symptoms of asthma and allergic rhinitis (p<0.0001), bronchial hyper-responsiveness (p<0.0001), and sputum eosinophilia (p<0.0001) were significantly more common in patients with atopic dermatitis than in healthy controls, especially in subjects with positive skin prick tests or elevated serum immunoglobulin E. During topical tacrolimus treatment the asthma and rhinitis (p=0.005 and p=0.002) symptoms and bronchial hyper-responsiveness (p=0.02) decreased significantly, and serum immunoglobulin E and sputum eosinophils showed a decreasing trend in patients with the best treatment response. Treatment of atopic blepharoconjunctivitis resulted in a marked clinical response and a significant decrease in eosinophils, lymphocytes, and neutrophils in the conjunctival cytology samples. No significant adverse effects or increase in skin infections occurred in any study. Conclusions: The studies included in this thesis, except the study showing an increase in skin collagen synthesis in tacrolimus-treated patients, were uncontrolled, warranting certain reservations. The results suggest, however, that tacrolimus ointment has several beneficial effects in the long-term intermittent treatment of atopic dermatitis. Tacrolimus ointment efficiently suppresses the T cell-induced inflammation of atopic dermatitis. It has a normalizing effect on the function of the skin measured by the decrease in staphylococcal colonization. It does not cause skin atrophy as do corticosteroids but restores the skin collagen synthesis in patients who have used corticosteroids. Tacrolimus ointment has no marked systemic effect, as the absorption of the drug is minimal and decreases along with skin improvement. The effects on the airway: decrease in bronchial hyper-responsiveness and respiratory symptoms, can be speculated to be caused by the decrease in T cell trafficking from the skin to the respiratory tissues as the skin inflammation resolves, as well as inhibition of epicutaneous invasion of various antigens causing systemic sensitization when the skin barrier is disrupted as in atopic dermatitis. Patients with moderate-to-severe atopic dermatitis seem to benefit from efficient long-term treatment with topical tacrolimus.

Quasi-periodic, global oscillations in sea level pressure on intraseasonal timescales

The sea level pressure (SLP) variability in 30-60 day intraseasonal timescales is investigated using 25 years of reanalysis data addressing two issues. The first concerns the non-zero zonal mean component of SLP near the equator and its meridional connections, and the second concerns the fast eastward propagation (EP) speed of SLP compared to that of zonal wind. It is shown that the entire globe resonates with high amplitude wave activity during some periods which may last for few to several months, followed by lull periods of varying duration. SLP variations in the tropical belt are highly coherent from 25A degrees S to 25A degrees N, uncorrelated with variations in mid latitudes and again significantly correlated but with opposite phase around 60A degrees S and 65A degrees N. Near the equator (8A degrees S-8A degrees N), the zonal mean contributes significantly to the total variance in SLP, and after its removal, SLP shows a dominant zonal wavenumber one structure having a periodicity of 40 days and EP speeds comparable to that of zonal winds in the Indian Ocean. SLP from many of the atmospheric and coupled general circulation models show similar behaviour in the meridional direction although their propagation characteristics in the tropical belt differ widely.

The Effect of Intrauterine Growth Restriction on Long-Term Outcome in Very or Extremely Low Birth Weight Infants

The project consisted of two long-term follow-up studies of preterm children addressing the question whether intrauterine growth restriction affects the outcome. Assessment at 5 years of age of 203 children with a birth weight less than 1000 g born in Finland in 1996-1997 showed that 9% of the children had cognitive impairment, 14% cerebral palsy, and 4% needed a hearing aid. The intelligence quotient was lower (p<0.05) than the reference value. Thus, 20% exhibited major, 19% minor disabilities, and 61% had no functional abnormalities. Being small for gestational age (SGA) was associated with sub-optimal growth later. In children born before 27 gestational weeks, the SGA had more neuropsychological disabilities than those appropriate for gestational age (AGA). In another cohort with birth weight less than 1500 g assessed at 5 years of age, echocardiography showed a thickened interventricular septum and a decreased left ventricular end-diastolic diameter in both SGA and AGA born children. They also had a higher systolic blood pressure than the reference. Laser-Doppler flowmetry showed different endothelium-dependent and -independent vasodilation responses in the AGA children compared to those of the controls. SGA was not associated with cardio-vascular abnormalities. Auditory event-related potentials (AERPs) were recorded using an oddball paradigm with frequency deviants (standard tone 500 Hz and deviant 750-Hz with 10% probability). At term, the P350 was smaller in SGA and AGA infants than in controls. At 12 months, the automatic change detection peak (mismatch negativity, MMN) was observed in the controls. However, the pre-term infants had a difference positivity that correlated with their neurodevelopment scores. At 5 years of age, the P1-deflection, which reflects primary auditory processing, was smaller, and the MMN larger in the preterm than in the control children. Even with a challenging paradigm or a distraction paradigm, P1 was smaller in the preterm than in the control children. The SGA and AGA children showed similar AERP responses. Prematurity is a major risk factor for abnormal brain development. Preterm children showed signs of cardiovascular abnormality suggesting that prematurity per se may carry a risk for later morbidity. The small positive amplitudes in AERPs suggest persisting altered auditory processing in the preterm in-fants.

P-T evolution of Glenelg eclogites, NW Scotland: Did they experience ultrahigh-pressure metamorphism?

Eclogites and their retrogressed equivalents from the eastern unit of the Glenelg-Attadale Inlier in NW Scotland preserve much microstructural evidence that indicates that very high-pressure/temperature eclogite facies conditions were reached, and followed by decompression and hydration during exhumation. Rutile exsolution in garnet and quartz exsolution in omphacite and titanite formed through mineral reactions during high P-T peak metamorphism. Isochemical phase diagrams modeled for samples from three different locations indicate that the outer part of the eastern unit preserves a peak metamorphic condition of c. 850-1000 degrees C at 18-25 kbar, whereas the central part has a similar pressure (c. 23 kbar), but a lower temperature (c. 670 degrees C). Due to the limitations in the phase diagram calculations the estimated P-T conditions represent the minimum conditions attained by the peak metamorphic assemblage, and the pre-exsoived peak assemblage probably stabilized at a higher pressure. This observation is strongly supported by the presence of exsolution microstructures. The present results demonstrate that the eastern unit experienced very high P-T conditions during peak metamorphism and a tight clockwise P-T trajectory and provide the first indication of possible ultrahigh-pressure metamorphism in the Glenelg eclogites. (C) 2009 Elsevier B.V. All rights reserved.

Neck length and mean arterial pressure in the sauropod dinosaurs

How blood was able to reach the heads of the long-necked sauropod dinosaurs has long been a matter of debate and several hypotheses have been presented. For example, it has been proposed that sauropods had exceptionally large hearts, multiple ‘normal’ sized hearts spaced at regular intervals up the neck or held their necks horizontal, or that the siphon effect was in operation. By means of an experimental model, we demonstrate that the siphon principle is able to explain how blood was able to adequately perfuse the sauropod brain. The return venous circulation may have been protected from complete collapse by a structure akin to the vertebral venous plexus. We derive an equation relating neck height and mean arterial pressure, which indicates that with a mean arterial pressure similar to that of the giraffe, the maximum safe vertical distance between heart and head would have been about 12 m. A hypothesis is presented that the maximum neck length in the fossil record is due to the siphon height limit. The equation indicates that to migrate over high ground, sauropods would have had to either significantly increase their mean arterial pressure or keep their necks below a certain height dependent on altitude.