Polarization of TH2 response is decreased during pregnancy in systemic lupus erythematosus

This study evaluated some cytokines involved in the Th1-Th2 shift during pregnancy in patients with systemic lupus erythematosus (SLE) and healthy women. Twenty-seven consecutive successful pregnancies in 26 SLE patients and 28 pregnancies in 28 matched healthy subjects, as controls, were enrolled and prospectively studied. Sera obtained at first and third trimesters of pregnancy were tested for IL-1α, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, INF-γ, and TNF-α with a highly sensitive, multiplexed sandwich ELISA (SearchLight Human Inflammatory Cytokine Array). Statistics were performed by SPSS package. IL-8 serum levels were higher in the first (P<0.0001) and third (P=0.003) trimesters of pregnancy in SLE patients compared with controls, INF-γ serum levels in the third trimester (P=0.009), and IL-10 serum levels in the first and third trimesters (P=0.055 and P<0.0001, respectively). IL-2 (r=0.524 P=0.010), IL-12 (r=0.549 P=0.007), IFN-γ (r=0.492 P=0.017), and IL-6 (r=0.515 P=0.020) serum levels correlated with disease activity in SLE patients in the first trimester of pregnancy. Cytokine profile was similar in patients with and without lupus nephritis both in the first and in the third trimesters of pregnancy. IL-8 serum levels were lower in patients with a previous diagnosis of antiphospholipid antibody syndrome compared with those without, both in the first and in the third trimesters of pregnancy. In SLE patients, a lower than expected decrease in Th1 cytokine serum levels was observed in the third trimester of gestation which could contribute to a lower Th2 cytokine polarization during pregnancy

Integrated stratigraphy and astrochronology of the Messinian GSSP at Oued Akrech (Atlantic Morocco)

A much improved high-resolution integrated stratigraphy (calcareous plankton biostratigraphy, magnetostratigraphy, cyclostratigraphy) is presented for the classic section of Oued Akrech (Atlantic Morocco) straddling the Tortonian^Messinian boundary. Magnetobiostratigraphic correlations with time-equivalent and astronomically dated sections in the Mediterranean indicate that cyclic alternations of indurated light beige coloured marls and softer, more clayey and reddish coloured marls are dominantly precession-controlled. Characteristic sedimentary cycle patterns, in particular those reflecting precession^obliquity interference, allow for one possible tuning, thus providing accurate astronomical ages for cycles, calcareous plankton events and magnetic reversals. The tuning further indicates that the reddish layers are the equivalent of sapropels in the Mediterranean. The Messinian Global boundary Stratotype Section and Point (GSSP) has recently been formally defined at the base of the reddish layer of cycle No. 15 in section Oued Akrech. This level coincides closely with the first regular occurrence of the Globorotalia miotumida group and is astronomically dated at 7.251 Ma. The global correlation potential is guaranteed by the straightforward calibration of the Oued Akrech magnetostratigraphy to the geomagnetic polarity time scale, locating the GSSP within C3Br.1r. In the marine realm the calcareous nannofossil genus Amaurolithus provides a series of extremely useful events to delimit the boundary on a global scale. The astronomical tuning guarantees a direct first-order calibration of the Messinian GSSP to the standard geological time scale once, as anticipated, the late Miocene part of the astronomical time scale has been incorporated

Application of advanced brain positron emission tomography-based molecular imaging for a biological framework in neurodegenerative proteinopathies

IntroductionA rapid transition from a clinical‐based classification to a pathology‐based classification of neurodegenerative conditions, largely promoted by the increasing availability of imaging biomarkers, is emerging. The Framework for Innovative Multi‐tracer molecular Brain Imaging, funded by the EU Joint Program ‐ Neurodegenerative Disease Research 2016 “Working Groups for Harmonisation and Alignment in Brain Imaging Methods for Neurodegeneration,” aimed at providing a roadmap for the applications of established and new molecular imaging techniques in dementia.MethodsWe consider current and future implications of adopting a pathology‐based framework for the use and development of positron emission tomography techniques.ResultsThis approach will enhance efforts to understand the multifactorial etiology of Alzheimer's disease and other dementias.DiscussionThe availability of pathology biomarkers will soon transform clinical and research practice. Crucially, a comprehensive understanding of strengths and caveats of these techniques will promote an informed use to take full advantage of these tools.</p

Glucose-6-phosphate dehydrogenase plays a crucial role in the protection from redox-stress induced apoptosis.

Glucose-6-phosphate dehydrogenase-deleted embryonic stem (ES) cells (G6pdD) proliferate in vitro without special requirements, but when challenged with oxidants fail to sustain glutathione disulphide reconversion to reduced glutathione (GSH), entering a condition of oxidative stress. Here, we investigate the signalling events downstream of GSH oxidation in G6pdD and wild-type (wt) ES cells. We found that G6pdD ES cells are very sensitive to oxidants, activating an apoptotic pathway at oxidant concentrations otherwise sublethal for wt ES cells. We show that the apoptotic pathway activated by low oxidant concentrations is accompanied by mitochondria dysfunction, and it is therefore blocked by the overexpression of Bcl-XL. Bcl-XL does not inhibit the decrease in cellular GSH and reactive oxygen species formation following oxidant treatment. We also found that oxidant treatment in ES cells is followed by the activation of the MEK/ extracellular signal-regulated kinase (ERK) pathway. Interest¬ingly, ERK activation has opposite outcomes in G6pdD ES cells compared to wt, which has a proapoptotic function in the first and a prosurvival function in the latter. We show that this phenomenon can be regulated by the cellular GSH level

Detection of serum anti-B/B' UsnRNP antibodies in patients with connective tissue diseases by immunoblotting

Objective: To investigate the reliability of the immunoblot method in the detection of serum immunoreactivity towards the B/B' polypeptides of U small nuclear ribonucleoproteins (UsnRNP) and to assess the significance of these antibodies in connective tissue disease (CTD) patients. Methods: We tested the sera of 348 patients with CTD (101 SLE, 51 systemic sclerosis, 53 primary Sjogren's syndrome, 27 poly/dermatomyositis, 15 rheumatoid arthritis and 101 overlap CTD), of 31 matched healthy subjects and 13 patients with primary Epstein-Barr virus (EBV) infection with high titre IgG anti-EBV antibodies. IgG anti-UsnRNP antibodies were determined by immunoblotting on nuclear extract from Raji cells (an EBV-immortalised human B lymphoid cell line) and Jurkat cells (a human T lymphoid cell line). Anti-dsDNA antibodies were detected by indirect immunofluorescence on Crithidia luciliae and anti-ENA by counterimmunoelectrophoresis. Anti-dsDNA activity and avidity were measured in SLE sera by ELISA with Scatchard analysis. Results were statistically analysed by chi-square and Mann-Whitney tests. Results: A high frequency of anti-B/B' antibodies was found in the sera of CTD patients, confined to SLE (54.4%) and overlap CTD with SLE features (55,2%). Anti-B/B' immune reactivity was closely associated with other anti-UsnRNP specificities, gel precipitating anti-nRNP and anti-P antibodies. Nine out of 15 (60%) anti-B/B' positive/anti-ENA negative lupus sera on Raji blots were confirmed to be positive also on Jurkat blots. The sera from patients with EBV infection provided, on Raji blots, completely different band patterns from those obtained with auto-immune sera. Conclusions. The Sm B/B' proteins are the predominant or, at least, the most frequently targeted antigens of the UsnRNP auto-immune response in SLE and "lupus-like" overlap CTD. Moreover, anti-B/B' is diagnostically specific for CTD with SLE features. Immunoblotting on human B lymphoid cells is a reliable method, in terms of sensitivity and specificity, for the detection of anti-Sm B/B' antibodies

Acute noradrenergic activation induces insulin resistance in human skeletal muscle

We assessed in normal subjects the effects of an acute increase in forearm norepinephrine (NE) release, evoked by -20 mmHg lower body negative pressure (LBNP), on insulin-mediated muscle glucose uptake. Seven normal subjects underwent the following two insulin euglycemic clamps in random sequence: one during application of LBNP and the other without LBNP (control study). In the control study, hyperinsulinemia (approximately 60 microU/ml) produced a significant increment in forearm NE release, measured by using the forearm perfusion technique combined with infusion of tritiated NE (from 4.91 +/- 1 to 7.94 +/- 1.33 ng.l-1.min-1; P < 0.05). Forearm glucose uptake rose from 0.97 +/- 0.13 to 5.2 +/- 0.2 mg.l-1.min-1 in response to insulin infusion. When the insulin clamp was performed during LBNP, forearm NE release rose to significantly higher values than those of the control study (from 4.33 +/- 0.52 to 12.7 +/- 1.46 ng.l-1.min-1; P < 0.01 vs. control). Under these conditions, the stimulatory effect of insulin on forearm glucose uptake was markedly reduced (from 0.78 +/- 0.10 to 3.2 +/- 0.7 mg.l-1.min-1; P < 0.02 vs. control). Forearm blood flow and plasma epinephrine and free fatty acid concentrations were comparable in the two study sessions. These data demonstrate that an acute activation of endogenous NE release antagonizes insulin-mediated glucose uptake in forearm skeletal muscle, probably accounted for by a direct metabolic effect of NE.We assessed in normal subjects the effects of an acute increase in forearm norepinephrine (NE) release, evoked by -20 mmHg lower body negative pressure (LBNP), on insulin-mediated muscle glucose uptake. Seven normal subjects underwent the following two insulin euglycemic clamps in random sequence: one during application of LBNP and the other without LBNP (control study). In the control study, hyperinsulinemia (≃60 μU/ml) produced a significant increment in forearm NE release, measured by using the forearm perfusion technique combined with infusion of tritiated NE (from 4.91 ± 1 to 7.94 ± 1.33 ng · l -1 · min -1 ; P < 0.05). Forearm glucose uptake rose from 0.97 ± 0.13 to 5.2 ± 0.2 mg · l -1 · min -1 in response to insulin infusion. When the insulin clamp was performed during LBNP, forearm NE release rose to significantly higher values than those of the control study (from 4.33 ± 0.52 to 12.7 ± 1.46 ng · l -1 · min -1 ; P < 0.01 vs. control). Under these conditions, the stimulatory effect of insulin on forearm glucose uptake was markedly reduced (from 0.78 ± 0.10 to 3.2 ± 0.7 mg · l -1 · min -1 ; P < 0.02 vs. control). Forearm blood flow and plasma epinephrine and free fatty acid concentrations were comparable in the two study sessions. These data demonstrate that an acute activation of endogenous NE release antagonizes insulin-mediated glucose uptake in forearm skeletal muscle, probably accounted for by a direct metabolic effect of NE

Evaluation of corneal distortion characteristics in different eyes using Scheimpflug camera device

Objective. To study the correlations between corneal distortion and morphological features in different kinds of eyes such as healthy ones (HE), ones previously undergone myopic PRK (PRKE), ones affected by keratoconus (KCE) and keratoconus eyes previously undergone corneal collagen crosslinking (CCCE). Materials and Methods. In this retrospective comparative study, a total of 106 HE of 106 patients, 58 PRKE of 58 patients, 33 KCE of 33 patients, 28 CCCE of 28 patients were included. A complete examination of all eyes was followed by tomographic (Pentacam, Oculus, Wetzlar, Germany) and biomechanical (Corvis ST, Oculus, Wetzlar, Germany) evaluation. Differences among Corvis ST (CST) parameters in the different groups have been analyzed. Linear regressions between central corneal thickness (CCT), intraocular pressure (IOP) and anterior corneal curvature measured with Simulated Keratometry (SK), versus corneal deformation parameters measured with Corvis ST in the different groups, have been run using SPSS software version 18.0. Results, HE showed a significant correlation between main curvature power of the cornea within the central 3 mm expressed in Diopters (KM) and 6 CST parameters; between CCT and 4 CST parameters and between IOP and 5 CST parameters. PRKE showed a significant correlation between KM and 3 CST parameters; between IOP and 4 CST parameters and none between CCT and CST parameters. KCE showed a significant correlation between SK and 3 CST parameters; between IOP and 3 CST parameters and none between CCT and CST parameters. CCCE showed a significant correlation between KM and 5 CST parameters; between CCT and 1 CST parameters and between IOP and 5 CST parameters. Discussion. Data of this study suggest that both corneal curvature and IOP could have a greater influence on the corneal deformation, compared to central corneal thickness (CCT). These results should be taken into account by further studies aiming to assess biomechanical corneal characteristics

Eigenvector perturbation methodology for uncertainty quantification of turbulence models

Reynolds-averaged Navier-Stokes (RANS) models are the primary numerical recourse to investigate complex engineering turbulent flows in industrial applications. However, to establish RANS models as reliable design tools, it is essential to provide estimates for the uncertainty in their predictions. In the recent past, an uncertainty estimation framework relying on eigenvalue and eigenvector perturbations to the modeled Reynolds stress tensor has been widely applied with satisfactory results. However, the methodology for the eigenvector perturbations is not well established. Evaluations using only eigenvalue perturbations do not provide comprehensive estimates of model form uncertainty, especially in flows with streamline curvature, recirculation, or flow separation. In this article, we outline a methodology for the eigenvector perturbations using a predictor-corrector approach, which uses the incipient eigenvalue perturbations along with the Reynolds stress transport equations to determine the eigenvector perturbations. This approach was applied to benchmark cases of complex turbulent flows. The uncertainty intervals estimated using the proposed framework exhibited substantial improvement over eigenvalue-only perturbations and are able to account for a significant proportion of the discrepancy between RANS predictions and high-fidelity data

[Myositis specific and myositis associated autoantibodies in idiopathic inflammatory myopathies: a serologic study of 46 patients]

Objective. To characterize serum autoantibody profiles of patients with idiopathic inflammatory myopathies (IIM) by searching for myositis-specific (MSA) and myositis-associated (MAA) antibodies with sensitive and specific laboratory tests. Methods. We tested the sera from 46 Caucasian patients diagnosed as affected with IIM at the Division of Rheumatology of Padova University (21 polimyositis, PM; 22 dermatomyositis, DM; 3 myositis overlap syndrome). All patients had definite IIM according to the criteria of Bohan-Peter. MSA including anti-tRNA synthetase (anti-Jo-1 and others) and anti-Mi-2 were determined by RNA immunoprecipitation and a modified immunoblot test, respectively. MAA (-U1RNP, -U2RNP, RoRNP, PM/Scl, Ku) were detected by counterimmunoelectrophoresis and immunoblot. Results. Serum MSA and/or MAA were found in 30/46 (65%) patients with IIM. Twenty-three patients (50%) were positive for at least one MSA: anti-Jo-1 in 15 (33%), anti-Mi-2 in 6 (13%), and other anti-tRNA synthetase in 3 (6%).One patient was anti-Jo-1/Mi-2 positive. Moreover, 18 patients (39%) were positive for at least one MAA: anti-Ro/SSA in 13 (28%), anti-U1RNP in 4 (9%), anti-PM/Scl in 1 (2%) and anti-Ku in 1 (2%). Coexisting MSA and MAA were observed in 8 patients (17%), anti-Jo-1/SSA positive in most cases. Anti-Jo-1 was predominantly associated with PM (57% in PM vs 14% in DM), whereas anti-Mi-2 was exclusively found in DM patients (27%). Anti-synthetase antibodies were closely associated with interstitial lung disease and polyarthritis; anti-Mi-2 positive DM patients did not have lung involvement. Notably, anti-Ro/SSA antibody was frequently observed and almost equally detected in either PM or DM (about 30%): in more than 50% of cases the antibody was associated with one MSA. Conclusions. By means of analytically reliable methods, MSA was detected in 50% of our IIM patients. Searching for MSA in patients with IIM is recommended because of its diagnostic and prognostic value