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Selected AbstractsFoxo1 regulates marginal zone B-cell developmentEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2010Jing Chen Abstract A fundamental component of signaling initiated by the BCR and CD19 is the activation of phosphoinositide 3-kinase. Downstream of phosphoinositide 3-kinase, the protein kinase AKT phosphorylates several substrates, including members of the forkhead box subgroup O (Foxo) transcription factor family. Among the Foxo proteins, Foxo1 has unique functions in bone marrow B-cell development and peripheral B-cell function. Here, we report a previously unrecognized role for Foxo1 in controlling the ratio of mature B-cell subsets in the spleen. Conditional deletion of Foxo1 in B cells resulted in an increased percentage of marginal zone B cells and a decrease in follicular (FO) B cells. In addition, Foxo1 deficiency corrected the absence of marginal zone B cells that occurs in CD19-deficient mice. These findings show that Foxo1 regulates the balance of mature B-cell subsets and is required for the marginal zone B-cell deficiency phenotype of mice lacking CD19. [source] Cladoceran community responses to biomanipulation and re-oligotrophication in Lake Vesijärvi, Finland, as inferred from remains in annually laminated sedimentFRESHWATER BIOLOGY, Issue 6 2010MIRVA NYKÄNEN Summary 1. We studied the role of zooplankton in biomanipulation and the subsequent recovery phase in the Enonselkä basin of Lake Vesijärvi, using subfossil cladocerans in annually laminated sediment. Measures to restore the Enonselkä basin included reduction in external nutrient loading and mass removal of plankti- and benthivorous fish. Water clarity increased and the lake changed from a eutrophic to a mesotrophic state. However, some signs of increased turbidity were observed after 5,10 years of successful recovery. 2. Annual laminae in a freeze core sample were identified and sliced, based on the seasonal succession of diatoms. Cladoceran remains and rotifer eggs were counted, and Daphnia ephippia and Eubosmina and Bosmina ephippia and carapaces were measured. Annual changes in pelagic species composition were studied with principal component analysis. Individual species abundance, size measurements and various cladoceran-based indices or ratios (commonly used to reconstruct changes in trophic state and fish predation) were tested for change between four distinct periods: I (1985,1988) dense fish stocks, poor water quality; II (1989,1992) fish removal; III (1993,1997) low fish density, improved water quality; IV (1998,2002) slightly increased fish density and poorer water quality. 3. After the removal of fish, the mean size of Daphnia ephippia and Eubosmina crassicornis ephippia and carapaces increased significantly. In contrast, the percentage of Daphnia did not increase. When based on ephippia, the ratio Daphnia/(Daphnia + E. crassicornis) increased, but the interpretation was obscured by the tolerance of fish predation by small Daphnia and by the fact that bosminids were the preferred food of roach. Moreover, ephippial production by E. crassicornis decreased in recent years. 4. The abundance of Diaphanosoma brachyurum and Limnosida frontosa increased significantly after the fish population was reduced, while that of Ceriodaphnia and rotifers decreased. 5. The expanding littoral vegetation along with improved water clarity was clearly reflected in the concentration of littoral species in the deep sediment core. The species diversity index for the entire subfossil community also increased. 6. The period of faltering recovery was characterised by greater interannual variability and an increased percentage of rotifers. Nevertheless, the mean sizes of Daphnia ephippia and E. crassicornis ephippia and carapaces indicated a low density of fish. The deteriorating water quality was apparently related to multiple stressors in the catchment after rehabilitation, such as intensified lakeshore building, as well as to exceptional weather conditions, challenging the management methods in use. [source] EEG-fMRI of focal epileptic spikes: Analysis with multiple haemodynamic functions and comparison with gadolinium-enhanced MR angiogramsHUMAN BRAIN MAPPING, Issue 3 2004Andrew P. Bagshaw Abstract Combined EEG-fMRI has recently been used to explore the BOLD responses to interictal epileptiform discharges. This study examines whether misspecification of the form of the haemodynamic response function (HRF) results in significant fMRI responses being missed in the statistical analysis. EEG-fMRI data from 31 patients with focal epilepsy were analysed with four HRFs peaking from 3 to 9 sec after each interictal event, in addition to a standard HRF that peaked after 5.4 sec. In four patients, fMRI responses were correlated with gadolinium-enhanced MR angiograms and with EEG data from intracranial electrodes. In an attempt to understand the absence of BOLD responses in a significant group of patients, the degree of signal loss occurring as a result of magnetic field inhomogeneities was compared with the detected fMRI responses in ten patients with temporal lobe spikes. Using multiple HRFs resulted in an increased percentage of data sets with significant fMRI activations, from 45% when using the standard HRF alone, to 62.5%. The standard HRF was good at detecting positive BOLD responses, but less appropriate for negative BOLD responses, the majority of which were more accurately modelled by an HRF that peaked later than the standard. Co-registration of statistical maps with gadolinium-enhanced MRIs suggested that the detected fMRI responses were not in general related to large veins. Signal loss in the temporal lobes seemed to be an important factor in 7 of 12 patients who did not show fMRI activations with any of the HRFs. Hum. Brain Mapp. 22:179,192, 2004. © 2004 Wiley-Liss, Inc. [source] The effect of soya flour and flaxseed as a partial replacement for bread flour in yeast breadINTERNATIONAL JOURNAL OF FOOD SCIENCE & TECHNOLOGY, Issue 2006Frank D. Conforti Summary The aim of the study was to incorporate and determine the effect of combining flaxseed meal (15%) and soya flour (5% and 10%) and monitoring the effect of the two ingredients on product quality in yeast bread while at the same time to evaluate the effect of soya flour in preventing the development of lipid rancidity in the stored soya/flax bread. Bread volume decreased (P < 0.05) with increased addition of grains (flax and soya flour). Firming (P < 0.05) of the crumb was observed with increased percentage of soya flour. There were no significant differences (P > 0.05) in moisture in the flax and soya/flax breads. Darker crusts (P < 0.05) were developed in the control and soya/flax breads, while a darker (P < 0.05) crumb was found in flax and soya/flax breads. A 10% substitution level of soya flour did not have a significant effect on inhibiting lipid rancidity, but a lower peroxide value was produced in the bread. A 10% level of soya flour substitution also produced bread with lower quality sensory scores. [source] Patterns Of Quantitative Sensation Testing Of Hypoesthesia And Hyperalgesia Are Predictive Of Diabetic Polyneuropathy,a Study Of Three CohortsJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 2 2000P.J. Dyck OBJECTIVE,To test quantitative sensation testing (QST) patterns of hypoesthesia and hyperalgesia as indicators of diabetic polyneuropathy (DPN) and its severity. RESEARCH DESIGN AND METHODS,We used Computer-Assisted Sensory Examination IV characterized the QST results of the foot of each patient in three diabetic cohorts (similar to 1,500 patients) as hyperesthetic (less than or equal to 2.5th percentile), low-normal (2.5th,50th percentiles), high-normal (50th,97.5th percentiles), or hypoesthetic (greater than or equal to 97.5th percentile), and tested associations with symptoms, impairments, and test abnormalities. RESULTS,Overall neuropathic impairment was most severe in the pancreas-renal transplant and nerve growth factor cohorts, but it was much less severe in the population-based Rochester Diabetic Neuropathy Study (RDNS) cohort. The frequency distribution of sensory abnormalities mirrored this difference. When the QST spectra of diabetic cohorts were compared with those of the control subject cohort for vibration and cooling sensations, the only abnormality observed was hypoesthesia, which was expressed as an increased number of subjects with values at or above the 97.5th percentile or by an increased percentage of cases with high-normal values. Symptoms and impairments of DPN were significantly more frequent in the subjects with Values at or above the 97.5th percentile than in the subjects whose values were between the 50th and 97.5th percentiles. For heat pain (HP) sensation thresholds (intermediate pain severity [HP:5], pain threshold [HP:0.5], and pain-stimulus response slope [HP:5-0.5]), an increased frequency of both hypoalgesia and hyperalgesia was observed (especially in the RDNS cohort). Steeper pain-stimulus response slopes were significantly associated with sensory symptoms, including severity of pain. CONCLUSIONS,1) Decreased vibratory sensation (hypoesthesia) appears to be characteristic of mild DPN, whereas pan-modality hypoesthesia is characteristic of severe DPN. 2) A shift of vibratory and cold detection thresholds and also of attributes of nerve conduction and a measure of autonomic dysfunction from low-normal (2.5th,50th percentiles) to high-normal (50th,37.5th percentiles) appears to precede overt expression of DPN and to thereby provide evidence of subclinical abnormality. 3) Heat stimulus-induced hyperesthesia (low thresholds) occurs especially in mild DPN, and, because it correlates with DPN symptoms and impairments, it must be attributed to hyperalgesia rather than to supersensitivity. Therefore, hypoalgesia or hyperalgesia may be an indicator of early DPN. [source] Evaluation of Antineutrophil IgG Antibodies in Persistently Neutropenic DogsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 3 2007Douglas J. Weiss DVM Background:Immune-mediated neutropenia (IMN) is one of several causes of persistent neutropenia in dogs. A test to detect IMN in dogs is not available. Hypothesis:A flow cytometric immunofluorescence assay will provide a sensitive method for detection of antineutrophil antibodies in dogs. Animals:The study included 12 neutropenic dogs and 20 healthy dogs. Methods:An indirect immunofluorescence assay was used to detect immunoglobulin G (IgG) binding to dog neutrophils. Leukoagglutination was evaluated by light microscopy. Neutrophil distribution in scatter plots, neutrophil fluorescence intensity, and the percentage of neutrophils with increased fluorescence intensity was evaluated by use of flow cytometry. Results:Antineutrophil antibodies were detected in the serum of 5 of 6 dogs with a clinical diagnosis of IMN. Leukoagglutination was present in 3 dogs. Four dogs had altered neutrophil distribution in forward-angle versus side-angle light scatter plots. Five of 6 dogs had increased neutrophil fluorescence intensity and 4 of 6 dogs had an increased percentage of neutrophils with increased fluorescence intensity. Conclusions and Clinical Importance: The flow cytometric test for antineutrophil antibodies detects dogs with a clinical diagnosis of IMN. Testing for antineutrophil antibodies should include observation for leukoagglutination, observation of scatter plots for altered distribution of the neutrophil population, observation of the shape of the fluorescence histogram, determination of neutrophil fluorescence intensity, and determination of the percentage of neutrophils with increased fluorescence intensity. [source] Comparison of Four Staining Methods for Detection of Mast Cells in Equine Bronchoalveolar Lavage FluidJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 2 2006Mathilde Leclere Mast cells normally are present in equine bronchoalveolar lavage fluid (BALF), but usually represent <2% of all cells in healthy horses. An increased percentage of mast cells has been associated with airway hyperactivity and inflammatory airway diseases, but marked differences are reported between studies in normal and diseased horses. Because an abnormal mast cell count may be of clinical relevance, we compared the ability of a fast Romanowsky method to stain mast cell granules with that of 3 metachromatic stains: automated Romanowsky, May-Grünwald Giemsa, and toluidine blue stains. The BALF cells from 24 horses were studied. A differential cell count was performed blindly on 400 cells. The percentages of mast cells obtained were analyzed by means of repeated-measures analysis of variance and Fischer's PLSD test. The Bland and Altman method was used to assess agreement among stains. The mean percentage of mast cells in BALF was significantly lower with the fast Romanowsky than with the automated Romanowsky, May-Grünwald Giemsa, and toluidine blue stains. With the fast Romanowsky stain, the metachromatic granules of mast cells were not stained, and their identification was based on morphologic criteria. Toluidine blue staining allowed detection of the highest mean percentage of mast cells, but was inadequate for performing a differential cell count on other cell types. In conclusion, fast Romanosky stain may be inadequate for detection of mast cells in equine BALF, whereas automated Romanowsky, May-Grünwald Giemsa, and toluidine blue stains provide metachromatic staining of mast cell granules. [source] Both ADP and Thrombin Regulate Arteriolar Thrombus Stabilization and Embolization, but Are Not Involved in Initial Hemostasis as Induced by MicropunctureMICROCIRCULATION, Issue 3 2007Miriam A. Van Gestel ABSTRACT Objective: Thrombosis and embolization are main causes of morbidity and mortality. Up to now, the relative importance of mediators involved is only partly known. It was the aim of this study to investigate the involvement of ADP and thrombin in subsequent phases of arteriolar hemostasis and thromboembolism in vivo. Methods: Rabbit mesenteric arterioles were punctured, which induced bleeding, hemostasis, and subsequent thromboembolism. This reaction as well as the activation state of platelets involved ([Ca2 +]i), was monitored in real time by intravital (fluorescence) microscopy. Results: Neither inhibition of thrombin formation or thrombin activity nor blockade of platelet ADP receptors P2Y1 and P2Y12 influenced the initial hemostatic reaction: in all experiments initial bleeding was stopped by a primary thrombus within 2,3 s. On the other hand, both thrombin inhibition and P2Y1 blockade increased rebleeding frequency, which indicates reduced thrombus stability in the long term. Finally, inhibition of either thrombin or ADP (via both receptors) reduced aggregate formation during the embolization phase by at least 90%. While most participating platelets exhibited a transient increase in [Ca2 +]i during embolization, an increased percentage of platelets showed no calcium response at all during P2Y1 blockade, which was accompanied by reduced platelet,platelet interaction strength. Conclusions: Whereas thrombin and ADP are not involved in the initial hemostatic reaction, both substances appear to be essential to prevent rebleedings in the long term. During subsequent embolization, ADP (via both receptors) and small amounts of thrombin are involved in platelet activation. [source] Inhibitory control and spatial working memory in Parkinson's diseaseMOVEMENT DISORDERS, Issue 10 2007Caroline Gurvich DPsych (Clin Neuro) Abstract Patients with Parkinson's disease (PD) have difficulty performing tasks relying on inhibitory control and working memory, functions of the prefrontal cortex. Eye movement paradigms can be used to investigate basic sensorimotor functions and higher order cognitive aspects of motor control. This study investigated inhibitory control and spatial working memory in the saccadic system of 13 individuals with mild-moderate PD and 13 age-matched controls. Tasks explored suppression of reflexive saccades during qualitatively different tasks, generation of express and anticipatory saccades, and the ability to respond to occasional, unpredictable ("oddball") targets that occurred during a sequence of well-learned, reciprocating saccades between horizontal targets. Spatial working memory was assessed using single and two-step (involving a visually guided saccade during the delay period) memory-guided tasks. Results for the PD group indicated an increased percentage of response selection errors during an oddball task, reduced suppression of inappropriate reflexive saccades during memory-guided tasks (but not during fixation or saccade-engagement tasks), and an increased percentage of express and anticipatory saccades. Spatial working memory was preserved in the PD group during single and two-step memory-guided tasks. These findings are consistent with dysfunction within fronto-striatal and prefrontal-collicular pathways influencing suppression and selection of eye movements. © 2007 Movement Disorder Society [source] Inhibition of the initial wave of NF-,B activity in rat muscle reduces ischemia/reperfusion injuryMUSCLE AND NERVE, Issue 4 2001Sean T. Lille MD Abstract Nuclear factor kappaB (NF-,B) is thought to play an important role in the expression of genes expressed in response to ischemia/reperfusion (I/R) injury. In this report, the activation of NF-,B in rat skeletal muscle during reperfusion following a 4-h ischemic period was studied. NF-,B activation displayed a biphasic pattern, showing peak activities from 30 min to 3 h postperfusion and 6 h to 16 h postperfusion, with a decline to baseline binding activity levels between 3 h and 6 h. Inhibition of NF-,B activation was investigated using proline dithiocarbamate (Pro-DTC). NF-,B binding activity during reperfusion was significantly reduced by intravenous administration of Pro-DTC. Additionally, Pro-DTC resulted in decreased muscle edema and neutrophil activity, with an increased percentage of muscle survival compared with vehicle controls. These results demonstrate that NF-,B is activated during reperfusion in a biphasic manner and that the regulation of the initial phase of NF-,B activation affords physiological protection against a severe ischemic stress. Selective inhibition of NF-,B during early reperfusion may therefore be a therapeutic intervention for I/R injury. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 534,541, 2001 [source] Immunodeficiency with recurrent panlymphocytopenia, impaired maturation of B lymphocytes, impaired interaction of T and B lymphocytes, and impaired integrity of epithelial tissue: A variant of idiopathic CD4+ T lymphocytopenia?PEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 5 2002Horst Von Bernuth Idiopathic CD4+ T lymphocytopenia (ICL) has been defined as a cause of immunodeficiency with a variable clinical course and an unknown etiology. Here we describe a now 18-year-old boy with ICL, chronic mucocutaneous candidiasis (CMC), recurrent abscesses, and relapsing aphthous and ulcerous lesions. In addition to ICL the patient frequently showed a panlymphocytopenia. An increased percentage of ,+,+ T lymphocytes and IgD+ IgM+ B lymphocytes, and a decreased percentage of CD21+ B lymphocytes, were observed. In vitro assays showed normal T-cell responses to candidin and T-cell mitogens, but impaired B-cell responses to pokeweed mitogen (PWM). B-cell maturation after stimulation with Staphylococcus aureus Cowan I (SAC) and interleukin 2 (IL-2) was nearly normal. The clinical course of the patient improved substantially on administration of constant low-dose therapy with fluconazole. [source] ORIGINAL ARTICLE: Women with Pre-Eclampsia Have an Altered NKG2A and NKG2C Receptor Expression on Peripheral Blood Natural Killer CellsAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 3 2009Nora Bachmayer Problem, Preeclampsia, a pregnancy disorder, is associated with exaggerated inflammation and increased serum monokines. Uterine natural killer (NK) cells are implicated in preeclampsia pathology, but little is known regarding peripheral NK cells in the disease. Method of Study, We examined blood NK cells at delivery in women with preeclampsia, in healthy pregnant women and in healthy non-pregnant blood donors as a reference. Results, Although the percentages of both NKG2A- and NKG2C-positive NK cells were normal in preeclamptic women, the levels of NKG2A and NKG2C on NK cells were significantly up-regulated in these women. In vitro stimulation of PBMCs from healthy pregnant women and blood donors with monokines resulted in increased percentage of NKG2A+ NK cells and increased NKG2A levels, while levels of NKG2C were decreased. Conclusions, Our results suggest that the peripheral NK-cell pool is skewed in preeclampsia and possibly under the influence of monokines like interleukin (IL)-15 and IL-12. [source] ORIGINAL ARTICLE: Tumor Necrosis Factor-,-Associated Mechanisms Affecting the Embryonic Response to CyclophosphamideAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 3 2009Keren Mammon Problem, We have previously shown that TNF-,,/, embryos are more sensitive to the exposure to cyclophosphamide (CP) compared with TNF-,+/+ embryos; however, the underlying mechanisms are not fully understood. Thus, in our present study, we tried to identify those molecules that might be responsible for the protective effect of the cytokine. Method of study, CP-treated TNF-,,/, and TNF-,+/+ embryos were analyzed for changes in apoptosis by TUNEL and flow cytometry, while cell proliferation was analyzed by BrdU incorporation. The expression of Bax, bcl-2, p53, the p65 subunit of NF-,B and I,B, was assessed by Western blotting and immunohistochemistry. Results, CP-treated TNF-,,/, embryos exhibited a more profound decrease in their weight, which was accompanied by an earlier appearance of cellular damage and apoptotic cells and an earlier decrease in cell proliferation in the embryonic brain compared with TNF-,+/+ embryos. Also, an increased percentage of Bax-positive cells and a decreased percentage of bcl-2-positive cells were detected in TNF-,,/, embryos 48 hr after exposure, which were accompanied by a decreased percentage of p53-positive cells. Conclusion, Our data implicate TNF-, to be involved in the protection of the embryo against CP teratogenicity, possibly via alteration in Bax, bcl-2 or p53 expression. [source] Effect of adamantylamide dipeptide as adjuvant therapy to praziquantel in mice infected with different S. mansoni isolates,APMIS, Issue 7-8 2006SANAA BOTROS This work investigated the possible use of AdDP as adjuvant therapy to praziquantel (PZQ) in mice infected with PZQ-insusceptible Schistosoma mansoni isolate in a trial to increase the susceptibility of this isolate to the drug. Two batches of C57 BL/6 mice were infected with PZQ-susceptible and -insusceptible S. mansoni isolates, and each batch was divided into five groups. Seven weeks postinfection, the experimental group received AdDP (5 mg/kg) in addition to PZQ in reduced dose (3×100 mg/kg). Three of the remaining four groups were treated controls; they received AdDP, PZQ in reduced dose and in full dose (2×500 mg/kg), and the fourth group was infected untreated. In mice infected with PZQ-susceptible or -insusceptible S. mansoni isolate, praziquantel alone, and in addition to AdDP, reduced worm and egg loads and increased percentage dead eggs. Also, they improved the histopathological changes (reduction in granuloma diameter, percentage fibrotic area with increased percentage degenerated eggs). Inducible nitric oxide synthase (iNOS), nitric oxide (NO) in culture of peritoneal macrophages, and number of CD68-positive cells were decreased with improved alanine amino transaminase. In mice receiving combined therapy AdDP+PZQ, the antischistosomal efficacy and the reductions in the inflammatory granulomatous reactions, NO in cultured peritoneal macrophages, percentage fibrotic areas recorded, were comparable to that in mice receiving full dose of PZQ, with significantly higher reduction in CD68 cells denoting enhanced antischistosomal efficacy and healing of the inflammatory reactions in the liver. [source] Lipid composition of malpigmented and normally pigmented newly settled yellowtail flounder, Limanda ferruginea (Storer)AQUACULTURE RESEARCH, Issue 15 2002L A Copeman Abstract The lipid composition of malpigmented (MP) and normally pigmented (NP), newly settled yellowtail flounder (Limanda ferruginea, Storer) was compared in order to elucidate a possible connection between lipids and pigmentation development. Larvae were fed commercially enriched live food for 12 weeks post hatch and then differences in lipid composition and size were analysed. NP fish were found to be significantly larger (standard length 35 mm) than MP fish (32 mm) at 100% settlement. There were higher proportions of triacylglycerols in NP fish (P = 0.01), whereas MP fish had an increased percentage of phospholipids (P = 0.01). NP fish had a higher percentage of docosahexaenoic acid (DHA) in the polar lipids of their body (P = 0.03) and total lipids of their eyes (P = 0.04). These data support previously proposed theories for the importance of DHA in pigmentation development. Principal components analysis (PCA) described the majority of the variance (77%) within the data set using just two principal components axes. PCA demonstrated that differences between body zones were greater than those between NP and MP fish within a given zone. [source] Intracellular Na+ and Ca2+ modulation increases the tensile properties of developing engineered articular cartilageARTHRITIS & RHEUMATISM, Issue 4 2010Roman M. Natoli Objective Significant collagen content and tensile properties are difficult to achieve in tissue-engineered articular cartilage. The aim of this study was to investigate whether treating developing tissue-engineered cartilage constructs with modulators of intracellular Na+ or Ca2+ could increase collagen concentration and construct tensile properties. Methods Inhibitors of Na+ ion transporters and stimulators of intracellular Ca2+ were investigated for their ability to affect articular cartilage development in a scaffoldless, 3-dimensional chondrocyte culture. Using a systematic approach, we applied ouabain (Na+/K+ -ATPase inhibitor), bumetanide (Na+/K+/2Cl, tritransporter inhibitor), histamine (cAMP activator), and ionomycin (a Ca2+ ionophore) to tissue-engineered constructs for 1 hour daily on days 10,14 of culture and examined the constructs at 2 weeks or 4 weeks. The gross morphology, biochemical content, and compressive and tensile mechanical properties of the constructs were assayed. Results The results of these experiments showed that 20 ,M ouabain, 0.3 ,M ionomycin, or their combination increased the tensile modulus by 40,95% compared with untreated controls and resulted in an increased amount of collagen normalized to construct wet weight. In constructs exposed to ouabain, the increased percentage of collagen per construct wet weight was secondary to decreased glycosaminoglycan production on a per-cell basis. Treatment with 20 ,M ouabain also increased the ultimate tensile strength of neo-tissue by 56,86% at 4 weeks. Other construct properties, such as construct growth and type I collagen production, were affected differently by Na+ modulation with ouabain versus Ca2+ modulation with ionomycin. Conclusion These data are the first to show that treatments known to alter intracellular ion concentrations are a viable method for increasing the mechanical properties of engineered articular cartilage and identifying potentially important relationships to hydrostatic pressure mechanotransduction. Ouabain and ionomycin may be useful pharmacologic agents for increasing tensile integrity and directing construct maturation. [source] Epitope-specific immunotherapy of rheumatoid arthritis: Clinical responsiveness occurs with immune deviation and relies on the expression of a cluster of molecules associated with T cell tolerance in a double-blind, placebo-controlled, pilot phase II trial,ARTHRITIS & RHEUMATISM, Issue 11 2009Eva C. Koffeman Objective Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis (RA). Accordingly, we are developing a tolerization approach to dnaJP1, a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA. We undertook this study to test 2 hypotheses: 1) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype, and 2) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement. Methods One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial. They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months. Results The dnaJP1 peptide was safe and well-tolerated. In response to treatment with dnaJP1, there was a significant reduction in the percentage of T cells producing tumor necrosis factor , and a corresponding trend toward an increased percentage of T cells producing interleukin-10. Coexpression of a cluster of molecules (programmed death 1 and its ligands) associated with T cell regulation was also found to be a prerequisite for successful tolerization in clinical responders. Analysis of the primary efficacy end point (meeting the American College of Rheumatology 20% improvement criteria at least once on day 112, 140, or 168) showed a difference between treatment groups that became significant in post hoc analysis using generalized estimating equations. Differences in clinical responses were also found between treatment groups on day 140 and at followup. Post hoc analysis showed that the combination of dnaJP1 and hydroxychloroquine (HCQ) was superior to the combination of HCQ and placebo. Conclusion Tolerization to dnaJP1 leads to immune deviation and a trend toward clinical efficacy. Susceptibility to treatment relies on the coexpression of molecules that can down-regulate adaptive immunity. [source] Increased expression of the natural killer cell inhibitory receptor CD94/NKG2A and CD158b on circulating and lesional T cells in patients with chronic plaque psoriasisBRITISH JOURNAL OF DERMATOLOGY, Issue 2 2006Y.H. Liao Summary Background, Psoriasis is a common inflammatory cutaneous disorder characterized by activated T-cell infiltration. T lymphocytes bearing natural killer cell receptors (NKRs) have been suggested to play an important role in the pathogenesis of psoriasis. However, the expression pattern of activating and inhibitory NKRs on T lymphocytes from psoriatic patients and its significance in psoriasis needs further study. Objectives, To investigate the pathogenesis of NKR-expressing T cells in psoriasis. Materials and methods, Thirty patients with chronic plaque psoriasis and 20 healthy controls were enrolled in this study. The immunophenotypic profiles of NKRs, including CD56, CD16 (activating NKRs), CD158a, CD158b, CD94 and NKG2A (inhibitory NKRs), were analysed in peripheral blood T lymphocytes, as well as psoriatic lesional infiltrating T cells, by triple-fluorescence flow cytometry. Results, A significant increase of inhibitory CD8+ CD158b+, CD4, CD8, CD158b+ and CD8+ CD94/NKG2A+ T cells was found in the peripheral blood of patients with psoriasis when compared with controls. Tissue-infiltrating T lymphocytes expressing inhibitory receptors CD158b, CD94 and NKG2A were found in psoriatic lesions. There was a significant positive correlation between the increased percentage of circulating CD8+ CD94/NKG2A+ T cells and the Psoriasis Area and Severity Index. Conclusions, In the present study, we demonstrated increased proportions of particular subsets of inhibitory CD158b+ and/or CD94/NKG2A+ T cells in patients with psoriasis. The elevation of these inhibitory NKR-expressing T cells was correlated with disease severity, which may signify the possibility of chronic antigen-driven stimulation and dysregulated cytokine production in the pathogenesis of psoriasis. [source] Simultaneous sodium lauryl sulphate testing improves the diagnostic validity of allergic patch tests.BRITISH JOURNAL OF DERMATOLOGY, Issue 4 2005Results from a prospective multicentre study of the German Contact Dermatitis Research Group (Deutsche Kontaktallergie-Gruppe Summary Background, There is evidence that a higher skin susceptibility may induce nonspecific erythematous or weak positive reactions to contact allergens in patch testing. Objectives, To evaluate whether simultaneous application of sodium lauryl sulphate (SLS) along with diagnostic patch tests with contact allergens can provide information regarding skin irritability which may help to discriminate allergic from nonspecific irritant reactions to contact allergens. Methods, Between July 2001 and June 2003, this prospective study collected patch test data of 5971 patients from 19 centres in Germany and Austria in the Information Network of Departments of Dermatology (IVDK). In addition to contact allergens (standard series and eight known ,problematic' allergens with a low reaction index and a high positivity ratio: 1,3-diphenylguanidine, amerchol L-101, benzalkonium chloride, benzoyl peroxide, cocamidopropyl betaine, octyl gallate, phenyl mercuric acetate and propylene glycol), patches with SLS 0·5% and 0·25% aq. were applied. Reactions to the allergens and to SLS were analysed at the IVDK data centre. The association between an erythematous or positive reaction to a certain allergen and an irritant reaction to SLS was assessed with logistic regression analysis, at the same time controlling for the influence of age and sex. Results, Of the 29 allergens of the standard series, 23 and 21 gave a higher percentage of nonspecific erythematous reactions in patients with an irritant reaction to 0·25% and 0·5% SLS, respectively, in comparison with SLS-negative patients. All eight ,problematic' allergens gave an increased percentage of nonspecific erythematous reactions. Similarly, 22 and 21 allergens of the standard series gave a higher percentage of positive allergic reactions in patients with an irritant reaction to 0·25% and 0·5% SLS, respectively, and seven of the eight ,problematic' allergens gave a higher percentage of positive allergic rections (exception: octyl gallate). For most allergens, the markers of skin reaction (reaction index and positivity ratio) were worse in SLS-positive patients. Differences were more pronounced when testing with SLS 0·25% than with SLS 0·5%. Conclusions, Because there is a convincing association between skin irritability (evaluated by SLS test) and the degree of skin reaction to contact allergens, the SLS test may help in deciding whether a doubtful erythematous or weakly ,positive' skin reaction should be interpreted as allergic or irritant. [source] | |||||||||||||||||||||||||