Heat shock protein 60 enhances CD4+ CD25+ regulatory T cell function via innate TLR2 signaling

CD4+CD25+ Tregs regulate immunity, but little is known about their own regulation. We now report that the human 60-kDa heat shock protein (HSP60) acts as a costimulator of human Tregs, both CD4+CD25int and CD4+CD25hi. Treatment of Tregs with HSP60, or its peptide p277, before anti-CD3 activation significantly enhanced the ability of relatively low concentrations of the Tregs to downregulate CD4+CD25- or CD8+ target T cells, detected as inhibition of target T cell proliferation and IFN-gamma and TNF-alpha secretion. The enhancing effects of HSP60 costimulation on Tregs involved innate signaling via TLR2, led to activation of PKC, PI3K, and p38, and were further enhanced by inhibition of ERK. HSP60-treated Tregs suppressed target T cells both by cell-to-cell contact and by secretion of TGF-beta and IL-10. In addition, the expression of ERK, NF-kappaB, and T-bet by downregulated target T cells was inhibited. Thus, HSP60, a self-molecule, can downregulate adaptive immune responses by upregulating Tregs innately through TLR2 signaling.     

Peptide p277 of HSP60 signals T cells: inhibition of inflammatory chemotaxis

Peptide p277 is a 24-amino acid fragment of the heat shock protein 60 molecule, first discovered to be an antigen for diabetogenic T-cell clones in non-obese diabetic (NOD) mice. Therapeutic vaccination with p277 can arrest the spontaneous diabetogenic process both in NOD mice and in humans associated with a T(h)1 to T(h)2 cytokine shift specific for the autoimmune T cells. We now report that p277 can directly signal human T cells via innate toll-like receptor (TLR)-2, leading to up-regulation of integrin-mediated adhesion to fibronectin, and inhibition of chemotaxis to the chemokine SDF-1alpha in vitro. Resting CD45RA(+) T cells responded to lower concentrations of p277 than resting CD45RO(+) T cells, but activation of CD45RO(+) T cells greatly increased their sensitivity to p277. Mouse T cells, but not macrophages, were also sensitive to the innate effects of peptide p277, and adoptive transfer of diabetes by splenic T cells from NOD mice could be inhibited by p277 treatment before transfer. Thus, T cells do respond innately to p277, and signaling by soluble p277 through TLR2 could contribute to the treatment of type 1 diabetes; p277 may stop the destruction of beta cells by signaling in concert both innate and adaptive receptors on T cells.     

The negative regulators Foxj1 and Foxo3a are up-regulated by a peptide that inhibits systemic lupus erythematosus-associated T cell responses

A peptide (hCDR1) based on the complementarity determining region-1 of an anti-DNA antibody ameliorates systemic lupus erythematosus (SLE) in induced and spontaneous lupus models. Our objectives were to determine the effects of hCDR1 on TCR signaling and on its negative regulators, Foxj1 and Foxo3a. BALB/c mice were immunized with the SLE-inducing anti-DNA antibody, designated 16/6Id, and treated with hCDR1. hCDR1 treatment specifically inhibited IFN-gamma secretion by T cells in association with down-regulated T-bet expression and NF-kappaB activation; however, GATA-3 expression was not affected. Furthermore, TCR signaling (ZAP-70 phosphorylation) was inhibited, and the mRNA expression of the two modulators of Th1 activation, Foxj1 and Foxo3a, was significantly up-regulated. The latter were also elevated in SLE-afflicted (NZBxNZW)F1 mice that were treated with hCDR1. Addition of TGF-beta, which was elevated following treatment with hCDR1, to T cells from 16/6Id immunized mice, up-regulated Foxj1 and Foxo3a mRNA expression, similarly to hCDR1. In contrast, anti-TGF-beta antibodies added to hCDR1-treated T cells abrogated its effect. Thus, hCDR1 elevates TGF-beta, which contributes to the up-regulation of T cell Foxj1 and Foxo3a expression, leading to inhibition of NF-kappaB activation and IFN-gamma secretion, which is required for the maintenance of SLE.     

Transient vertical diplopia and nystagmus associated with acute thalamic infarction

We describe a patient who presented with a 1-h history of vertical diplopia and nystagmus and was found to have acute left ventrolateral thalamic infarction on the diffusion-weighted magnetic resonance imaging (DWI MRI). This is the first case report demonstrating that vertical diplopia and nystagmus, which typically suggest a lesion in the brainstem or cerebellum, may also occur in acute thalamic infarction. DWI MRI can detect thalamic infarction as early as 1 h after its clinical manifestations.     

Repeated GnRH agonist doses for luteal support: a proof of concept

Research questionWhat are the safety and feasibility of repeated subcutaneous doses of gonadotrophin-releasing hormone (GnRH) agonist for luteal support in IVF cycles triggered by a GnRH agonist?DesignIn this prospective trial, patients exhibiting oestradiol concentrations of over 2500 pg/ml after use of a GnRH agonist for triggering ovulation were initially randomized to GnRH agonist luteal support (0.1 mg subcutaneously every other day, starting on day 3 after embryo transfer) or to a control group supported by 80 µg of recombinant human chorionic gonadotrophin (HCG) on day 3 after embryo transfer. All patients underwent a day 5 blastocyst transfer. Randomization to the HCG luteal support was stopped owing to two cases of ovarian hyperstimulation syndrome (OHSS) and the study was continued solely with GnRH agonist luteal support.ResultsThe study included 39 women in the repeated GnRH agonist luteal support group and seven in the HCG micro dose group. There were no cases of OHSS among patients supported by a GnRH agonist, and no other adverse events were recorded. There were no cases of bleeding before the pregnancy test, and hence no cases of an insufficient luteal phase. A clinical pregnancy rate of 43.6% was achieved with GnRH agonist luteal support. Hormone dynamics during the stimulation cycle reflected rising LH and progesterone concentrations after the introduction of GnRH agonist support.ConclusionsRepeated doses of GnRH agonist every other day as a method of luteal support provided safe and effective luteal support for women who underwent GnRH agonist triggering in a GnRH antagonist IVF cycle.     

Inflammatory bowel disease patient profiles are related to specific information needs: A nationwide survey

BACKGROUND Inflammatory bowel diseases(IBD) is a heterogenous, lifelong disease, with an unpredictable and potentially progressive course, that may impose negative psychosocial impact on patients.While informed patients with chronic illness have improved adherence and outcomes, previous research showed that the majority of IBD patients receive insufficient information regarding their disease.The large heterogeneity of IBD and the wide range of information topics makes a one-size fits all knowledge resource overwhelming and cumbersome.We hypothesized that different patient profiles may have different and specific information needs, the identification of which will allow building personalized computer-based information resources in the future.AIM To evaluate the scope of disease-related knowledge among IBD patients and determine whether different patient profiles drive unique information needs.METHODS We conducted a nationwide survey addressing hospital-based IBD clinics.A Total of 571 patients completed a 28-item questionnaire, rating the amount of information received at time of diagnosis and the importance of information, as perceived by participants, for a newly diagnosed patient, and for the participants themselves, at current time.We performed an exploratory factor analysis of the crude responses aiming to create a number of representative knowledge domains(factors), and analyzed the responses of a set of 15 real-life patient profiles generated by the study team.RESULTS Participants gave low ratings for the amount of information received at disease onset(averaging 0.9/5) and high ratings for importance, both for the newly diagnosed patients(mean 4.2/5) and for the participants themselves at current time(mean 3.5/5).Factor analysis grouped responses into six informationdomains.The responses of selected profiles, compared with the rest of the participants, yielded significant associations(defined as a difference in rating of >0.5 points with a P < 0.05).Patients with active disease showed a higher interest in work-disability, stress-coping, and therapy-complications.Patients newly diagnosed at age > 50, and patients with long-standing disease(> 10 years)showed less interest in work-disability.Patients in remission with mesalamine or no therapy showed less interest in all domains except for nutrition and long-term complications.CONCLUSION We demonstrate unmet patient information needs.Analysis of various patient profiles revealed associations with specific information topics, paving the way for building patient-tailored information resources.     

Genetic load determines atrophy in hand cortico‐striatal pathways in presymptomatic Huntington's disease

Huntington's disease (HD) is an inherited neurodegenerative disorder that causes progressive breakdown of striatal neurons. Standard white matter integrity measures like fractional anisotropy and mean diffusivity derived from diffusion tensor imaging were analyzed in prodromal‐HD subjects; however, they studied either a whole brain or specific subcortical white matter structures with connections to cortical motor areas. In this work, we propose a novel analysis of a longitudinal cohort of 243 prodromal‐HD individuals and 88 healthy controls who underwent two or more diffusion MRI scans as part of the PREDICT‐HD study. We separately trace specific white matter fiber tracts connecting the striatum (caudate and putamen) with four cortical regions corresponding to the hand, face, trunk, and leg motor areas. A multi‐tensor tractography algorithm with an isotropic volume fraction compartment allows estimating diffusion of fast‐moving extra‐cellular water in regions containing crossing fibers and provides quantification of a microstructural property related to tissue atrophy. The tissue atrophy rate is separately analyzed in eight cortico‐striatal pathways as a function of CAG‐repeats (genetic load) by statistically regressing out age effect from our cohort. The results demonstrate a statistically significant increase in isotropic volume fraction (atrophy) bilaterally in hand fiber connections to the putamen with increasing CAG‐repeats, which connects the genetic abnormality (CAG‐repeats) to an imaging‐based microstructural marker of tissue integrity in specific white matter pathways in HD. Isotropic volume fraction measures in eight cortico‐striatal pathways are also correlated significantly with total motor scores and diagnostic confidence levels, providing evidence of their relevance to HD clinical presentation.     

Impaired white matter connectivity between regions containing mirror neurons,and relationship to negative symptoms and social cognition,in patients with first-episode schizophrenia

In schizophrenia, abnormalities in structural connectivity between brain regions known to contain mirror neurons and their relationship to negative symptoms related to a domain of social cognition are not well understood. Diffusion tensor imaging (DTI) scans were acquired in 16 patients with first episode schizophrenia and 16 matched healthy controls. FA and Trace of the tracts interconnecting regions known to be rich in mirror neurons, i.e., anterior cingulate cortex (ACC), inferior parietal lobe (IPL) and premotor cortex (PMC) were evaluated. A significant group effect for Trace was observed in IPL-PMC white matter fiber tract (F (1, 28) = 7.13, p = .012), as well as in the PMC-ACC white matter fiber tract (F (1, 28) = 4.64, p = .040). There were no group differences in FA. In addition, patients with schizophrenia showed a significant positive correlation between the Trace of the left IPL-PMC white matter fiber tract, and the Ability to Feel Intimacy and Closeness score (rho = .57, p = 0.034), and a negative correlation between the Trace of the left PMC-ACC and the Relationships with Friends and Peers score (rho = remove -.54, p = 0.049). We have demonstrated disrupted white mater microstructure within the white matter tracts subserving brain regions containing mirror neurons. We further showed that such structural disruptions might impact negative symptoms and, more specifically, contribute to the inability to feel intimacy (a measure conceptually related to theory of mind) in first episode schizophrenia. Further studies are needed to understand the potential of our results for diagnosis, prognosis and therapeutic interventions.     

A comparison of fatigue crack growth in human enamel and hydroxyapatite

Cracks and craze lines are often observed in the enamel of human teeth, but they rarely cause tooth fracture. The present study evaluates fatigue crack growth in human enamel, and compares that to the fatigue response of sintered hydroxyapatite (HAp) with similar crystallinity, chemistry and density. Miniature inset compact tension (CT) specimens were prepared that embodied a small piece of enamel (N=8) or HAp (N=6). The specimens were subjected to mode I cyclic loads and the steady state crack growth responses were modeled using the Paris Law. Results showed that the fatigue crack growth exponent (m) for enamel (m=7.7+/-1.0) was similar to that for HAp (m=7.9+/-1.4), whereas the crack growth coefficient (C) for enamel (C=8.7 E-04 (mm/cycle)x(MPa m(0.5))(-m)) was significantly lower (p<0.0001) than that for HAp (C=2.0 E+00 (mm/cycle)x(MPa m(0.5))(-m)). Micrographs of the fracture surfaces showed that crack growth in the enamel occurred primarily along the prism boundaries. In regions of decussation, the microstructure promoted microcracking, crack bridging, crack deflection and crack bifurcation. Working in concert, these mechanisms increased the crack growth resistance and resulted in a sensitivity to crack growth (m) similar to bone and lower than that of human dentin. These mechanisms of toughening were not observed in the crack growth response of the sintered HAp. While enamel is the most highly mineralized tissue of the human body, the microstructural arrangement of the prisms promotes exceptional resistance to crack growth.