Destructive arthritis in a patient with chikungunya virus infection with persistent specific IgM antibodies

<p>Abstract</p> <p>Background</p> <p>Chikungunya fever is an emerging arboviral disease characterized by an algo-eruptive syndrome, inflammatory polyarthralgias, or tenosynovitis that can last for months to years. Up to now, the pathophysiology of the chronic stage is poorly understood.</p> <p>Case presentation</p> <p>We report the first case of CHIKV infection with chronic associated rheumatism in a patient who developed progressive erosive arthritis with expression of inflammatory mediators and persistence of specific IgM antibodies over 24 months following infection.</p> <p>Conclusions</p> <p>Understanding the specific features of chikungunya virus as well as how the virus interacts with its host are essential for the prevention, treatment or cure of chikungunya disease.</p

Orientia tsutsugamushi Stimulates an Original Gene Expression Program in Monocytes: Relationship with Gene Expression in Patients with Scrub Typhus

Orientia tsutsugamushi is the causal agent of scrub typhus, a public health problem in the Asia-Pacific region and a life-threatening disease. O. tsutsugamushi is an obligate intracellular bacterium that mainly infects endothelial cells. We demonstrated here that O. tsutsugamushi also replicated in monocytes isolated from healthy donors. In addition, O. tsutsugamushi altered the expression of more than 4,500 genes, as demonstrated by microarray analysis. The expression of type I interferon, interferon-stimulated genes and genes associated with the M1 polarization of macrophages was significantly upregulated. O. tsutsugamushi also induced the expression of apoptosis-related genes and promoted cell death in a small percentage of monocytes. Live organisms were indispensable to the type I interferon response and apoptosis and enhanced the expression of M1-associated cytokines. These data were related to the transcriptional changes detected in mononuclear cells isolated from patients with scrub typhus. Here, the microarray analyses revealed the upregulation of 613 genes, which included interferon-related genes, and some features of M1 polarization were observed in these patients, similar to what was observed in O. tsutsugamushi-stimulated monocytes in vitro. This is the first report demonstrating that monocytes are clearly polarized in vitro and ex vivo following exposure to O. tsutsugamushi. These results would improve our understanding of the pathogenesis of scrub typhus, during which interferon-mediated activation of monocytes and their subsequent polarization into an M1 phenotype appear critical. This study may give us a clue of new tools for the diagnosis of patients with scrub typhus

Adaptation to Visual Feedback Delay Influences Visuomotor Learning

Computational theory of motor control suggests that the brain continuously monitors motor commands, to predict their sensory consequences before actual sensory feedback becomes available. Such prediction error is a driving force of motor learning, and therefore appropriate associations between motor commands and delayed sensory feedback signals are crucial. Indeed, artificially introduced delays in visual feedback have been reported to degrade motor learning. However, considering our perceptual ability to causally bind our own actions with sensory feedback, demonstrated by the decrease in the perceived time delay following repeated exposure to an artificial delay, we hypothesized that such perceptual binding might alleviate deficits of motor learning associated with delayed visual feedback. Here, we evaluated this hypothesis by investigating the ability of human participants to adapt their reaching movements in response to a novel visuomotor environment with 3 visual feedback conditions—no-delay, sudden-delay, and adapted-delay. To introduce novelty into the trials, the cursor position, which originally indicated the hand position in baseline trials, was rotated around the starting position. In contrast to the no-delay condition, a 200-ms delay was artificially introduced between the cursor and hand positions during the presence of visual rotation (sudden-delay condition), or before the application of visual rotation (adapted-delay condition). We compared the learning rate (representing how the movement error modifies the movement direction in the subsequent trial) between the 3 conditions. In comparison with the no-delay condition, the learning rate was significantly degraded for the sudden-delay condition. However, this degradation was significantly alleviated by prior exposure to the delay (adapted-delay condition). Our data indicate the importance of appropriate temporal associations between motor commands and sensory feedback in visuomotor learning. Moreover, they suggest that the brain is able to account for such temporal associations in a flexible manner

Tailored design of NKT-stimulatory glycolipids for polarization of immune responses

Natural killer T (NKT) cell is a distinct population of T lymphocytes that can rapidly release massive amount of Th1 and Th2 cytokines upon the engagement of their T cell receptor with glycolipids presented by CD1d. The secreted cytokines can promote cell-mediated immunity to kill tumor cells and intracellular pathogens, or suppress autoreactive immune cells in autoimmune diseases. Thus, NKT cell is an attractive target for developing new therapeutics to manipulate immune system. The best-known glycolipid to activate NKT cells is α-galactosylceramide (α-GalCer), which has been used as a prototype for designing new NKT stimulatory glycolipids. Many analogues have been generated by modification of the galactosyl moiety, the acyl chain or the phytosphingosine chain of α-GalCer. Some of the analogues showed greater abilities than α-GalCer in polarizing immune responses toward Th1 or Th2 dominance. Among them, several analogues containing phenyl groups in the lipid tails were more potent in inducing Th1-skewed cytokines and exhibited greater anticancer efficacy than α-GalCer. Analyses of the correlation between structure and activity of various α-GalCer analogues on the activation of iNKT cell revealed that CD1d–glycolipid complexes interacted with the same population of iNKT cell expressing similar T-cell receptor Vβ as α-GalCer. On the other hand, those phenyl glycolipids with propensity for Th1 dominant responses showed greater binding avidity and stability than α-GalCer for iNKT T-cell receptor when complexed with CD1d. Thus, it is the avidity and stability of the ternary complexes of CD1d-glycolipid-iNKT TCR that dictate the polarity and potency of immune responses. These findings provide a key to the rationale design of immune modulating glycolipids with desirable Th1/Th2 polarity for clinical application. In addition, elucidation of α-GalCer-induced anergy, liver damage and accumulation of myeloid derived suppressor cells has offered explanation for its lacklustre anti-cancer activities in clinical trials. On other hand, the lack of such drawbacks in glycolipid analogues containing phenyl groups in the lipid tails of α-GalCer coupled with the greater binding avidity and stability of CD1d-glycolipid complex for iNKT T-cell receptor, account for their superior anti-cancer efficacy in tumor bearing mice. Further clinical development of these phenyl glycolipids is warranted

Carpal Tunnel Syndrome: A Review of the Recent Literature

Carpal Tunnel Syndrome (CTS) remains a puzzling and disabling condition present in 3.8% of the general population. CTS is the most well-known and frequent form of median nerve entrapment, and accounts for 90% of all entrapment neuropathies. This review aims to provide an overview of this common condition, with an emphasis on the pathophysiology involved in CTS. The clinical presentation and risk factors associated with CTS are discussed in this paper. Also, the various methods of diagnosis are explored; including nerve conduction studies, ultrasound, and magnetic resonance imaging

Hepatic arterial chemotherapy for primary and metastatic liver cancers

Hepatic arterial chemotherapy represents a means of selectively exposing hepatic tumor to cytotoxic agents. Although 5-fluoro-2′-deoxyuridine has been shown to generate a higher response rate in the treatment of colorectal liver metastases than that achieved by intravenous infusion, responses are largely incomplete and rarely of long duration. This review describes the rationale for the use of the thymidine analogs 5-bromo-2′-deoxyuridine and 5-iodo-2′-deoxyuridine in hepatic arterial infusions and indicates how combination therapy adding radiotherapy, specifically with hepatic arterially administered yttrium-90 microspheres, might generate a new, more efficient and effective therapeutic approach.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46919/1/280_2004_Article_BF00647244.pd

The Microprocessor controls the activity of mammalian retrotransposons

More than half of the human genome is made of transposable elements whose ongoing mobilization is a driving force in genetic diversity; however, little is known about how the host regulates their activity. Here, we show that the Microprocessor (Drosha-DGCR8), which is required for microRNA biogenesis, also recognizes and binds RNAs derived from human long interspersed element 1 (LINE-1), Alu and SVA retrotransposons. Expression analyses demonstrate that cells lacking a functional Microprocessor accumulate LINE-1 mRNA and encoded proteins. Furthermore, we show that structured regions of the LINE-1 mRNA can be cleaved in vitro by Drosha. Additionally, we used a cell culture–based assay to show that the Microprocessor negatively regulates LINE-1 and Alu retrotransposition in vivo. Altogether, these data reveal a new role for the Microprocessor as a post-transcriptional repressor of mammalian retrotransposons and a defender of human genome integrity.S.R.H. was supported by a Marie Curie Intra-European Fellowship and a Marie Curie CIG-Grant (PCIG10-GA-2011-303812). M.P. and E.E. were supported by the Spanish Ministry of Science (BIO2011-23920) and by the Sandra Ibarra Foundation (CSD2009-00080). M.P. is supported by the Novo Nordisk Foundation. J.L.G.-P. is supported by FP7-PEOPLE-2007-4-3-IRG, CICE-FEDER-P09-CTS-4980, PeS-FEDER-PI-002, FIS-FEDER-PI11/01489 and the Howard Hughes Medical Institute (IECS-55007420). J.F.C. was supported by Core funding from the Medical Research Council and by the Wellcome Trust (grant 095518/B/11/Z)