Otolith organ function according to subtype of benign paroxysmal positional vertigo.

OBJECTIVES/HYPOTHESIS: The clinical features and treatment outcomes of benign paroxysmal positional vertigo (BPPV) are known to be different depending on the type of and involved canal. This difference could be due to differences in the functional change of the otolith organ. STUDY DESIGN: Case series. METHODS: Forty-nine patients were diagnosed to primary BPPV; 18 were categorized as posterior canal canalolithiasis (PC canalolithiasis), and 31 were categorized as horizontal canal (HC) BPPV with canalolithiasis or cupulolithiasis (HC canalolithiasis or HC cupulolithiasis). Diagnostic interventions to measure vestibular functions were performed such as electronystagmography (ENG), videonystagmography (VNG), and static and dynamic subjective visual vertical (SVV). BPPV was confirmed with nystagmus during positioning/positional test under ENG and VNG. Static SVV was recorded with a light-emitting diode (LED) bar located in front of the patients before eccentric rotation and dynamic SVV was recorded during eccentric rotation with the LED bar. SVV angles were read by the examiner and analyzed. The measured values were compared to those of normal controls and each other. RESULTS: Dynamic SVV toward the lesion side in all subtypes of BPPV were significantly different from those of the controls; HC cupulolithiasis showed significantly lower values than those of PC canalolithiasis and HC canalolithiasis. CONCLUSIONS: HC cupulolithiasis shows a lesser degree of utricular dysfunction compared with other subtypes. It could postulate the difference of pathophysiology between canalolithiasis and cupulolithiasis. LEVEL OF EVIDENCE: 4.

4-1BB signaling breaks the tolerance of maternal CD8+ T cells that are reactive with alloantigens.

4-1BB (CD137, TNFRSF9), a member of the activation-induced tumor necrosis factor receptor family, is a powerful T-cell costimulatory molecule. It generally enhances CD8(+) T responses and even breaks the tolerance of CD8(+) T cells in an antigen-specific manner. In the present study we found that it was expressed in the placentas of pregnant mice and that its expression coincided with that of the immunesuppressive enzyme indoleamine 2,3-dioxygenase (IDO). Therefore, we investigated whether 4-1BB signaling is involved in fetal rejection using agonistic anti-4-1BB mAb and 4-1BB-deficient mice. Treatment with agonistic anti-4-1BB mAb markedly increased the rate of rejection of allogeneic but not syngeneic fetuses, and this was primarily dependent on CD8(+) T cells. Complement component 3 (C3) seemed to be the effector molecule because 4-1BB triggering resulting in accumulation of C3 in the placenta, and this accumulation was also reversed by anti-CD8 mAb treatment. These findings demonstrate that 4-1BB triggering breaks the tolerance of CD8(+) T cells to alloantigens in the placenta. Moreover, triggering 4-1BB protected the pregnant mice from Listeria monocytogenes (LM) infection, but led to rejection of semi-allogeneic fetuses. Therefore, given the cross-recognition of alloantigen by pathogen-reactive CD8(+) T cells, the true function of 4-1BB may be to reverse the hypo-responsiveness of pathogen-reactive CD8(+) T cells in the placenta in cases of infection, even if that risks losing the fetus.

Reverse signaling through the costimulatory ligand CD137L in epithelial cells is essential for natural killer cell-mediated acute tissue inflammation.

Renal ischemia-reperfusion injury (IRI) after kidney transplantation is a major cause of delayed graft function. Even though IRI is recognized as a highly coordinated and specific process, the pathways and mechanisms through which the innate response is activated are poorly understood. In this study, we used a mouse model of acute kidney IRI to examine whether the interactions of costimulatory receptor CD137 and its ligand (CD137L) are involved in the early phase of acute kidney inflammation caused by IRI. We report here that the specific expressions of CD137 on natural killer cells and of CD137L on tubular epithelial cells (TECs) are required for acute kidney IRI. Reverse signaling through CD137L in TECs results in their production of the chemokine (C-X-C motif) receptor 2 ligands CXCL1 and CXCL2 and the subsequent induction of neutrophil recruitment, resulting in a cascade of proinflammatory events during kidney IRI. Our findings identify an innate pathogenic pathway for renal IRI involving the natural killer cell-TEC-neutrophil axis, whereby CD137-CD137L interactions provide the causal contribution of epithelial cell dysregulation to renal IRI. The CD137L reverse signaling pathway in epithelial cells therefore may represent a good target for blocking the initial stage of inflammatory diseases, including renal IRI.

Oritavancin, a new lipoglycopeptide antibiotic: results from a thorough QT study.

Oritavancin is a lipoglycopeptide with broad activity against gram-positive bacteria. To exclude an effect on cardiac repolarization, oritavancin was studied in a thorough QT study. In vitro assays have demonstrated a 10-fold safety margin between the concentration that resulted in 50% block of the cardiac potassium current and therapeutic plasma levels in patients and no safety margin for block of the sodium currents. In a parallel-group study, 240 male and female subjects received treatment with either the clinical dose (200 mg intravenously) or a supratherapeutic dose (800 mg intravenously) of oritavancin, placebo, or a positive control (400 mg of oral moxifloxacin). Electrocardiograms were recorded in triplicate at several time points after dosing. The primary end point was the largest baseline-adjusted, placebo-corrected QTcI observed at any point after oritavancin dosing. The study's sensitivity to demonstrate a sufficiently small QTc change was confirmed by the moxifloxacin effect. The baseline-adjusted, placebo-corrected QTcI was between -3 milliseconds and 3 milliseconds after 800 mg of oritavancin, and an effect exceeding 6 milliseconds was confidently excluded. Other electrocardiographic parameters were unaffected by the treatment. It was concluded that oritavancin did not cause QTc prolongation in this thorough QT study.

Glycogen storage and muscle glucose transporters (GLUT-4) of mice selectively bred for high voluntary wheel running.

To examine the evolution of endurance-exercise behaviour, we have selectively bred four replicate lines of laboratory mice (Mus domesticus) for high voluntary wheel running (;high runner' or HR lines), while also maintaining four non-selected control (C) lines. By generation 16, HR mice ran approximately 2.7-fold more than C mice, mainly by running faster (especially in females), a differential maintained through subsequent generations, suggesting an evolutionary limit of unknown origin. We hypothesized that HR mice would have higher glycogen levels before nightly running, show greater depletion of those depots during their more intense wheel running, and have increased glycogen synthase activity and GLUT-4 protein in skeletal muscle. We sampled females from generation 35 at three times (photophase 07:00 h-19:00 h) during days 5-6 of wheel access, as in the routine selection protocol: Group 1, day 5, 16:00 h-17:30 h, wheels blocked from 13:00 h; Group 2, day 6, 02:00 h-03:30 h (immediately after peak running); and Group 3, day 6, 07:00 h-08:30 h. An additional Group 4, sampled 16:00 h-17:30 h, never had wheels. HR individuals with the mini-muscle phenotype (50% reduced hindlimb muscle mass) were distinguished for statistical analyses comparing C, HR normal, and HR mini. HR mini ran more than HR normal, and at higher speeds, which might explain why they have been favored by the selective-breeding protocol. Plasma glucose was higher in Group 1 than in Group 4, indicating a training effect (phenotypic plasticity). Without wheels, no differences in gastrocnemius GLUT-4 were observed. After 5 days with wheels, all mice showed elevated GLUT-4, but HR normal and mini were 2.5-fold higher than C. At all times and irrespective of wheel access, HR mini showed approximately three-fold higher [glycogen] in gastrocnemius and altered glycogen synthase activity. HR mini also showed elevated glycogen in soleus when sampled during peak running. All mice showed some glycogen depletion during nightly wheel running, in muscles and/or liver, but the magnitude of this depletion was not large and hence does not seem to be limiting to the evolution of even-higher wheel running.

Mechanisms involved in synergistic anticancer immunity of anti-4-1BB and anti-CD4 therapy.

Anti-4-1BB-mediated anticancer effects were potentiated by depletion of CD4+ cells in B16F10 melanoma-bearing C57BL/6 mice. Anti-4-1BB induced the expansion and differentiation of polyclonal tumor-specific CD8+ T cells into IFN-gamma-producing CD11c+CD8+ T cells. The CD4+ cell depletion was responsible for facilitating immune cell infiltration into tumor tissues and removing some regulatory barriers such as T regulatory and indoleamine-2,3-dioxygenase (IDO)+ dendritic cells. Both monoclonal antibodies (mAb) contributed to the efficient induction of MHC class I molecules on the tumor cells in vivo. The effectors that mediated the anti-4-1BB effect were NKG2D+KLRG1+CD11c+CD8+ T cells that accumulated preferentially in the tumor tissues. Blocking NKG2D reduced the therapeutic effect by 20% to 26%, which may indicate that NKG2D contributes partially to tumor killing by the differentiated CD8+ T cells. Our results indicate that the combination of the two mAbs, agonistic anti-4-1BB and depleting anti-CD4, results in enhanced production of efficient tumor-killing CTLs, facilitation of their infiltration, and production of a susceptible tumor microenvironment.

Glucocorticoid-induced tumour necrosis factor receptor family-related receptor signalling exacerbates hapten-induced colitis by CD4+ T cells.

The glucocorticoid-induced tumour necrosis factor receptor family related gene (GITR) has been reported to be expressed on the activated T and CD4(+)CD25(+) regulatory T cells (Treg). Signalling triggered by GITR not only neutralizes the suppressive effect of Treg cells, but also augments activation, proliferation and cytokine production of effector T cells. To test the role of GITR in 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis - a murine model of mucosal inflammation - TNBS-injected Balb/c mice were treated with agonistic anti-GITR monoclonal antibody (mAb). Anti-GITR treatment increased the death rate compared to rat IgG-treated mice. Typically, death occurred within 4 days after the TNBS injection when the mice were treated with anti-GITR. The mice that survived anti-GITR treatment suffered from severe inflammation in their entire intestines. CD4(+) T-depletion protected the mice from colitis; even an anti-GITR effect was not apparent. In contrast, CD8(+) T depletion showed less protective than did CD4(+) T depletion. Stimulation of GITR enhanced the production of proinflammatory cytokines including interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-12. It also enhanced the humoral response such as serum levels of IgG(2b) and IgA, which was completely dependent on CD4(+) T cells. Taken together, this study demonstrated that GITR signalling on CD4(+) T cells is involved in the development and progress of colitis by enhancing both T helper type 1 (Th1) and Th2 type responses.

4-1BB costimulation enhances HSV-1-specific CD8+ T cell responses by the induction of CD11c+CD8+ T cells.

Since 4-1BB plays a predominant role in CD8+ T cell responses, we investigated the effects of 4-1BB triggering on the primary and memory CD8+ T responses to HSV-1 infection. 4-1BB was detected on 10-15% of CD4+ and CD8+ T cells following the infection. 4-1BB-positive T cells were in the proliferative mode and showed the enhanced expression of anti-apoptotic proteins. Agonistic anti-4-1BB treatment exerted preferential expansion of CD8+ T cells and gB/H-2Kb-positive CD8+ T cells, and enhanced cytotoxicity against HSV-1 that was mainly mediated by CD11c+CD8+ T cells. CD11c+CD8+ T cells were re-expanded following re-challenge with HSV-1 at post-infection day 50, indicating that CD11c+CD8+ phenotype was maintained in memory CD8+ T cell pool. Our studies demonstrated that 4-1BB stimulation enhanced both primary and memory anti-HSV-1 CD8+ T cell responses, which was mediated by a massive expansion of antigen-specific CD11c+CD8+ T cells.

Absolute strain measurements made with fiber bragg grating sensors.

A strain sensor system based on optical fiber Bragg gratings (FBGs) is proposed with a new matched-filter design. The strain variation on the sensor FBG is continuously followed and matched by a filter FBG by use of a feedback control loop that produces an identical strain condition on the filter FBG. The matched strain on the filter FBG is then determined from the resonance vibration of the fiber piece embedding the filter FBG. The implementation and the performance of the proposed system are described. It is demonstrated that the proposed system can distinguish strain variation on the sensor FBG with resolution of one microstrain.