IgE is induced by the presence of IL‐4 by class switching from IgM through IgG1 to IgE. IL‐21 inhibits the IgE class switch by induction of Blimp1 leading to Stat6 and AID downregulation, and ...plasmablast/plasma cell differentiation.
Logistic regression analysis revealed a significant relationship between preanesthesia blocks, and intraoperative headaches (Odds Ratio; 0.334 95%Confidence Interval; 0.135–0.826 P = 0.017). ...this ...retrospective review suggests that preanesthetic scalp blocks were associated with less intraoperative headaches and hypertension. ...performing preanesthetic scalp blocks may be more effective in providing analgesia for AC than scalp blocks performed under general anesthesia.Acknowledgements The authors would like to thank Editage (https://www.editage.jp) for the English language review.Declaration of competing interest All authors did not receive financial aid for this work and declare no conflicts of interest. Group S n = 108 Group P n = 44 P-value Age (years) 42.00 36.0, 50.0 38.5 30.75, 47.5 0.17 Height (cm) 166.0 161.0, 171.0 164.0 158.7, 170.2 0.42 Weight (kg) 64.0 54.7, 71.6 60.8 52.8, 67.2 0.17 BMI (kg/m2) 22.5 20.15, 25.02 21.40 19.8, 24.0 0.27 Sex (Male/female) 70/39 24/21 0.19 Awake time (min) 174.5 128.7, 236.5 156.5 121.0, 189.5 0.054 Total infusion (ml) 3580.0 2842.54295.0 3575.0 3087.54050.0 0.9 Bleeding (ml) 491.50 319.5, 821.5 337.0 169.2, 615.0 0.006⁎⁎ Headache at awake phase (cases) 45 9 0.01⁎ Total amount of ropivacaine (mg/kg) 3.00 2.13, 4.33 4.22 3.55, 5.01 <0.001⁎⁎ HT at awake phase (case) 75 20 0.009⁎⁎ Highest arterial pressure at awake phase (mmHg) 159.0 142.0, 170.0 135.0 128.5, 147.0 <0.001⁎⁎ Seizure (cases) 12 3 0.55 Vomiting (cases) 7 0 0.1 Agitation (cases) 6 3 1 Table 1 Characteristics of patient's data and results.
Thalidomide was sold worldwide as a sedative over 60 years ago, but it was quickly withdrawn from the market due to its teratogenic effects. Thalidomide was later found to have therapeutic effects in ...several diseases, although the molecular mechanisms remained unclear. The discovery of cereblon (CRBN), the direct target of thalidomide, a decade ago greatly improved our understanding of its mechanism of action. Accumulating evidence has shown that CRBN functions as a substrate of Cullin RING E3 ligase (CRL4
), whose specificity is controlled by ligands such as thalidomide. For example, lenalidomide and pomalidomide, well-known thalidomide derivatives, degrade the neosubstrates Ikaros and Aiolos, resulting in anti-proliferative effects in multiple myeloma. Recently, novel CRBN-binding drugs have been developed. However, for the safe handling of thalidomide and its derivatives, a greater understanding of the mechanisms of its adverse effects is required. The teratogenic effects of thalidomide occur in multiple tissues in the developing fetus and vary in phenotype, making it difficult to clarify this issue. Recently, several CRBN neosubstrates (e.g., SALL4 (Spalt Like Transcription Factor 4) and p63 (Tumor Protein P63)) have been identified as candidate mediators of thalidomide teratogenicity. In this review, we describe the current understanding of molecular mechanisms of thalidomide, particularly in the context of its teratogenicity.
Cereblon (CRBN) is a primary target of thalidomide and mediates its multiple pharmacological activities, including teratogenic and antimyeloma activities. CRBN functions as a substrate receptor of ...the E3 ubiquitin ligase CRL4, whose substrate specificity is modulated by thalidomide and its analogs. Although a number of CRL4
substrates have recently been identified, the substrate involved in thalidomide teratogenicity is unclear. Here we show that p63 isoforms are thalidomide-dependent CRL4
neosubstrates that are responsible, at least in part, for its teratogenic effects. The p53 family member p63 is associated with multiple developmental processes. ∆Np63α is essential for limb development, while TAp63α is important for cochlea development and hearing. Using a zebrafish model, we demonstrate that thalidomide exerts its teratogenic effects on pectoral fins and otic vesicles by inducing the degradation of ∆Np63α and TAp63α, respectively. These results may contribute to the invention of new thalidomide analogs lacking teratogenic activity.
When participants undergo eccentric rotation (ER), i.e., they are rotated while displaced from the axis of rotation, they undergo both rotational stimulation and linear acceleration, which induces ...both the angular vestibulo-ocular reflex (aVOR) and linear VOR (lVOR). During ER, the lVOR induced by tangential linear acceleration enhances the eye movement induced by aVOR. In this study, we attempted to measure aVOR and lVOR separately, while participants underwent ER while facing the ground in a dark room. We analyzed three-dimensional eye movements using a video-oculography system. The participants sat on the ER chair either directly above the center of rotation, or with their head out, head in, right ear out, or left ear out against the center of rotation. Under these conditions, the rotational axis of the eye was perpendicular to the ground for rotational stimulation (aVOR), and the axis was parallel to the ground for linear stimulation (lVOR). Thus, measured eye movements could be separated into these two components. At 0.1 and 0.3 Hz rotation, we observed aVOR but not lVOR. However, when the stimulation frequency was above 0.5 Hz, we observed both aVOR and lVOR. These data indicate that lVOR is activated when the stimulation frequency is above 0.5 Hz. We conclude that it is possible to separately analyze aVOR and lVOR, and to simultaneously assess the function of aVOR and lVOR by analyzing eye movements induced when participants undergo ER above 0.5 Hz while facing the ground.
Gene expression is controlled by alterations in the epigenome, including DNA methylation and histone modification. Recently, it was reported that 5‐methylcytosine (5mC) is converted to ...5‐hydroxymethylcytosine (5hmC) by proteins in the ten‐eleven translocation (TET) family. This conversion is believed to be part of the mechanism by which methylated DNA is demethylated. Moreover, histones undergo modifications such as phosphorylation and acetylation. In addition, modification with O‐linked‐N‐acetylglucosamine (O‐GlcNAc) by O‐GlcNAc transferase (OGT) was recently identified as a novel histone modification. Herein, we focused on TET3, the regulation of which is still unclear. We attempted to elucidate the mechanism of its regulation by biochemical approaches. First, we conducted mass spectrometric analysis in combination with affinity purification of FLAG–TET3, which identified OGT as an important partner of TET3. Co‐immunoprecipitation assays using a series of deletion mutants showed that the C‐terminal H domain of TET3 was required for its interaction with OGT. Furthermore, we showed that TET3 is GlcNAcylated by OGT, although the GlcNAcylation did not affect the global hydroxylation of methylcytosine by TET3. Moreover, we showed that TET3 enhanced its localization to chromatin through the stabilization of OGT protein. Taken together, we showed a novel function of TET3 that likely supports the function of OGT.
The aim of this study was to investigate whether the insertion of an implant into the cochlea is accompanied by a deterioration in otolith function. Cervical and ocular vestibular evoked myogenic ...potentials (cVEMP and oVEMP) and linear vestibulo-ocular reflex (lVOR) during eccentric rotation were assessed before and after cochlear implantation (CI) to evaluate otolith function.
Twelve patients with bilateral severe sensorineural hearing loss who had undergone CI surgery in our hospital between May 2016 and November 2017 were included in this study. cVEMP and oVEMP were assessed using the asymmetry ratio (AR), calculated with the following formula: (peak-to-peak amplitude calculated as the sum of the p13 and n23 amplitudes in the non-operated side) − (that in the operated side)/(that in the non-operated side) + (that in the operated side). The ratio of VOR gain during eccentric rotation against VOR gain during center rotation was used to assess lVOR. For eccentric rotation, patients were rotated while displaced from the axis of rotation. At the same time, linear acceleration stimulated the utricle and induced lVOR. All patients underwent cVEMP and oVEMP tests and center and eccentric rotation tests before and about 30days after CI surgery.
Three patients with absent cVEMP responses before surgery were excluded, leaving pre-surgery cVEMP results for 9/12 patients. In five of these patients, the AR of cVEMP increased after CI, indicating that saccular function, as evaluated by cVEMP, did not deteriorate significantly postoperatively. One patient with an absent oVEMP response before CI was excluded, leaving pre-surgery oVEMP results for 11/12 patients. In 10 of these patients, the AR of oVEMP increased after CI surgery, indicating that utricular function, as evaluated by oVEMP, deteriorated significantly postoperatively. However, because the ratio of VOR gain during eccentric rotation against VOR gain during center rotation did not become worse after CI, utricular function, as evaluated by lVOR, did not deteriorate significantly postoperatively. Symptoms of vertigo became worse after CI in two of the 12 patients.
CI does not cause a deterioration in saccular function, as evaluated by cVEMP. Although CI does cause a deterioration in utricular function in oVEMP tests, this is not consistent in lVOR tests. These results indicate that CI causes a slight deterioration in utricular function that is insufficient to cause vertigo or deterioration of lVOR.
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•Eye movements during eccentric rotation (ER) were analyzed three-dimensionally.•We show that linear vestibulo-ocular reflex worked at 0.5 and 0.7Hz during ER in humans.•We can assess ...otolith function by rotational testing of ER.
When a participant is rotated while displaced from the axis of rotation (eccentric rotation, ER), both rotational stimulation and linear acceleration are applied to the participant. As linear acceleration stimulates the otolith, the vestibulo-ocular reflex (VOR) caused by the otolith (linear VOR; lVOR) would be induced during ER. Ten participants were rotated sinusoidally at a maximum angular velocity of 50°/s and at frequencies of 0.1, 0.3, 0.5, and 0.7Hz. The radius of rotation during ER was 90cm. The participants sat on a chair at three different positions: on the axis (center rotation, CR), at 90cm backward from the axis (nose-in ER, NI-ER) and at 90cm forward from the axis (nose-out ER, NO-ER). Their eye movements during rotation were recorded and analyzed three-dimensionally. The VOR gain during NI-ER was lower at 0.5 and 0.7Hz, and that during NO-ER was higher at 0.3, 0.5, and 0.7Hz than during CR. These results indicate that lVOR actually worked at 0.5 and 0.7Hz during ER and that the enhancement and decline of the VOR gain relative to the VOR gain during CR was seen in humans. Thus, we suggest that otolith function can be assessed via rotational testing of NI-ER and NO-ER.
•Participants were rotated with displacement from the axis of rotation.•Eye movements were analyzed three-dimensionally.•Recognition of the direction of centripetal acceleration was analyzed.
This ...study was conducted to evaluate the linear vestibulo-ocular reflex (lVOR) mediated by the saccule, and to investigate the relationship between the lVOR and the ability to distinguish the direction of centripetal acceleration during centric and eccentric rotation. Participants sat on a chair in darkness, with the right ear facing downwards, either directly above the center of rotation, or with their nose out, nose in, right shoulder out, or left shoulder out against the center of rotation (eccentric rotation). Participants were given no information about the chair position, and were rotated sinusoidally at 0.1–0.7 Hz. Three-dimensional eye movements during rotation were analyzed. Participants were asked to describe the position of the chair after rotation. Correctly reporting the five possible chair positions requires recognition of the direction of centripetal acceleration. We analyzed the rate of correct answers to assess participants’ ability to identify the direction of centripetal acceleration. lVOR mediated by the saccule was observed only at high rotational frequencies. The rate of correct answers was higher at high rotational frequencies than that at low rotational frequencies. These results indicate that high rotational frequency is important for both lVOR mediated by the saccule and distinguishing the direction of centripetal acceleration.
Posturography (PG) shows various patterns corresponding to a patient's equilibrium condition; however, PG is not useful for the differential diagnosis of peripheral vestibular diseases (PVDs). The ...aim of this study was to identify parameters of PG that can distinguish between PVDs.
The differences in PG parameters between PVDs were evaluated retrospectively. Two hundred and two patients with Ménière's disease (MD), 154 patients with benign paroxysmal positional vertigo (BPPV), 20 patients with sudden sensorineural hearing loss with vertigo (SSNHLwV), and 31 patients with vestibular neuritis (VN) underwent PG during the non-acute phase of vertigo, from January 2010 to March 2017.
The velocity of body oscillation of BPPV patients with eyes open and closed were significantly faster than those of MD patients with eyes open (p < 0.001) and closed (p = 0.033). The velocity of body oscillation of VN patients with eyes open was significantly faster than that of MD patients with eyes open (p = 0.0083). There were no significant differences among the other PG parameters between PVDs. Although there were significant differences among the velocity with eyes open and closed between males and females (eye open: p = 0.0009, eye close: p < 0.0001), there was no significant difference in the ratio of males to females among PVDs (p = 0.1834). Therefore, the ratio did not influence the difference in velocity among PVDs. Patient age correlated with the velocity with eyes open (p < 0.001) and with eyes closed (p < 0.001). Post-hoc analysis revealed significant differences in patient age, and comparisons of MD and BPPV, MD and SSNHLwV, BPPV and VN, and VN and SSNHLwV. Therefore, we performed multiple regression analysis to determine whether the significant differences in the velocity of body oscillation among PVDs were caused by the difference in age distribution between PVD groups, rather than by differences in the PVDs themselves. There were correlations between age and the velocity of body oscillation with eyes open (p < 0.001) and with eyes closed (p < 0.001). There also were correlations between MD or VN and the velocity of body oscillation with eyes open (p = 0.0194).
There were significant differences in the velocity of body oscillation with eyes open between MD and VN patients. The difference between MD and VN was significant regardless of the age distribution. To distinguish between MD and VN, the velocity of body oscillation with eyes open is a useful PG index.
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