Proteomic identification of 14‐3‐3ϵ as a linker protein between pERK1/2 inhibition and BIM upregulation in human osteosarcoma cells

Despite advancements in multimodality chemotherapy, conventional cytotoxic treatments still remain ineffective for a subset of patients with aggressive metastatic or multifocal osteosarcoma. It has been shown that pERK1/2 inhibition enhances chemosensitivity to doxorubicin and promotes osteosarcoma cell death in vivo and in vitro. One of the pro‐apoptotic mechanisms is upregulation of Bim by pERK1/2 inhibitors. To this end, we examined proteomic changes of 143B human osteosarcoma cells with and without treatment of PD98059, pERK1/2 inhibitor. Specifically, we identified 14‐3‐3? protein as a potential mediator of Bim expression in response to inhibition of pERK1/2. We hypothesized that 14‐3‐3? mediates upregulation of Bim expression after pERK1/2 inhibition. We examined the expression of Bim after silencing 14‐3‐3? using siRNA. The 14‐3‐3? gene silencing resulted in downregulation of Bim expression after PD98059 treatment. These data indicate that 14‐3‐3? is required for Bim expression and that it has an anti‐cancer effect under pERK1/2 inhibition in 143B cells. By playing an essential role upstream of Bim, 14‐3‐3? may potentially be a coadjuvant factor synergizing the effect of pERK1/2 inhibitors in addition to conventional cytotoxic agents for more effective osteosarcoma treatments. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:848–854, 2014.

     

Role of cysteinyl leukotriene signaling in a mouse model of noise-induced cochlear injury

Noise-induced hearing loss is one of the most common types of sensorineural hearing loss. In this study, we examined the expression and localization of leukotriene receptors and their respective changes in the cochlea after hazardous noise exposure. We found that the expression of cysteinyl leukotriene type 1 receptor (CysLTR1) was increased until 3 d after noise exposure and enhanced CysLTR1 expression was mainly observed in the spiral ligament and the organ of Corti. Expression of 5-lipoxygenase was increased similar to that of CysLTR1, and there was an accompanying elevation of CysLT concentration. Posttreatment with leukotriene receptor antagonist (LTRA), montelukast, for 4 consecutive days after noise exposure significantly decreased the permanent threshold shift and also reduced the hair cell death in the cochlea. Using RNA-sequencing, we found that the expression of matrix metalloproteinase-3 (MMP-3) was up-regulated after noise exposure, and it was significantly inhibited by montelukast. Posttreatment with a MMP-3 inhibitor also protected the hair cells and reduced the permanent threshold shift. These findings suggest that acoustic injury up-regulated CysLT signaling in the cochlea and cochlear injury could be attenuated by LTRA through regulation of MMP-3 expression. This study provides mechanistic insights into the role of CysLTs signaling in noise-induced hearing loss and the therapeutic benefit of LTRA.The number of people with hearing impairment is rapidly increasing, and it has become an important health care issue. Excessive noise exposure is one of the most common causes of sensorineural hearing loss. Noise-induced hearing loss (NIHL) is one of the most common occupational diseases, and it has also been proposed as a contributor to presbycusis (1). Moreover, there are some concerns regarding the negligent use of portable listening devices or noise exposure in leisure environments such as nightclubs or music concerts as potent causes of NIHL (2, 3). In these populations, wearing hearing protection devices, the current most effective method for preventing NIHL, was not useful, thereby indicating that additional strategies are needed (4).Great efforts have been made to elucidate the pathogenesis of NIHL. Accumulating evidence indicates that noise induces an intense metabolic activity, which is the primary cause of reactive oxygen species (ROS) overproduction, and overproduced ROS have been known to be the major contributors to NIHL. In addition, several pathophysiological mechanisms including oxidative stress, excitotoxicity, ischemia/reperfusion injury in the stria vascularis, ion imbalance in the endolymph, and inflammatory responses have been proposed to be involved in the pathogenesis of NIHL (5–7).Leukotrienes (LTs) are potent lipid mediators in response to several immune and inflammatory stimuli. In particular, cysteinyl LTs (CysLTs), including LTC4, LTD4, and LTE4, have been known to be involved in several inflammatory responses (8). The actions of CysLTs are mediated via at least two types of CysLT receptors, designated as CysLT receptor 1 (CysLTR1) and 2 (CysLTR2). CysLTs–CysLTR1 signal has been considered a major pharmacological target for the treatment of asthma and allergic rhinitis (9). Recently, expanded roles of this signaling in the pathogenesis of cardiovascular diseases, cerebrovascular diseases, malignant tumors, fibrosis, and immune host defense (10, 11) have been suggested, thereby indicating that they could be involved in a variety of pathophysiological conditions as well as in inflammation in a tissue-specific manner.To elucidate the involvement of LT signaling in the auditory system in association with excessive noise exposure, we explored the detailed expression and regulation of LTs and their receptors in a mouse model of noise-induced cochlear injury and the protective effect of LTRA on NIHL.     

Acute physical stress induces the alteration of the serotonin 1A receptor density in the hippocampus

Stress affects the serotonergic system, which is associated with depression. Previous research has showed that chronic stress causes the deactivation of the limbic system. However, the influence of the acute physical stress on the serotonergic system in vivo was primarily unclear. The purpose of this research is to elucidate the effects of the acute physical stress in vivo using PET. For quantification of the 5‐HT_1A receptors in the brain, we measured [¹⁸F]Mefway uptake in the two experiment groups (control and despair rats). The despair group was subjected to the external stressful situation (i.e., forced swimming) and total duration time of immobility, refers to the despair severity, and was analyzed. In the intercomparison experiment, the resulting PET images of [¹⁸F]Mefway in the despair rat displayed a significant reduction of radioactivity in the hippocampus (HP) compared with the control. The nondisplaceable binding potential (BP_ND) refers to the ratio of the concentration of radioligand in the receptor‐rich region (i.e., HP) to the concentration of that in the receptor‐free region (i.e., cerebellum). The hippocampal uptake and the BP_ND in the despair group were respectively about 25 and 18% lower than those of the control group. The ratio of specific binding to nonspecific binding in the despair group was 18% lower than that of the control. In the intracomparison experiments, the BP_ND and immobility in the despair group showed a strong negative correlation. Taken together, the data illustrates that an acute physical stress induces the change in the serotonergic system that correlates with the behavioral despair. Synapse 68:363–368, 2014 . © 2014 Wiley Periodicals, Inc.     

Interventional treatment of a biliary stricture after adult right-lobe living-donor liver transplantation with duct-to-duct anastomosis

Backgroud

A biliary stricture is the most common complication after living-donor liver transplantation (LDLT). The present study was performed to examine treatment methods and outcomes after treatment for a biliary stricture after LDLT.

Methods and Results

From January 2000 to December 2010, 488 patients underwent LDLT using the right lobe with duct-to-duct anastomosis at our transplantation centre. Overall biliary strictures were detected in 160 patients (32.8%), and the majority occurred within 2 years after LDLT. Biliary strictures were related to bile leakage (P < 0.001) and the urgency of the surgery (P = 0.012) in a multivariate analysis. All biliary strictures were treated with interventional modalities including an endoscopic or a percutaneous approach. Failure of interventional treatment was demonstrated in 13 patients (8.5%), among them, four (2.6%) underwent re-transplantation and nine (5.9%) died of sepsis and biliary cirrhosis during the follow-up period. A biliary stricture was not related to the survival rate (P = 0.586).

Conclusion

The incidence of overall biliary stricture was related to bile leakage and the urgency of the surgery. All biliary strictures could be treated by interventional modalities. These approaches are effective, complementary and help to avoid the need for surgery for a biliary stricture.     

Epidemiological Aspects of Pertussis among Adults and Adolescents in a Korean Outpatient Setting: A Multicenter,PCR-Based Study

Epidemiological data of Bordetella pertussis infection among adolescents and adults are limited in Korea. Patients (≥ 11 yr of age) with a bothersome cough for less than 30 days were enrolled during a 1-yr period at 22 hospitals in Korea. Nasopharyngeal swabs were collected for polymerase chain reaction (PCR) and for bacteriologic culture. In total, 490 patients were finally enrolled, and 34 (6.9%) patients tested positive for B. pertussis; cough duration (14.0 days [7.0-21.0 days]) and age distribution were diverse. The incidence was the highest in secondary referral hospitals, compared to primary care clinics or tertiary referral hospitals (24/226 [10.6%] vs. 3/88 [3.4%] vs. 7/176 [4.0%], P = 0.012), and the peak incidence was observed in February and August (15.8% and 15.9%), with no confirmed cases between March and June. In the multivariate analysis, post-tussive vomiting was significantly associated with pertussis (odds ratio, 2.508; 95% confidence interval, 1.146-5.486) and secondary referral hospital showed a borderline significance. In conclusion, using a PCR-based method, 6.9% of adolescent and adult patients with an acute cough illness had pertussis infection in an outpatient setting. However, hospital levels and seasonal trends must be taken into account to develop a better strategy for controlling pertussis.

Graphical Abstract

相似文献   

Examination of the Pronator Quadratus Muscle during Hardware Removal Procedures after Volar Plating for Distal Radius Fractures

Background

It is not clear whether the pronator quadratus (PQ) muscle actually heals and provides a meaningful pronation force after volar plating for distal radius fractures (DRFs). We aimed to determine whether the length of the PQ muscle, which is dissected and then repaired during volar plating for a DRF, affects the forearm rotation strength and clinical outcomes.

Methods

We examined 41 patients who requested hardware removal after volar plating. We measured the isokinetic forearm rotation strength and clinical outcomes including grip strength, wrist range of motion, and disabilities of the arm, shoulder and hand (DASH) scores at 6 months after fracture fixation. During the hardware removal surgery, which was performed at an average of 9 months (range, 8.3 to 11.5 months) after fracture fixation, we measured the PQ muscle length.

Results

The average PQ muscle length was 68% of the normal muscle length, and no significant relationship was found between the PQ muscle length and the outcomes including isokinetic forearm rotation strength, grip strength, wrist range of motion, and DASH scores.

Conclusions

This study demonstrates that the length of the healed PQ muscle does not affect isokinetic forearm rotation strength and clinical outcomes after volar plating for DRFs. The results of this study support our current practice of loose repair of the PQ that is performed by most of the surgeons to prevent tendon irritation over the plate, and suggest that tight repair of the PQ is not necessary for achieving improved forearm function.     

Responsiveness of the Korean Version of the Michigan Hand Outcomes Questionnaire after Carpal Tunnel Release

Background

The Korean version of the Michigan Hand Outcomes Questionnaire (K-MHQ) was recently validated; however, the questionnaire''s responsiveness as well as the degree to which the instrument is sensitive to change has not been thoroughly evaluated in a specific condition in Koreans. We evaluated the responsiveness of the K-MHQ in a homogenous cohort of patients with carpal tunnel syndrome (CTS) and we compared it with that of the Korean version of the Disability of the Arm, Shoulder, and Hand Questionnaire (K-DASH), which was found to have a large degree of responsiveness after carpal tunnel release for Korean patients with CTS.

Methods

Thirty-seven patients with CTS prospectively completed the K-MHQ and the K-DASH before and 6 months after surgery. The responsiveness statistics were assessed for both the K-MHQ and the K-DASH by using the standardized response mean (SRM), which was defined as the mean change of the original scores after surgery divided by the standard deviation of the change.

Results

All domains of the K-MHQ significantly improved after carpal tunnel release (p < 0.001). The SRM for all scales but one (the aesthetics scale) showed large responsiveness of ≥ 0.8. The aesthetics scale showed medium responsiveness of 0.6. The combined function/symptom scale of the K-DASH significantly improved after surgery (p < 0.001). The SRM of the K-DASH revealed large responsiveness of 0.9.

Conclusions

The K-MHQ was found to have a large degree of responsiveness after carpal tunnel release for Korean patients with CTS, which is comparable not only to the K-DASH, but also to the original version of the MHQ. The region-specific K-MHQ can be useful for outcomes research related to carpal tunnel surgery, especially for research comparing CTS with various other hand and wrist health conditions.     

Korean Type Distal Radius Anatomical Volar Plate System: A Preliminary Report

Background

Distal radius fracture is the most common fracture of the upper extremity, and approximately 60,000 distal radius fractures occur annually in Korea. Internal fixation with an anatomical volar locking plate is widely used in the treatment of unstable distal radius fractures. However, most of the currently used distal radius anatomical plate systems were designed based on the anatomical characteristics of Western populations. Recently, the Korean-type distal radius anatomical volar plate (K-DRAVP) system was designed and developed based on the anatomical characteristics of the distal radius of Koreans. The purpose of this study was to evaluate the preliminary results of the new K-DRAVP system, and to compare its radiologic and functional results with those of the other systems.

Methods

From March 2012 to October 2012, 46 patients with acute distal radius fractures who were treated with the K-DRAVP system at three hospitals were enrolled in this study. Standard posteroanterior and lateral radiographs were obtained to assess fracture healing, and three radiographic parameters (volar tilt, radial inclination, and radial length) were assessed to evaluate radiographic outcomes. The range of motion and grip strength, the Gartland and Werley scoring system, and the disabilities of the arm, shoulder and hand (DASH) questionnaire were used to assess clinical and functional outcomes.

Results

All radiologic parameters were restored to normal values, and maintained without any loosening or collapse until the time of final follow-up. Grip strength was restored to 84% of the value for the unaffected side. The mean range of motion of the wrist at final follow-up was restored to 77%-95% of the value for the unaffected side. According to the Gartland and Werley scoring system, there were 16 excellent, 26 good, and 4 fair results. The mean DASH score was 8.4 points. There were no complications after surgery.

Conclusions

The newly developed K-DRAVP system could be used to restore and maintain good anatomical parameters, and provide good clinical outcomes with low complication rates. This system is a promising surgical option for the treatment of distal radius fractures in the Korean population.     

Negative‐pressure wound dressings to secure split‐thickness skin grafts in the perineum

Several researches have shown that negative‐pressure wound dressings can secure split‐thickness skin grafts and improve graft survival. However, in anatomically difficult body regions such as the perineum it is questionable whether these dressings have similar beneficial effects. In this study, we evaluated the effects of negative‐pressure wound dressings on split‐thickness skin grafts in the perineum by comparing wound healing rate and complication rate with that of tie‐over dressings. A retrospective chart review was performed for the patients who underwent a split‐thickness skin graft to reconstruct perineal skin defects between January 2007 and December 2011. After grafting, the surgeon selected patients to receive either a negative‐pressure dressing or a tie‐over dressing. In both groups, the initial dressing was left unchanged for 5 days, then changed to conventional wet gauze dressing. Graft success was assessed 2 weeks after surgery by a single clinician. A total of 26 patients were included in this study. The mean age was 56·6 years and the mean wound size was 273·1 cm². Among them 14 received negative‐pressure dressings and 12 received tie‐over dressings. Negative‐pressure dressing group had higher graft taken rate (P = 0·036) and took shorter time to complete healing (P = 0·01) than tie‐over dressing group. The patients with negative‐pressure dressings had a higher rate of graft success and shorter time to complete healing, which has statistical significance. Negative‐pressure wound dressing can be a good option for effective management of skin grafts in the perineum.     

心理干预联合药物对吸烟者的戒烟效果评价

目的 评价伐尼克兰在临床实践中对戒烟门诊患者戒烟的有效性.方法 采用前瞻性观察性研究设计,选择符合纳入标准的吸烟者799人,每名患者首诊时进行标准的基线问卷评估,并在第1、第3和第6个月进行随访.由经过培训的医师对每名患者完成面对面的咨询和个体化戒烟干预.接受药物辅助戒烟者定为心理干预联合药物组(n=272),未用药者为单纯心理干预组(n=527).采用意向性分析的统计学方法分析比较两组的7天时点戒烟率、3个月随访时的1个月持续戒烟率和6个月随访时的3个月持续戒烟率.结果 6个月随访时,心理干预联合药物组的7天时点戒烟率显著高于单纯心理干预组(34.6% vs. 23.1%;OR=1.75,95% CI:1.27～2.42;P<0.001),心理干预联合药物组的3个月持续戒烟率也显著高于单纯心理干预组(31.3% vs. 18.2%;OR=2.04,95%CI:1.46～2.86;P<0.001).1和3个月随访时,心理干预联合药物组无论是7天时点戒烟率还是1个月持续戒烟率均高于单纯心理干预组.结论 在真实临床实践的戒烟门诊中,给予戒烟者药物辅助戒烟可有效提高戒烟率.