Effects of Deletion of ERα in Osteoblast‐Lineage Cells on Bone Mass and Adaptation to Mechanical Loading Differ in Female and Male Mice

Estrogen receptor alpha (ERα) has been implicated in bone's response to mechanical loading in both males and females. ERα in osteoblast lineage cells is important for determining bone mass, but results depend on animal sex and the cellular stage at which ERα is deleted. We demonstrated previously that when ERα is deleted from mature osteoblasts and osteocytes in mixed‐background female mice, bone mass and strength are decreased. However, few studies exist examining the skeletal response to loading in bone cell–specific ERαKO mice. Therefore, we crossed ERα floxed (ERα^fl/fl) and osteocalcin‐Cre (OC‐Cre) mice to generate animals lacking ERα in mature osteoblasts and osteocytes (pOC‐ERαKO) and littermate controls (LC). At 10 weeks of age, the left tibia was loaded in vivo for 2 weeks. We analyzed bone mass through micro‐CT, bone formation rate by dynamic histomorphometry, bone strength from mechanical testing, and osteoblast and osteoclast activity by serum chemistry and immunohistochemistry. ERα in mature osteoblasts differentially regulated bone mass in males and females. Compared with LC, female pOC‐ERαKO mice had decreased cortical and cancellous bone mass, whereas male pOC‐ERαKO mice had equal or greater bone mass than LC. Bone mass results correlated with decreased compressive strength in pOC‐ERαKO female L₅ vertebrae and with increased maximum moment in pOC‐ERαKO male femora. Female pOC‐ERαKO mice responded more to mechanical loading, whereas the response of pOC‐ERαKO male animals was similar to their littermate controls. © 2015 American Society for Bone and Mineral Research. © 2015 American Society for Bone and Mineral Research.     

Repositioning Potential of PAK4 to Osteoclastic Bone Resorption

Drug repositioning is a rational approach for expanding the use of existing drugs or candidate drugs to treat additional disorders. Here we investigated the possibility of using the anticancer p21‐activated kinase 4 (PAK4)‐targeted inhibitor PF‐3758309 to treat osteoclast‐mediated disorders. PAK4 was highly expressed in bone marrow cells and was phosphorylated during their differentiation into osteoclasts, and osteoclast differentiation was significantly inhibited by the dominant negative form of PAK4 and by PF‐3758309. Specifically, PF‐3758309 significantly inhibited the fusion of preosteoclasts, the podosome formation, and the migration of preosteoclasts. PF‐3758309 also had in vivo antiresorptive activity in a lipopolysaccharide‐induced bone erosion model and in vitro antiosteoclastogenic activity in the differentiation of human bone marrow–derived cells and peripheral blood mononuclear cells into osteoclasts. These data demonstrate the relevance of PAK4 in osteoclast differentiation and the potential of PAK4 inhibitors for treating osteoclast‐related disorders. © 2015 American Society for Bone and Mineral Research © 2015 American Society for Bone and Mineral Research.     

The optimal therapy of calcineurin inhibitors for pregnancy in kidney transplantation

We investigated the effects of pregnancy and delivery on renal function in transplant recipients and the relationship between doses of immunosuppressants and blood drug levels during pregnancy in 75 women with 88 deliveries. Significant serum creatinine elevation (> 0.5 mg/dL) was found in eight deliveries. In the remaining 80 cases, serum creatinine was reduced by an average of 0.14 mg/dL and returned to pre‐pregnant levels after delivery. Tacrolimus was used in 28 deliveries and cyclosporine in others. Tacrolimus blood trough level declined from 5.8 ± 2.8 ng/mL 12 months before delivery to 4.2 ± 1.8 ng/mL at second trimester; therefore, drug dose was increased from 4.1 ± 1.9 mg/d at first trimester to 5.5 ± 2.5 mg/d at delivery. Similarly, cyclosporine levels were 125.1 ± 65.1 ng/mL 12 months before delivery and 75.4 ± 35.0 ng/mL at second trimester resulting in dose elevation from 183.0 ± 71.8 mg/d at first trimester to 225.4 ± 85.1 mg/d at delivery. Renal function in female kidney transplant recipients improved slightly during pregnancy and returned to pre‐pregnant level after delivery. The dose elevation of calcineurin inhibitor by approximately 20–25% should be considered during gestational period to maintain optimal blood drug level.     

Connecting the P300 to the diagnosis and prognosis of unconscious patients

The residual consciousness of unconscious patients can be detected by studying the P300, a wave among event-related potentials. Previous studies have applied tones, the subject's name and other names as stimuli. However, the results were not satisfactory. In this study, we changed the constituent order of subjects' two-character names to create derived names. The subject's derived names, together with tones and their own names, were used as auditory stimuli in event-related potential experiments. Healthy controls and unconscious patients were included in this study and made to listen to these auditory stimuli. In the two paradigms, a sine tone followed by the subject's own name and the subject's derived name followed by the subject's own name were used as standard and deviant stimuli, respectively. The results showed that all healthy controls had the P300 using both paradigms, and that the P300 in the second paradigm had a longer latency and two peaks. All minimally conscious state patients had the P300 in the first paradigm and the majority of them had the P300 in the second paradigm. Most vegetative state patients had no P300. Patients who showed the P300 in the two paradigms had more residual consciousness, and patients with the two-peak P300 had a higher probability of awakening within a short time. Our experimental findings suggest that the P300 event-related potential could reflect the conscious state of unconscious patients.     

Analysis of Altered Baseline Brain Activity in Drug-Naive Adult Patients with Social Anxiety Disorder Using Resting-State Functional MRI

Objective

We hypothesize that the amplitude of low-frequency fluctuations (ALFF) is involved in the altered regional baseline brain function in social anxiety disorder (SAD). The aim of the study was to analyze the altered baseline brain activity in drug-naive adult patients with SAD.

Methods

We investigated spontaneous and baseline brain activities by obtaining the resting-state functional magnetic resonance imaging data of 20 drug-naïve adult SAD patients and 19 healthy controls. Voxels were used to analyze the ALFF values using one- and two-sample t-tests. A post-hoc correlation of clinical symptoms was also performed.

Results

Our findings show decreased ALFF in the bilateral insula, left medial superior frontal gyrus, left precuneus, left middle temporal gyrus, right middle temporal pole, and left fusiform gyrus of the SAD group. The SAD patients exhibited significantly increased ALFF in the right inferior temporal gyrus, right middle temporal gyrus, bilateral middle occipital gyrus, orbital superior frontal gyrus, right fusiform gyrus, right medial superior frontal gyrus, and left parahippocampal gyrus. Moreover, the Liebowitz Social Anxiety Scale results for the SAD patients were positively correlated with the mean Z values of the right middle occipital and right inferior occipital but showed a negative correlation with the mean Z values of the right superior temporal gyrus and right medial superior frontal gyrus.

Conclusion

These results of the altered regional baseline brain function in SAD suggest that the regions with abnormal spontaneous activities are involved in the underlying pathophysiology of SAD patients.     

老年肿瘤患者PICC导管相关性感染危险因素及病原菌分析

目的分析老年肿瘤化疗患者PICC导管相关性感染的感染病原菌分布及其危险因素,为临床工作中有效防治导管相关性感染提供参考。方法收集2013年1月至2014年12月行PICC置管的老年肿瘤化疗患者246例,分析PICC导管相关性感染的病原菌分布,对PICC导管相关性感染的危险因素进行分析。结果 246例老年肿瘤化疗患者中发生PICC导管相关性感染为28例,发生率为11.4%。病原菌分布为革兰阳性菌(55.9%),革兰阴性菌(26.5%)和真菌(17.6%)。单次穿刺次数、PICC留置时间、输液类型、使用激素、白细胞计数、糖尿病史及静脉炎史是导管相关性感染发生率的影响因素(P0.05,P0.01)。结论老年肿瘤化疗患者是导管相关性感染的高发人群。应采取PICC置管前充分评估,严格执行PICC置管无菌操作,规范PICC日常维护,加强患者免疫机能等措施,减少老年肿瘤化疗患者PICC导管相关性感染的发生。     

精索静脉曲张手术疑似失败一例报告及再手术指证探讨

本文报告一例精索静脉曲张手术疑似失败病例的处理经过。患者双侧精索静脉曲张(左侧Ⅲ度,右侧Ⅱ度)伴局部疼痛不适及精液质量严重异常,行腹腔镜双侧精索静脉高位结扎术,术后2个月自觉局部坠胀、疼痛症状明显缓解,但双侧阴囊的迂曲较术前更加明显,疑似手术失败并再次入院。经临床和实验室检查后,发现患者无明确手术失败证据,选择对症治疗而避免再次手术。观察等待3个月后复诊,患者临床表现(鞘膜积液及坠胀感)减轻,实验室检查精液质量改善,超声检查乏氏动作后双侧精索静脉未见返流,双侧睾丸鞘膜未见明显积液,进一步确诊术后症状为术后暂时性侧枝循环建立不佳所致,而这种情况在同类手术中比较常见。综合本病例及文献报道,我们建议要严格掌握再手术的指证:明确的复发征象(与体位相关的精索静脉曲张及血液返流);患者的原始诉求(疼痛不适、精液质量异常)仍然存在且无改善。难以判断者,建议观察等待,以避免不必要的再次手术。通常术后应观察3~6个月再进行综合判定。