Distinct perceptive pathways selected with tonic and bursting patterns of thalamic stimulation

BackgroundNovel patterns of electrical stimulation of the brain and spinal cord hold tremendous promise to improve neuromodulation therapies for diverse disorders, including tremor and pain. To date, there are limited numbers of experimental studies in human subjects to help explain how stimulation patterns impact the clinical response, especially with deep brain stimulation.We propose using novel stimulation patterns during electrical stimulation of somatosensory thalamus in awake deep brain stimulation surgeries and hypothesize that stimulation patterns will influence the sensory percept without moving the electrode.MethodsIn this study of 15 fully awake patients, the threshold of perception as well as perceptual characteristics were compared for tonic (trains of regularly-repeated pulses) and bursting stimulation patterns.ResultsIn a majority of subjects, tonic and burst percepts were located in separate, non-overlapping body regions (i.e., face vs. hand) without moving the stimulating electrode (p < 0.001; binomial test). The qualitative features of burst percepts also differed from those of tonic-evoked percepts as burst patterns were less likely to evoke percepts described as tingling (p = 0.013; Fisher’s exact test).ConclusionsBecause somatosensory thalamus is somatotopically organized, percept location can be related to anatomic thalamocortical pathways. Thus, stimulation pattern may provide a mechanism to select for different thalamocortical pathways. This added control could lead to improvements in neuromodulation - such as improved efficacy and side effect attenuation - and may also improve localization for sensory prostheses.     

Differential involvement of glutathione S‐transferase mu 1 and multidrug resistance protein 1 in melanoma acquired resistance to vinca alkaloids

On account of its extreme intrinsic resistance to apoptosis and of its strong ability to become chemoresistant after a primary response to drugs, malignant melanoma (MM) is still a therapeutic challenge. We previously showed that glutathione S‐transferase mu 1 (GSTM1) acts in synergy with multidrug resistance protein 1 (MRP1) to protect GSTM1‐transfected human CAL1 melanoma cells from toxic effects of vincristine (VCR). Herein, we investigated the role of these proteins in the acquired resistance of CAL1 cells to vinca alkaloids (VAs). Resistant lines were established by continuous exposure (>1 year) of parental CAL1‐wt cells to VCR, vindesine (VDS), or vinorelbine (VRB): CAL1R‐VCR, CAL1R‐VDS, CAL1R‐VRB, respectively. All resistant lines displayed more than 10‐fold increase in resistance to their selection VA, and specifically expressed GSTM1. Suggesting a direct interaction between this protein and VAs, each VA specifically decreased the GSTM1‐mediated glutathione conjugation activity in cell lysates. Curcumin (GSTM1 inhibitor), BSO (glutathione synthesis inhibitor), and MK571 (MRP1 inhibitor) considerably reversed the acquired resistance to VCR and VDS, but not to VRB. Microarray data analysis revealed similar gene expression patterns of CAL1R‐VCR and CAL1R‐VDS, and a distinct one for CAL1R‐VRB. These data suggest a differential involvement of GSTM1 and MRP1 in acquired resistance to VAs. A coordinated expression and activity of GSTM1 and MRP1 is required to protect CAL1 cells from VCR and VDS, while the simple expression of GSTM1 is sufficient, possibly by a direct drug/protein interaction, to confer resistance against VRB.     

Immunohistochemical and molecular analysis of PI3K/AKT/mTOR pathway in esophageal carcinoma

Among the numerous signaling pathways involved in tumorigenesis, PI3K‐AKT‐mTOR is a key one that regulates diverse cellular functions. However, its prognostic value in esophageal carcinoma remains unclear. In our study, we examined the immunohistochemical expression of phosphorylated (p‐) AKT, mTOR, p70S6K and 4E‐BP1 along with the mutational status of PIK3CA and AKT1 genes by High Resolution Melting Analysis and Pyrosequencing in 44 esophageal carcinomas. The results were correlated with the clinicopathological characteristics of the patients in an effort to define their possible prognostic significance. Total p‐mTOR cytoplasmic expression, assessed in 10 random areas, was positively correlated with tumor stage (Kruskal–Wallis ANOVA, I/II vs III/IV, p = 0.0500). Μoreover, maximum p‐mTOR cytoplasmic immunoexpression, estimated in hot spot areas, was positively associated with tumor grade (Mann–Whitney U test, I/II vs III, p = 0.0565). Interestingly, p‐4E‐BP1 immunoreactivity was negatively correlated with tumor histological grade (Mann–Whitney U test, I/II vs III, p = 0.0427). No mutation was observed in exons 9 and 20 of PIK3CA gene and in exon 4 of AKT1 gene. In conclusion, our findings depict the presence of activated PI3K/AKT/mTOR pathway in esophageal cancer bringing forward p‐mTOR and p‐4E‐BP1 for their potential role in esophageal carcinogenesis. Additional studies are warranted to validate our findings.     

VPS35WT能够逆转LRRK2G2019S所致的非神经细胞的Tau蛋白过度磷酸化及相关功能缺陷

目的探究逆膜复合体亚基VPS35对LRRK2G2019S所导致的Tau功能缺陷的影响。方法通过在He La细胞内过表达LRRK2G2019S和共表达VPS35WT+LRRK2G2019S后进一步检测Hela细胞内Tau蛋白磷酸化水平、细胞骨架形态及在低剂量毒物作用下细胞死亡率的变化。结果共转VPS35WT可以进一步逆转过表达LRRK2G2019S的Hela细胞的Tau蛋白的磷酸化,稳定细胞骨架,提高细胞对毒物的抵抗力,降低细胞的死亡率。结论VPS35WT可以逆转LRRK2G2019S所致的He La细胞相关功能障碍。     

Implementation of Recommendations for Long-Acting Contraception Among Women Aged 13 to 18 Years in Primary Care

ObjectiveClinical specialty societies recommend long-acting reversible contraceptives (LARCs) as first-line contraception for adolescent women. We evaluated whether a combined educational and process improvement intervention enhanced LARC placement in primary care within an integrated health care system.MethodsThe intervention included journal clubs, live continuing education, point-of-care guidelines, and new patient materials. We conducted a retrospective cohort study across 3 time periods: baseline (January 2013?September 2015), early implementation (October 2015–March 2016), and full implementation (April 2016–June 2017). The primary outcome was the proportion of LARCs placed by primary care clinicians among women aged 13 to 18 years compared with gynecology clinicians.ResultsKaiser Foundation Health Plan of Colorado cared for approximately 20,000 women aged 13 to 18 years in each calendar quarter between 2013 and 2017. Overall, LARC placement increased from 7.0 per 1000 members per quarter at baseline to 13.0 per 1000 during the full intervention. Primary care clinicians placed 6.2% of all LARCs in 2013, increasing to 32.1% by 2017 (P < .001), including 45.5% of contraceptive implants. Clinicians who attended educational sessions were more likely to adopt LARCs than those who did not (17.9% vs 6.4% respectively, P = .009). Neither overall LARC placement rates (relative risk, 1.9; 95% confidence interval, 0.7?5.6) nor contraceptive implant rates (relative risk, 3.0; 95% confidence interval, 0.9?9.8) increased significantly in clinicians who attended educational activities.ConclusionsThis multimodal intervention was associated with increased LARC placement for adolescent women in primary care. The combination of education and process improvement is a promising strategy to promote clinician behavior change.     

口腔黏膜幼年性黄色肉芽肿1例报告及文献复习

幼年性黄色肉芽肿是非朗格汉斯组织细胞增生症中的一种,主要发生于皮肤,可单发或多发,皮肤外器官主要累及眼、中枢神经系统、肝脏、肾脏等,口腔病变罕见。本文报告1例发生于腭部的幼年性黄色肉芽肿病例。该患儿表现为腭部黏膜下黄色结节,无明显疼痛,不影响进食及语言功能,治疗采取手术切除,术后免疫组织化学报告为幼年性黄色肉芽肿。