Pharmacological characterization of LPS and opioid interactions at the toll-like receptor 4

Background and Purpose

Previous work in our laboratory showed opioid agents inhibit cytokine expression in astrocytes. Recently, Watkins and colleagues hypothesized that opioid agonists activate toll-like receptor 4 (TLR4) signalling, which leads to neuroinflammation. To test this hypothesis, we characterized LPS and opioid effects on TLR4 signalling in reporter cells.

Experimental Approach

NF-κB reporter cells expressing high levels of TLR4 were used to compare LPS and opioid effects on NF-κB activation, a pathway activated by TLR4 stimulation.

Key Results

LPS increased TLR4 signalling in a concentration-dependent manner and was antagonized by LPS antagonist (LPS-RS, from Rhodobacter sphaeroides). A concentration ratio analysis showed that LPS-RS was a competitive antagonist. The opioid agonists, morphine and fentanyl, produced minor activation of TLR4 signalling when given alone. When tested following LPS stimulation, opioid agonists inhibited NF-κB activation but this inhibition was not blocked by the general opioid antagonist, naloxone, nor by the selective μ opioid receptor antagonist, β-FNA. Indeed, both naloxone and β-FNA also inhibited NF-κB activation in reporter cells. Further examination of fentanyl and β-FNA effects revealed that both opioid agents inhibited LPS signalling in a non-competitive fashion.

Conclusions and Implications

These results show that LPS-RS is a competitive antagonist at the TLR4 complex, and that both opioid agonists and antagonists inhibit LPS signalling in a non-competitive fashion through a non-GPCR, opioid site(s) in the TLR4 signalling pathway. If confirmed, existing opioid agents or other drug molecules more selective at this novel site may provide a new therapeutic approach to the treatment of neuroinflammation.     

超声检测和量化肩关节积液的可靠性

目的评价超声检测和量化肩关节积液的可靠性。方法30例病人在MR肩关节成像前、后分别进行超声检查。记录不同部位(肱二头肌肌腱鞘区、正中位和内旋位肩胛下凹陷区、正中位和外展位肩关节后凹陷区)可探测到的无回声区及其宽度。以肩关节注入8～12mL液体作为金标准,分     

Classification of trochlear dysplasia as predictor of clinical outcome after trochleoplasty

Purpose  

Sulcus-deepening trochleoplasty restores the trochlear groove in patients with patellofemoral instability and underlying trochlear dysplasia. There are types of dysplasia both with (B and D) and without (A and C) a supratrochlear spur. The aim of this study was to identify influencing factors for the clinical outcome following trochleoplasty.     

Ramp lesions in ACL deficient knees in children and adolescent population: a high prevalence confirmed in intercondylar and posteromedial exploration

Purpose

Ramp lesions are common in ACL deficient knees. Their diagnosis is difficult and, therefore, they may be underestimated. So far, no study analyzed their prevalence in a pediatric population. The diagnosis of these Ramp lesions is of major clinical relevance because of a frequent misestimating and technic difficulties. Ramp lesions might be associated with residual knee pain and instability after ACL reconstruction. The aim of this study was to evaluate the prevalence of ramp lesions explored through a systematic intercondylar and posteromedial arthroscopic approach during an ACL reconstruction in a pediatric and adolescent population.

Methods

Children and adolescents who underwent an ACL reconstruction were screened prospectively between October 2014 and 2016. The presence or absence of a ramp lesion was evaluated after each of three arthroscopic steps: (1) an anterior approach, (2) an intercondylar inspection, and (3) a posteromedial approach. Ramp lesions were screened at each step and their prevalence was evaluated. Furthermore, their presence was correlated to age, weight, size, sex, and state of the physis (open or closed). Finally, the meniscal status on MRI and arthroscopic findings were compared.

Results

Fifty-six patients were analyzed. The median age was 14.0?±?1.3 years (12–17). The median interval between injury and surgery was 11.5 months (1–108). During step 1 (anterior approach), only 1 ramp lesion (2%) was diagnosed. 13 (23%) ramp lesions were found after inspection through the intercondylar notch. No additional lesions were found with a direct view through the posteromedial approach. No correlation between ramp lesions and side, sex, weight, size, or state of physis was found. 10 ramp lesions out of 13 could not be diagnosed on MRI.

Conclusions

The prevalence of ACL-associated ramp lesions in children and adolescents is similar to adult populations. A systematic inspection through the intercondylar notch is recommended during ACL reconstruction to make a precise diagnosis. The posteromedial approach is essentially useful for meniscal repair

Level of evidence

Testing, previously developed diagnostic criteria in a consecutive series of patients and a universally applied “gold” standard, Level I.

     

Secrets,shame and guilt: HIV disclosure in rural Chinese families from the perspective of caregivers

This in-depth ethnographic study examines the processes, barriers and impacts experienced by Mainland Chinese caregivers residing in rural Yunnan for disclosing HIV status to their adolescents born with the infection and other community members. In particular, highlighted are their associated personal, social, relational and cultural vulnerabilities. A purposeful sample of 13 pairs of HIV-born adolescents between the ages of 11–19 years and their primary caregivers were recruited in December 2014. The Conceptual Model Sexual Health Disclosure (CMSHD) was modified with Chinese culturally specific adaptation to guide the exploration of the complex aspects of the adolescents and caregiver’s relationships. All interviews were audiotaped, transcribed verbatim and then translated into English.

Complex sociocultural interactions emerging in these dyadic interviews included guilt, shame, unintended disclosure, the need for secrecy, perceived stigma, ‘loss of face’, protection of parents, inability to support their families and deep concerns over lineage and future marriage prospects amongst the parents, which had significant psychosocial and even physical impacts for these adolescents born with HIV and their families. Frontline health-care workers and HIV peer support programs are recommended to counteract China’s current top-down biomedical disease-related approach to health services. It is crucial to provide instrumental avenues of confidential psychosocial support including disclosure approaches for caregivers of HIV positive adolescents within a uniquely Chinese cultural context.     

银杏叶提取物改善反复脑缺血再灌注小鼠血液流变学的作用

目的：研究银杏叶提取物（ＥＧＢ）改善反复脑缺血再灌注小鼠血液流这的作用。方法：采用反复脑缺血再注模型鼠,应用毛细管微量热沉法和毛细管微量法分别检测血纤维蛋白原含量和红细胞压积数值,并将结果输入全自动血液流变仪得出血浆粘度、血液粘度、血细胞聚集系数,血栓形成系数及微循环滞留时间（ＭＳＴ）。结果：ＥＢＧ２５￣１００ｍｇ／ｋｇ均可不同程度地降低Ｆｉｂ、ＨＣＴ、降低ηｂ、ηｐ、ηｈ,缩小ＶＡＬ及ＴＷＥＬ,