Effect of deuteration on the single dose pharmacokinetic properties and postoperative analgesic activity of methadone

Although methadone is effective in the management of acute pain, the complexity of its absorption-distribution-metabolism-excretion profile limits its use as an opioid of choice for perioperative analgesia. Because deuteration is known to improve the pharmacokinetic, pharmacodynamic and toxicological properties of some drugs, here we characterized the single dose pharmacokinetic properties and post-operative analgesic efficacy of d₉-methadone.The pharmacokinetic profiles of d₉-methadone and methadone administered intravenously to CD-1 male mice revealed that deuteration leads to a 5.7- and 4.4-fold increase in the area under the time-concentration curve and maximum concentration in plasma, respectively, as well as reduction in clearance (0.9 ± 0.3 L/h/kg vs 4.7 ± 0.8 L/h/kg). The lower brain-to-plasma ratio of d₉-methadone compared to that of methadone (0.35 ± 0.12 vs 2.05 ± 0.62) suggested that deuteration decreases the transfer of the drug across the blood-brain barrier. The estimated LD₅₀ value for a single intravenous dose of d₉-methadone was 2.1-fold higher than that for methadone. Moreover, d₉-methadone outperformed methadone in the efficacy against postoperative pain by primarily activating peripheral opioid receptors. Collectively, these data suggest that the replacement of three hydrogen atoms in three methyl groups of methadone altered its pharmacokinetic properties, improved safety, and enhanced its analgesic efficacy.     

Cervical cancer in Morocco: A systematic review

BackgroundThis systematic review aims to determine the epidemiological profile, etiology and risk factors, prevention, diagnosis, treatment, cost-effectiveness, survival, and quality of life related to cervical cancer in Morocco.MethodsThis study was conducted according to the recommendations of the "preferred reporting items for systematic reviews and meta-analysis." The PubMed, ScienceDirect, Springer, Web of Science data bases were used, as was Google Scholar for the grey literature. The review protocol was registered in the PROSPERO register (CRD42021235241).ResultsFifty studies were selected. The mean age was 49.31 ±6.3 years. HPV infection prevalence ranged from 13.30% to 76%, with a peak in HIV-positive women. Acceptability of the HPV vaccine was higher among parents (35% and 82%) than among adolescents (16.9% to 46.6%). Knowledge of the vaccine and its price are two key factors related to vaccine acceptability among parents. This systematic review highlights that the fact that few eligible women (not more than 11%) were participating in the cervical cancer screening program. Moroccan women's level of knowledge and awareness regarding cervical cancer screening was low, negatively impacting their use of such screening tools, as illustrated by the high percentage (mean 76.32% ± 17.21) of women who had never been screened for cervical cancer. Treatment was the most significant component of the global care budget (95.87%), with an annual cost of $13,027,609. Five-year overall survival ranged from 41.3% to 73.6%, with higher survival rates for patients diagnosed at an earlier stage (77.3–85% for stage I). Lastly, low quality of life was observed in women with tumors at an advanced stage who had received brachytherapy and lacked social support.ConclusionsSubjects that require further investigation include Moroccan women's knowledge, attitudes, and awareness, especially among those at high risk of developing cervical cancer, and its impact on their quality of life and survival.     

靶向测序诊断黑棘皮病1家系

【摘要】 报道临床症状不典型的家族性黑棘皮病1家系。先证者女，4岁，自1周岁时，颈部、腹部出现黑色斑片，近年来逐渐扩大至唇周、躯干前部。腹部皮肤全反式共聚焦显微镜检查可见乳头环下延扭曲及沟壑结构，乳头环内可见中高折光颗粒结构。先证者父亲及祖母既往有类似病史，但随着年龄增长色素沉着自发性消退，仅有局部皮纹增粗。采集先证者及父母、祖母外周血，对先证者外周血DNA行Panel靶向测序，结果显示，先证者存在FGFR3基因14号外显子c.1949A>C（p.Lys650Thr）错义突变，Sanger测序验证证实先证者及其父亲和祖母均存在此突变。诊断：家族性黑棘皮病。     

Effects of synthetic and biological disease modifying antirheumatic drugs on lipid and lipoprotein parameters in patients with rheumatoid arthritis

BackgroundDyslipidemia in rheumatoid arthritis (RA) patients is frequently observed, and treatment with anti-rheumatic drugs has an impact on lipid profiles. Pathophysiologically, inflammation leads to decreased blood lipids and lipoproteins; RA treatment reduces inflammation and therefore may increase lipids and lipoproteins. Whether the lipid changes with RA treatment confer an increased risk of cardiovascular disease or just reflect their potentially atheroprotective anti-inflammatory effect is currently unclear due to limited and conflicting data.ObjectiveThe aim of this review is to summarize the current knowledge on the effects of synthetic and biological disease modifying antirheumatic drugs for the treatment of RA on lipid and lipoprotein parameters.ResultsRecent studies on methotrexate emphasize its anti-atherogenic effect. Golimumab combined with methotrexate revealed a trend towards an anti-atherogenic potential. The known pro-atherogenic lipid-spectrum alterations caused by tofacitinib can be effectively treated with atorvastatin. Tocilizumab signals a favorable impact on the extent of lipid modifications when combined with methotrexate. Abatacept indicated a trend towards an anti-atherogenic lipid profile demonstrated by favorable effects on HDL-C and on the TC/HDL-C ratio. Rituximab has beneficial effects on HDL-C and ApoA1, as well as on the ApoB/ApoA1 ratio.Clinical implicationsAnti-rheumatic drugs have various effects on lipid parameters, which in part appear pro-atherogenic. However, because many of these lipid changes may well reflect their potentially atheroprotective anti-inflammatory action the cardiovascular impact of these changes remains unclear. Whatsoever, cardiovascular safety trials for antirheumatic drugs would be valuable.     

Smad2 increases the apoptosis of activated human hepatic stellate cells induced by TRAIL

The activation of hepatic stellate cells (HSCs) plays a critical role in the development of liver fibrosis. The induction of apoptosis in activated HSCs during the recovery phase of hepatic fibrosis represents a potential anti-fibrotic therapy. We have previously shown that Smad2 protects against hepatic fibrogenesis; however, the role of Smad2 in the regulation of activated HSC apoptosis remains unknown. We hypothesized that Smad2 regulates the apoptosis of activated HSCs, leading to the resolution of liver fibrosis. To test this hypothesis, the livers of rats were harvested at 0 and 4 weeks after hepatic fibrosis was established by CCl₄ injection. Furthermore, TGF-β1-activated HSCs were treated with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) following the silencing or overexpression of Smad2. Both the phosphorylation of Smad2 and TRAIL were detected in fibrotic liver tissues. The results of TUNEL and α-SMA double-staining showed an increase in the apoptosis of activated HSCs during the spontaneous recovery phase. The knockdown of Smad2 reduced TRAIL-induced apoptosis in TGF-β1-activated human LX-2 cells and resulted in an increased expression of α-SMA and collagen I (Col. I). In contrast, the overexpression of Smad2 increased TRAIL-induced HSC apoptosis and reduced the expression of α-SMA and Col. I. The mechanisms underlying these findings were associated with the Smad2-mediated down-regulation of X-linked inhibitor of apoptosis protein (XIAP), resulting in enhanced caspase-3 activity and apoptosis. In conclusion, Smad2 enhances TRAIL-induced apoptosis in activated HSCs, which facilitates the resolution of hepatic fibrosis.     

农村青少年不同时期家庭逆境与精神病理症状的关联

目的探讨家庭逆境致精神病理症状结局的累积性与关键期效应,为预防与干预逆境伤害提供依据。方法2017年12月,采用方便抽样的方法选取安徽省阜阳地区2所农村学校的710名青少年。采用《童年期不良经历问卷》评估家庭逆境,《MacArthur健康与行为问卷》评价内化症状和外化症状。采用多元线性回归分析家庭逆境发生时间与数量和精神病理症状的关联。结果持续家庭逆境组与内化症状、外化症状增加均有相关性[β值(95%CI)分别为0.35(0.15~0.54),0.16(0.01~0.32)]。家庭逆境数量为2和≥3与内化症状[β值(95%CI)分别为0.20(0.04~0.36),0.42(0.24~0.60)]、外化症状[β值(95%CI)分别为0.14(0.01~0.26),0.23(0.09~0.37)]增加有关。在仅童年期家庭逆境中,家庭逆境数量为2和≥3的内化症状[β值(95%CI)分别为0.23(0.06~0.41),0.34(0.11~0.58)]、外化症状[β值(95%CI)分别为0.17(0.02~0.31),0.21(0.02~0.39)]的风险增高。在持续家庭逆境组中,逆境数量≥3与内化症状、外化症状相关[(β值(95%CI)分别为0.56(0.31~0.82),0.24(0.02~0.45)]。仅青春期家庭逆境与精神病理症状无关。结论家庭逆境的多次发生可增加精神病理症状风险,童年期可能是家庭逆境致精神病理症状的关键期。     

特异性神经元抗体对神经系统副肿瘤综合征筛检价值的研究

目的　探讨特异性神经元抗体 (尤其是抗 Hu抗体 )对国内人群神经系统副肿瘤综合征 (paraneoplasticsyndromesofnervoussystem ,PNSNS)筛检诊断的特异性和灵敏性。方法　采用免疫组织化学ABC法和Westernblot对 2 0例PNSNS和 12 0例非PNSNS患者的血清进行检测 ,并采用流行病学筛检公式计算出特异度和灵敏度。结果　PNSNS组和非PNSNS组ABC法阳性结果差异有统计学意义 (χ2 =33 4 5 ,P <0 0 1) ,特异性神经元抗体筛检诊断PNSNS的灵敏度为 95 % ,特异度为 72 5 % ;PNSNS组和非PNSNS组Westernblot法阳性率差异有统计学意义 (χ2 =117 12 ,P <0 0 1) ,抗 Hu抗体筛检诊断的PNSNS的灵敏度为 95 % ,特异度为 98 3%。结论　血清特异性神经元抗体 (尤其是抗 Hu抗体 )是国内人群中PNSNS患者较敏感和特异性的血清标志物 ,在神经元的免疫损伤中具有重要作用     

贝那普利降压疗效与校正QT间期的关系

目的探讨原发性高血压患者心电图心率校正QT间期(QTc)和贝那普利降压疗效之间的关系.方法采用前瞻性队列研究方法调查安徽A县899名高血压病患者的基线心电图、治疗15 d前后的血压变化及相关临床和流行病学特点等情况.结果 QTc和血压下降呈负相关.QTc每增加0.1秒1/2,收缩压和舒张压的下降值分别减少3.6 mmHg和3.3 mmHg,且差异均有显著性(P＜0.05).将QTc三等分后,随着QTc等分的增加,收缩压和舒张压的下降值均逐渐减少,且差异具有显著性(P＜0.05);将QTc等分后的变量放入方程中进行趋势性分析,发现在收缩压和舒张压组中的负相关关系具有显著性(P＜0.05).随着QTc等级的增加,舒张压有效率逐渐降低,且有显著性差异(P＜0.05),收缩压的效应关系不如舒张压明显.结论 QTc和贝那普利降压疗效呈负相关,对贝那普利短期降压疗效具有重要的预测价值.