Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling

This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.     

Risk Factors for a First Febrile Seizure: A Matched Case-Control Study

Summary We conducted a matched casecontrol study to identify risk factors for first febrile seizures, with special emphasis on characteristics of the acute illness episode. Cases were identified through hospital emergency departments; controls were identified through outpatient clinics and emergency departments. Sixtynine children with first febrile seizures and no history of previous unprovoked seizures were matched for age (±6 months), site of routine pediatric care, and date of visit (±weeks) with 1 or 2 febrile controls who had no history of previous febrile or unprovoked seizures. Medical records for the index visit were reviewed, and parents were interviewed by telephone. Illness characteristics examined included height of temperature, type of underlying illness, contact with a physician during the illness but before the index visit, and use of acetaminophen or decongestants. Family history of febrile and of unprovoked seizures, sociodemographic characteristics, daycare use, and selected preand perinatal variables were also studied. On multivariable analysis, significant independent risk factors were height of temperature, history of febrile seizures in a firstor in a higher degree relative. Gastroenteritis as the underlying illness had a significant inverse (i.e., protective) association with febrile seizures. Maternal smoking during pregnancy was a marginally significant predictor of febrile seizures.     

Mivazerol, a new α2-adrenergic agonist, blunts cardiovascular effects following surgical stress in pentobarbital-anesthetized rats

Background: Mivazerol is a new and selective α₂-adrenoceptor agonist, devoid of hypotensive effects, which has been designed to prevent adverse cardiac outcome in perioperative patients with, or at risk of coronary artery disease. Methods: In the present study, the effects of mivazerol on hemodynamic changes induced by trachea-exposure surgery stress were investigated in pentobarbital-anesthetized rats, and compared to those of dexmedetomidine. Results: Intravenous infusion of 3 different doses of mivazerol (3.75, 7.5 and 15 μg kg^-1 h^-1) did not significantly alter BP but caused a dose-related decrease in HR. The maximal decrease in HR was approximately 87 beats/min. Contrary to mivazerol, dexmedetomidine (7.5 μg kg^-1 h^-1, i.v.) decreased both BP (11±3.2 mmHg) and HR. The maximum decrease in HR was approximately 104 beats/min. Surgical stress produced a rapid increase in BP (maximal increase of 50 mmHg) and HR (maximal increase of 100 beats/min), which lasted for at least 15 min. Constant infusion of mivazerol, at a dose of 15 μg kg^-1 h^-1, beginning 20 min prior to surgery and lasting for 35 min, significantly inhibited surgical stress-induced increases in BP (P < 0.05) and HR (P < 0.001). Dexmedetomidine, at a dose which produced hypotension and profound bradycardia prior to surgery, did not have any effect on the surgical stress-induced elevation in BP (P>0.05), but prevented the increase in HR (P < 0.05). Pretreatment with the α₂-adrenoceptor antagonist rau-wolscine (0.5 mg/kg, i.v.) blocked the bradycardia induced by mivazerol as well as the inhibitory effect of mivazerol on surgical stress-induced elevations in HR and BP. Conclusion: Mivazerol attenuates surgical stress-induced elevations in BP and HR during pentobarbital anesthesia in rats, and these effects are mediated by stimulation of α₂-adrenoceptors. Unlike dexmedetomidine, mivazerol does not reduce BP, and is also more potent than dexmedetomidine in blunting surgical stress-induced increases in BP in pentobarbital-anesthetized rats.     

脐带缠绕的临床护理

目的总结脐带缠绕的临床护理体会。方法通过对129例脐带缠绕患者的临床观察，根据病情辩证地提出施扣要点，给予整体护理。结果129例（占同期分娩602例的21．4％）脐带缠绕患者中初产妇104例（80．6％），经产妇25例（19．4％）；经产妇脐带缠绕发生率36．2％（25／69）较初产妇19．5％（104／533）显著增高p〈0．01（u=3．183）；结论对患者临产前、临产中、临产后的各阶段应进行细致临床观察和针对性护理，根据患者的个体特点进行针对性护理是获得满意效果的重要因素。     

Elastohydrodynamic separation of pleural surfaces during breathing

To examine effects of lung motion on the separation of pleural surfaces during breathing, we modeled the pleural space in two dimensions as a thin layer of fluid separating a stationary elastic solid and a sliding flat solid surface. The undeformed elastic solid contained a series of bumps, to represent tissue surface features, introducing unevenness in fluid layer thickness. We computed the extent of deformation of the solid as a function of sliding velocity, solid elastic modulus, and bump geometry (wavelength and amplitude). For physiological values of the parameters, significant deformation occurs (i.e. bumps are 'flattened') promoting less variation in fluid thickness and decreased fluid shear stress. In addition, deformation is persistent; bumps of sufficient wavelength, once deformed, require a recovery time longer than a typical breath-to-breath interval to return near their undeformed configuration. These results suggest that in the pleural space during normal breathing, separation of pleural surfaces is promoted by the reciprocating sliding of lung and chest wall.     

休克期大面积切痂对严重烧伤大鼠细胞免疫功能影响的研究

目的 观察休克期大面积切痂对严重烧伤大鼠细胞免疫功能的影响，探索改善烧伤后机体免疫功能紊乱的有效方法。方法 将大鼠分成休克期切痂组（A组）、常规切痂组（B组）和正常对照组（C组）。A、B组造成30％TBSAⅢ度烫伤，C组不烫伤。A组伤后第6h、B组伤后第4d切痂，并于伤后第1、5、9d各活杀10只，取材送检，观察其免疫指标的变化。结果 （1）A、B组与C组比较：A、B组烫伤大鼠各时相点CD3^＋T细胞变化不大（P〉0．05），但CD4^＋T细胞、CD4^＋／CD8^＋比值明显下降、CD8^＋T细胞增高（P〈0．05或P〈0．01）。NK细胞活性明显下降（P〈0．05或P〈0.01），外周血CD25^＋T淋巴细胞表达及经活化后脾脏CD25^＋T淋巴细胞表达明显下降（P〈0．05或P〈0．01）。（2）A组与B组比较：A组CD4^＋T细胞、CD4^＋／CD8^＋比值明显升高、CD8^＋T细胞降低（P〈0．05或P〈0．01），NK细胞活性明显升高（P〈0．05或P〈0．01），外周血CD25^＋T淋巴细胞表达及经活化后脾脏CD25^＋T淋巴细胞表达均明显升高（P〈0．05或P〈0．01）。结论 （1）大鼠烫伤后细胞免疫状况发生了明显变化。（2）休克期切痂可以改善烫伤大鼠T淋巴细胞亚群分布，提高NK细胞活性，增加外周血CD25^＋T淋巴细胞的表达。提高经活化后脾脏CD25^＋T淋巴细胞数。从而改善烫伤大鼠伤后机体的细胞免疫功能。     

A history of personal violence and postpartum depression: is there a link?

Summary Background: A link between violence and depression has been shown, but not a link between violence and postpartum depression. This study sought to determine if there is an association between a history of abuse (physical, sexual, emotional as a child or adult) and postpartum depression (PPD). Method: 200 postpartum women were recruited from 6 hospitals. At 8–10 weeks postpartum, a telephone interviewer asked women about physical, emotional or sexual abuse as an adult or child and sociodemographic, obstetrical and personal medical history. PPD was assessed using the Edinburgh Postnatal Depression Scale (EPDS, score of ≥12). Abuse was determined by the Conflict Tactics Scale or the Abuse Assessment Screen. Chi-square and logistic regression were used to determine the relationship between violence and PPD. Results: 11% of women had EPDS scores of ≥12. Rates of childhood (6.5%), or adult (6.5%) physical abuse; and childhood (13%) or adult (14%) sexual abuse were reported by respondents. Emotional abuse in the current relationship (29.6%) exceeded that of childhood abuse (3.5%). Overall 43.2% of respondents had at least one form of abuse. Having a history of depression (OR = 3.3 (95% CI, 1.3–8.7)), panic attack during pregnancy (OR = 5.4 (1.6–19.0)), maternal complications (OR = 5.0 (1.7–15.1)), low social support (OR = 3.3 (1.3–8.7)) and emotional abuse (OR = 2.8 (1.1–7.4) were associated with PPD. Conclusion: Emotional abuse but not physical or sexual abuse was found to be associated with PPD. A possible explanation for this relationship may be that being in an abusive situation puts one at risk for depression and in turn, postpartum depression.     

A simple breathing circuit to maintain isocapnia during measurements of the hypoxic ventilatory response

We report the development and testing of a simple breathing circuit that maintains isocapnia in human subjects during hypoxic hyperpnea. In addition, the circuit permits rapid switching between two gas mixtures with different partial pressures of oxygen. Eleven volunteers breathed repeated cycles of exposure to air (2 min of 21% O(2), balance N(2)) and hypoxia (2 min of 8.3+/-0.1% O(2), balance N(2)). Hypoxia induced significant increases in minute ventilation, breathing frequency and tidal volume (P < 0.05) that were consistent over repeated cycles of hypoxia (P > 0.1, one-way ANOVA). The system successfully maintained isocapnia in all subjects, with an average change in end-tidal CO(2) of only -0.2 mmHg during hyperventilation in hypoxia (range 0.4 to -0.8 mmHg). This system may be suitable for repeated tests of the hypoxic ventilatory response (HVR) and may prove useful for exploring intra- and inter-individual variability of HVR in humans.     

妊娠期高血压患者妊娠结局调查及相关影响因素分析

目的 调查温州市人民医院2018—2021年妊娠期高血压疾病(hypertensive disorders of pregnancy,HDP)患者妊娠结局,并分析其妊娠结局的相关影响因素,为临床采取对应干预措施、降低不良妊娠结局发生风险提供参考。 方法 选取2018年1月—2021年12月于温州市人民医院分娩的400例HDP患者(单胎妊娠)的临床资料,开展回顾性分析,根据其妊娠结局分为不良妊娠结局组(n=157)与正常妊娠结局组(n=243)。比较两组临床资料,分析HDP患者不良妊娠结局发生的影响因素,构建logistic回归模型方程,并分析logistic回归模型的预测价值。 结果 400例HDP患者中共157例(39.25%)发生不良妊娠结局;单因素分析显示患者年龄、孕前BMI、分娩方式、妊娠期糖尿病(gestational diabetes mellitus,GDM)、负性情绪与不良妊娠结局的发生有关(P＜0.05);logistic回归模型显示,年龄≥35岁(OR=23.815,95%CI:10.370～54.655)、孕前BMI≥24.0(OR=16.010,95%CI:6.832～34.620)、阴道分娩(OR=16.336,95%CI:7.325～36.403)、GDM(OR=26.337,95%CI:11.908～58.253)、负性情绪(OR=20.682,95%CI:2.791～54.876)均为HDP患者不良妊娠结局发生的独立危险因素(P＜0.05);5个独立危险因素构建logistic回归模型方程为logistic(P)=-4.125+年龄×3.170+孕前BMI×2.773+阴道分娩×2.793+GDM×3.271+负性情绪×3.029;当logistic(P)=4.11,预测HDP患者发生不良妊娠结局的曲线下面积为0.899(95%CI:0.865～0.926),预测敏感度为84.36%,特异度为82.17%;根据设定的评分标准与不良妊娠结局发生情况,可将HDP患者划分为低风险(0～4分)、中风险(5～8分)与高风险(9～12分)。 结论 HDP患者不良妊娠结局发生率较高,年龄、孕前BMI、阴道分娩、GDM、负性情绪均为不良妊娠结局发生的影响因素,构建logistic回归模型可预测不良妊娠结局发生风险,有助于临床制定相关干预措施。     

ITGβ1、IFI16、TTR血清水平与妊娠期高血压疾病进展程度关联性及临床表达意义探究

目的 探究整合素β1(integrin β1,ITGβ1)、人γ干扰素诱导蛋白16(interferon - inducible protein 16,IFI16)、转甲状腺素蛋白(transthyretin,TTR)血清水平与妊娠期高血压疾病进展程度关联性及临床表达意义。 方法 选取2018年11月—2020年1月在攀枝花市中心医院住院分娩的妊娠期高血压疾病患者91例为研究组,另随机选取同期正常妊娠孕妇91例为对照组。对比两组血清ITGβ1、IFI16、TTR水平,采用Spearson秩相关分析血清各指标与妊娠期高血压疾病进展程度的相关性,采用受试者工作(receiver operating characteristic,ROC)曲线分析探讨血清各指标对妊娠期高血压疾病患者妊娠结局的预测价值。 结果 研究组血清ITGβ1、IFI16水平高于对照组,血清TTR水平低于对照组(P＜0.05);妊娠期高血压疾病进展程度与血清ITGβ1、IFI16水平呈正相关,与血清TTR水平呈负相关(P＜0.05);血清ITGβ1＞2.38 ng/ml、IFI16＞24.39 ng/ml、TTR≤315.08 mg/L联合预测妊娠期高血压疾病患者有无不良妊娠结局的曲线下面积(area under the carve,AUC)为0.861,大于各指标单一预测的AUC(0.782、0.813、0.790),联合预测的敏感度、特异度分别为80.00%、81.82%。 结论 妊娠期高血压疾病患者血清ITGβ1、IFI16表达明显升高,血清TTR表达水平降低,与妊娠期高血压疾病的发生及病情进展程度密切相关,且能辅助临床预测患者妊娠结局。