The complexity of pathophysiological mechanisms is beyond the capabilities of traditional approaches. Many of the decision-making problems in public health, such as initiating mass screening, are complex. Progress in genomics and proteomics, and the resulting extraordinary increase in knowledge with regard to interactions between gene expression, the environment and behaviour, the customisation of risk factors and the need to combine therapies that individually have minimal though well documented efficacy, has led doctors to raise new questions: how to optimise choice and the application of therapeutic strategies at the individual rather than the group level, while taking into account all the available evidence? This is essentially a problem of complexity with dimensions similar to the previous ones: multiple parameters with nonlinear relationships between them, varying time scales that cannot be ignored etc. Numerical modelling and simulation (in silico investigations) have the potential to meet these challenges. Such approaches are considered in drug innovation and development. They require a multidisciplinary approach, and this will involve modification of the way research in pharmacology is conducted. 相似文献
OBJECTIVES: The aim of our study was to examine the influence of atorvastatin on lipid parameters, particularly on HDL, and on the activity of LCAT and CETP and how they affect the activity of the HDL-associated antioxidant enzyme paraoxonase. DESIGN AND METHODS: Thirty-three patients with types II.a and II.b primary hyperlipoproteinemia were enrolled into our study. The patients received atorvastatin, 20 mg daily, for 3 months. We measured the serum paraoxonase activity and concentration, oxidized LDL, LCAT and CETP activities. RESULTS: Atorvastatin significantly reduced the levels of cholesterol, triglyceride, LDL-C and apoB, while it did not influence the levels of HDL-C and apo A-I. The increases in serum PON-specific activity, PON/HDL ratio and LCAT activity were significant, while oxLDL and CETP activities were significantly decreased. CONCLUSION: Atorvastatin may influence the composition and function of HDL, thereby possibly increasing the activity of paraoxonase and preventing atherosclerosis. 相似文献
This study describes the risk of thrombotic and hemorrhagic complications, both intraoperatively, and up to 1 month following visceral transplantation. Data from 48 adult visceral transplants performed between 2010 and 2017 were retrospectively studied [32 multivisceral (MVTx); 10 isolated intestine; six modified‐MVTx]. Intraoperatively, intracardiac thrombosis (ICT)/pulmonary embolism (PE) occurred in 25%, 0% and 0% of MVTx, isolated intestine and modified MVTx, respectively, and was associated with 50% (4/8) mortality. Preoperative portal vein thrombosis (PVT) was a significant risk factor for ICT/PE (P = 0.0073). Thromboelastography resembling disseminated intravascular coagulation (DIC) (r time <4 mm combined with fibrinolysis or flat‐line) was statistically associated with occurrence of ICT/PE (P < 0.0001). Compared to subgroup without ICT/PE, occurrence of ICT/PE was associated with an increased demand for all blood product components both overall, and each surgical stage. Hyperfibrinolysis (56%) was identified as cause of bleeding in MVTx. Incidence of postoperative thrombotic event at 1 month was 25%, 30% and 17% for MVTx, isolated intestine and modified MVTx, respectively. Incidence of postoperative bleeding complications at 1 month was 11%, 20% and 17% for MVTx, isolated intestine and modified MVTx. In conclusion, MVTx recipients with preoperative PVT are at an increased risk of developing intraoperative life‐threatening ICT/PE events associated with DIC‐like coagulopathy. 相似文献
Background: Among adolescents, the self-pacing of sleep and experimentation with psychotropic substances increases. Poor sleep and susceptibility to addiction (SA) may therefore share common cognitive-emotional processes. The aim of the present study was to investigate the shared cognitive-emotional basis of SA and sleep-related dysfunction, and to explore their predictive value for sleep patterns.
Methods: A total of 300 adolescents (mean age: 15.57 years; 50% females) took part in this questionnaire-based study. Participants completed a booklet covering sociodemographic, sleep-related (Sleep Hygiene Index: SHI; Pittsburgh Sleep Quality Index: PSQI) and SA-related variables.
Results: Greater sleep-related dysfunction based on the SHI was strongly associated with higher SA scores. Parents’ educational level was negatively associated with SHI and SA scores. An exploratory factor analysis of SHI and SA items yielded three distinct factors: (i) risky behavior and irregular sleep-wake schedules, (ii) poor sleep environment and hygiene, and (iii) psychological arousal and distress. All three factors independently contributed to the prediction of poor sleep quality and quantity.
Conclusions: Adolescents reporting dysfunctional cognitive-emotional processes are at increased risk of reporting poor sleep patterns. Additionally, poor sleep and SA were related to parents’ education, suggesting that both parents and their children might benefit from sleep hygiene counseling. 相似文献
BACKGROUND: Previous observations suggested recruitment of platelets (PLTs) and white blood cells (WBCs) during plateletpheresis and recruitment of hematopoietic progenitor cells (HPCs) by HPC apheresis. Quantification of recruitment helps to optimize yields and safety of these procedures; detection of WBC or HPC recruitment during plateletpheresis may further elucidate the mechanisms. STUDY DESIGN AND METHODS: This study was a prospective cohort study with 68 single‐needle plateletpheresis donations (23 double, PLT yield ≥4.8 × 1011; 23 triple, ≥7.2 × 1011; 22 quadruple, ≥9.6 × 1011). We measured PLTs, WBCs, WBC subpopulations, and circulating HPCs (CD34 mRNA) before, during, and after apheresis; calculated PLT recruitment and ratio of recruited to yielded PLT; and propose a novel concept to optimize the prediction of the PLT counts after apheresis (PLTpost). RESULTS: PLT recruitment (mean ± SD, 1.56 ± 0.31) caused a higher PLTpost than predicted by the instrument (164 × 109 ± 23 × 109 vs. 111 × 109 ± 31 × 109/L; p < 0.0001) in all three groups. The ratio of recruited to yielded PLT was 0.36 ± 0.15. The WBC count decreased by 9% to the time before rinse‐back and returned to the baseline thereafter. No changes in circulating HPCs occurred. CONCLUSIONS: PLT recruitment during high‐yield plateletpheresis facilitates the harvest of multiple PLT units in a single donation. The use of the ratio of recruited to yielded PLT may optimize the algorithm to predict PLTpost. There was no recruitment of WBCs and HPCs during plateletpheresis. Therefore, the previously observed recruitment of HPCs during HPC apheresis seems to be related to other factors than the apheresis procedure itself. 相似文献
SUMMARY: BACKGROUND: Recruitment of platelets (PLT) during donor PLT apheresis may facilitate the harvest of multiple units within a single donation. METHODS: We compared two PLT apheresis procedures (Amicus and Trima Accel) in a prospective, randomized, paired cross-over study in 60 donors. The 120 donations were compared for depletion of circulating PLT in the donors, PLT yields and PLT recruitment. A recruitment was defined as ratio of total PLT yield and donor PLT depletion > 1. RESULTS: Despite comparable differences of pre- and post-apheresis PLT counts (87 × 10(9)/l in Trima Accel vs. 92 × 10(9)/l in Amicus, p = 0.383), PLT yields were higher with Trima Accel (7.48 × 10(11) vs. 6.06 × 10(11), p < 0.001), corresponding to a higher PLT recruitment (1.90 vs. 1.42, p < 0.001). We observed a different increase of WBC counts after aphereses, which was more pronounced with Trima Accel than with Amicus (1.30 × 10(9)/l vs. 0.46 × 10(9)/l, p < 0.001). CONCLUSION: Both procedures induced PLT recruitment. This was higher in Trima Accel, contributing to a higher yield in spite of a comparable depletion of circulating PLT in the donors. This recruitment facilitates the harvest of multiple units within a single donation and seems to be influenced by the procedure utilized. The different increases of circulating donor white blood cells after donation need further investigation. 相似文献
Data on the effect of acutely administered serotonin reuptake inhibitors (SSRIs) in animal anxiety models have been inconsistent. In some of the models these compounds showed anxiolytic properties, while in others they were ineffective or even anxiogenic. In the foot shock-induced ultrasonic vocalization (USV) test in the adult rat, SSRIs were reported to be effective, however, they were only tested with protocols using multiple shocking design. In the present study, anxiolytic effects of various SSRI compounds (sertraline, fluoxetine, paroxetine, escitalopram) were tested in three distinct USV test protocols in comparison with alprazolam and 8-OH-DPAT. In the single shocking protocol, animals were exposed to one shocking session after the drug treatment. In the multiple shocking protocol, rats went through a foot shock priming session before each drug test. On priming days animals received foot shocks without drug treatment. On the test day (the day after), rats received drug treatment and then were shocked again. In the context conditioning protocol animals were exposed to foot shocks on two consecutive days before the drug test. On the third, test day, after drug treatment animals were replaced to the shocking chamber, but this time shocks were not delivered. SSRIs were ineffective using the single shocking protocol. In the context conditioned protocol, all SSRIs showed linear dose-response relationship with ED50 values of 8.5, 2.2, 0.77 and 0.93 mg/kg i.p. for fluoxetine, sertraline, paroxetine and escitalopram, respectively. Using the multiple shocking protocol, SSRIs were only partially effective with maximum inhibitions ranging between 44% and 62%. In contrast to SSRIs, the benzodiazepine anxiolytics, alprazolam showed anxiolytic activity with linear dose-response relationship in all of the test protocols, with ED50 values varying from 1.3 to 4.0 mg/kg i.p. The serotonin 5HT1A receptor antagonist 8-OH-DPAT also showed linear dose-response relationship in all protocols, but this compound was less potent in the single shocking design (ED50 values were 0.27, 0.04 and 0.07 mg/kg i.p. in the single shocking, multiple shocking and context conditioned protocol, respectively). In conclusion, our results show that priming has a major impact on the effectiveness of SSRIs in the USV test, and the three test protocols applied in this study have different predictive and face validity. 相似文献