Carboxylesterase 1 family knockout alters drug disposition and lipid metabolism

The mammalian carboxylesterase 1 (Ces1/CES1) family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids. To investigate the pharmacological and physiological roles of Ces1/CES1, we generated Ces1 cluster knockout (Ces1 -/- ) mice, and a hepatic human CES1 transgenic model in the Ces1 -/- background (TgCES1). Ces1 -/- mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues. TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney. Ces1 and hCES1 activity increased irinotecan toxicity, likely by enhancing the formation of pharmacodynamically active SN-38. Ces1 -/- mice also showed markedly increased capecitabine plasma exposure, which was moderately decreased in TgCES1 mice. Ces1 -/- mice were overweight with increased adipose tissue, white adipose tissue inflammation (in males), a higher lipid load in brown adipose tissue, and impaired blood glucose tolerance (in males). These phenotypes were mostly reversed in TgCES1 mice. TgCES1 mice displayed increased triglyceride secretion from liver to plasma, together with higher triglyceride levels in the male liver. These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification. Ces1 -/- and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.

Unsupervised Machine Learning to Identify Depressive Subtypes / 대한의료정보학회지

Objectives@#This study evaluated an unsupervised machine learning method, latent Dirichlet allocation (LDA), as a method for identifying subtypes of depression within symptom data. @*Methods@#Data from 18,314 depressed patients were used to create LDA models. The outcomes included future emergency presentations, crisis events, and behavioral problems. One model was chosen for further analysis based upon its potential as a clinically meaningful construct. The associations between patient groups created with the final LDA model and outcomes were tested. These steps were repeated with a commonly-used latent variable model to provide additional context to the LDA results. @*Results@#Five subtypes were identified using the final LDA model. Prior to the outcome analysis, the subtypes were labeled based upon the symptom distributions they produced: psychotic, severe, mild, agitated, and anergic-apathetic. The patient groups largely aligned with the outcome data. For example, the psychotic and severe subgroups were more likely to have emergency presentations (odds ratio [OR] = 1.29; 95% confidence interval [CI], 1.17–1.43 and OR = 1.16; 95% CI, 1.05–1.29, respectively), whereas these outcomes were less likely in the mild subgroup (OR = 0.86; 95% CI, 0.78–0.94). We found that the LDA subtypes were characterized by clusters of unique symptoms. This contrasted with the latent variable model subtypes, which were largely stratified by severity. @*Conclusions@#This study suggests that LDA can surface clinically meaningful, qualitative subtypes. Future work could be incorporated into studies concerning the biological bases of depression, thereby contributing to the development of new psychiatric therapeutics.

Patient Experience Following Kyphoplasty: Safety, Efficacy, and Patient Satisfaction.

Aims: Kyphoplasty is a minimally invasive treatment used to reduce pain, restore vertebral height and improve mobility in patients with painful spinal VCF. Pain from vertebral compression fractures (VCF) comprises an important health issue with significant social and economic impact, particularly in elderly patients with osteoporosis where treatment options are limited. We assessed outcomes in patients with VCF who failed conservative management and underwent kyphoplasty. Study Design: Prospective and retrospective case series. Place and Duration of Study: At a single neurosurgical practice February 2003 and September 2012. Methodology: A total of 203 patients with 288 treated vertebral body fractures treated with kyphoplasty were enrolled. The Visual Analog Scale (VAS) was used to prospectively measure back pain before and after surgery. Pre and post operative disability and quality of life were retrospectively measured with the Roland Morris Disability Index (RMDI) and EuroQol 5-Domain scale (EQ5D), respectively, via patient survey. Pre and post-operative narcotic analgesic usage and incidence of subsequent fractures were recorded. Results: There was a statistically significant improvement (P < .001) in each of the assessed measures following surgery. The post-operative rate of narcotic use was reduced from 63% to 17%. Eight patients (4.2%) developed and underwent repair of an adjacent fracture with a mean time between surgeries of 461 days. Conclusion: Following kyphoplasty, patients experienced significant, rapid, and sustained reduction of back pain, improved quality of life, and reduced disability with a low complication rate. Timely repair of VCF is indicated, not only to prevent complications associated with prolonged inactivity but also for effective treatment of severe pain in the acute setting.

A comparison between L-4F and SC-4F in preventing low density lipoprotein induced endothelial cell dysfunction in cell culture / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the importance of the specific structure of L-4F, an apolipoprotein A-1 mimetic, in inhibiting atherosclerosis. The study was designed to compare the effect of L-4F and scramble-4F (SC-4F) in preventing low density lipoprotein (LDL) induced endothelial cell dysfunction. L-4F and SC-4F has the same amino acids but different nucleotide sequence.</p><p><b>METHODS</b>Bovine aortic endothelial cells (BAEC) were incubated with single L-4F 10 microg/ml or SC-4F 10 microg/ml, or LDL 6.2 mmol/L in the absence or presence of L-4F 10 microg/ml or SC-4F 10 microg/ml for 24 h and assayed for (1) changes of superoxide anion (O2-*) generation in BAEC by superoxide dismutase (SOD)-inhibitable ferricytochrome C reduction, and (2) the production of nitric oxide (NO) in BAEC by ozone chemiluminescence with VCL3.</p><p><b>RESULTS</b>(1) L-4F and SC-4F themselves had no affect on BAEC O2-* generation. (2) LDL significantly increased O2-* generation in BAEC and LDL-induced O2-* generation was inhibited by pretreatment of LDL with L-4F. However, pretreatment of LDL with SC-4F had no effect on inhibition of LDL-induced O2-* generation. (3) LDL significantly inhibited NO generation in BAEC and pretreatment of LDL with L-4F could inhibit LDL-induced decrease of NO generation, but pretreatment of LDL with SC-4F still inhibited NO generation in BAEC.</p><p><b>CONCLUSION</b>L-4F can prevent LDL induced endothelial cell dysfunction by maintaining the balance of NO and O2-*, but SC-4F doesn't. It suggests that the specific structure of L-4F may play a crucial role in preventing atherosclerosis and it may provide a new clue for searching a novel approach on prevention and therapeutics of atherosclerosis in the future.</p>

The pro-allergic influences of helminth parasites

Parasitic infection is highly allergenic, and the present paper illustrates how parasites might disrupt the regulation of IgE synthesis, resulting in heightened Th-2 responses. The study of parasites, and dysregulation of the IgE network, could in turn provide information relating to the aetiology of allergic diseases such as asthma and atopic dermatitis.