Chronic L‐DOPA induces hyperactivity,normalization of gait and dyskinetic behavior in MitoPark mice

Dopamine (DA) replacement therapy continues to be the gold standard treatment for Parkinson's disease (PD), as it improves key motor symptoms including bradykinesia and gait disturbances. With time, treatment induces side effects in the majority of patients, known as L‐DOPA‐induced dyskinesia (LID), which are often studied in animals by the use of unilateral, toxin‐induced rodent models. In this study, we used the progressive, genetic PD model MitoPark to specifically evaluate bilateral changes in motor behavior following long‐term L‐DOPA treatment at three different stages of striatal DA depletion. Besides locomotor activity, we assessed changes in gait with two automated gait analysis systems and the development of dyskinetic behavior. Long‐term treatment with a moderate, clinically relevant dose of L‐DOPA (8 mg/kg) gradually produced age‐dependent hyperactivity in MitoPark mice. In voluntary and forced gait analyses, we show that MitoPark mice with severe DA depletion have distinct gait characteristics, which are normalized to control levels following long‐term L‐DOPA treatment. The cylinder test showed an age‐dependent and gradual development of bilateral LID. Significant increase in striatal FosB and prodynorphin expression was found to accompany the behavior changes. Taken together, we report that MitoPark mice model both behavioral and biochemical characteristics of long‐term L‐DOPA treatment in PD patients and provide a novel, consistent and progressive animal model of dyskinesia to aid in the discovery and evaluation of better treatment options to counteract LID.     

Risk‐Group‐Specific Dose Finding Based on an Average Toxicity Score

Summary We propose a Bayesian dose‐finding design that accounts for two important factors, the severity of toxicity and heterogeneity in patients' susceptibility to toxicity. We consider toxicity outcomes with various levels of severity and define appropriate scores for these severity levels. We then use a multinomial‐likelihood function and a Dirichlet prior to model the probabilities of these toxicity scores at each dose, and characterize the overall toxicity using an average toxicity score (ATS) parameter. To address the issue of heterogeneity in patients' susceptibility to toxicity, we categorize patients into different risk groups based on their susceptibility. A Bayesian isotonic transformation is applied to induce an order‐restricted posterior inference on the ATS. We demonstrate the performance of the proposed dose‐finding design using simulations based on a clinical trial in multiple myeloma.     

A dysmorphology score system for assessing embryo abnormalities in rat whole embryo culture

BACKGROUND: The rodent whole embryo culture (WEC) system is a well‐established model for characterizing developmental toxicity of test compounds and conducting mechanistic studies. Laboratories have taken various approaches in describing type and severity of developmental findings of organogenesis‐stage rodent embryos, but the Brown and Fabro morphological score system is commonly used as a quantitative approach. The associated score criteria is based upon developmental stage and growth parameters, where a series of embryonic structures are assessed and assigned respective scores relative to their gestational stage, with a Total Morphological Score (TMS) assigned to the embryo. This score system is beneficial because it assesses a series of stage‐specific anatomical landmarks, facilitating harmonized evaluation across laboratories. Although the TMS provides a quantitative approach to assess growth and determine developmental delay, it is limited to its ability to identify and/or delineate subtle or structure‐specific abnormalities. Because of this, the TMS may not be sufficiently sensitive for identifying compounds that induce structure or organ‐selective effects. METHOD: This study describes a distinct morphological score system called the “Dysmorphology Score System (DMS system)” that has been developed for assessing gestation day 11 (approximately 20–26 somite stage) rat embryos using numerical scores to differentiate normal from abnormal morphology and define the respective severity of dysmorphology of specific embryonic structures and organ systems. This method can also be used in scoring mouse embryos of the equivalent developmental stage. RESULT AND CONCLUSION: The DMS system enhances capabilities to rank‐order compounds based upon teratogenic potency, conduct structure‐ relationships of chemicals, and develop statistical prediction models to support abbreviated developmental toxicity screens. Birth Defects Res (Part B) 89:485–492, 2010. © 2010 Wiley‐Liss, Inc.     

Clock polymorphisms and circadian rhythms phenotypes in a sample of the Brazilian population

A Clock polymorphism T to C situated in the 3' untranslated region (3'-UTR) has been associated with human diurnal preference. At first, Clock 3111C had been reported as a marker for evening preference. However these data are controversial, and data both corroborating and denying them have been reported. This study hypothesizes that differences in Clock genotypes could be observed if extreme morning-type subjects were compared with extreme evening-type subjects, and the T3111C and T257G polymorphisms were studied. The possible relationship between both polymorphisms and delayed sleep phase syndrome (DSPS) was also investigated. An interesting and almost complete linkage disequilibrium between the polymorphisms T257G in the 5' UTR region and the T3111C in the 3' UTR region of the Clock gene is described. Almost always, a G in position 257 corresponds to a C in position 3111, and a T in position 257 corresponds to a T in position 3111. The possibility of an interaction of these two regions in the Clock messenger RNA structure that could affect gene expression was analyzed using computer software. The analyses did not reveal an interaction between those two regions, and it is unlikely that this full allele correspondence affects Clock gene expression. These results show that there is no association between either polymorphism T3111C or T257G in the Clock gene with diurnal preference or delayed sleep phase syndrome (DSPS). These controversial data could result from the possible effects of latitude and clock genes interaction on circadian phenotypes.     

An analysis approach to identify specific functional sites in orthologous proteins using sequence and structural information: Application to neuroserpin reveals regions that differentially regulate inhibitory activity

The analysis of sequence conservation is commonly used to predict functionally important sites in proteins. We have developed an approach that first identifies highly conserved sites in a set of orthologous sequences using a weighted substitution‐matrix‐based conservation score and then filters these conserved sites based on the pattern of conservation present in a wider alignment of sequences from the same family and structural information to identify surface‐exposed sites. This allows us to detect specific functional sites in the target protein and exclude regions that are likely to be generally important for the structure or function of the wider protein family. We applied our method to two members of the serpin family of serine protease inhibitors. We first confirmed that our method successfully detected the known heparin binding site in antithrombin while excluding residues known to be generally important in the serpin family. We next applied our sequence analysis approach to neuroserpin and used our results to guide site‐directed polyalanine mutagenesis experiments. The majority of the mutant neuroserpin proteins were found to fold correctly and could still form inhibitory complexes with tissue plasminogen activator (tPA). Kinetic analysis of tPA inhibition, however, revealed altered inhibitory kinetics in several of the mutant proteins, with some mutants showing decreased association with tPA and others showing more rapid dissociation of the covalent complex. Altogether, these results confirm that our sequence analysis approach is a useful tool that can be used to guide mutagenesis experiments for the detection of specific functional sites in proteins. Proteins 2015; 83:135–152. © 2014 Wiley Periodicals, Inc.     

MEWS系统在指导院前急性脑血管意外急救的临床应用

目的 探讨应用改良早期预警（MEWS）评分指导急性脑血管意外院前急救的临床价值.方法 将院前急救中临床诊断为急性脑血管意外的患者分为常规病情评估急救组（对照组）和进行现场MEWS评分指导急救组（实验组）,并比较两组患者的病死率及好转出院率.结果 对照组病死率为17.23%,好转出院率为82.77%;实验组病死率为8.76%,好转出院率为91.24%.两组比较,差异有统计学意义（P＜0.05）.结论 急性脑血管意外患者院前应用MEWS评分进行病情评估和指导急救,能降低患者的病死率及提高好转出院率,具有较好的应用价值,值得在院前脑血管意外急救中推广应用.     

An update analysis of two polymorphisms in encoding ribonuclease L gene and prostate cancer risk: involving 13,372 cases and 11,953 controls

Encoding ribonuclease L (RNASEL) is a ubiquitously expressed latent endoribonuclease involved in the mediation of antiviral and pro-apoptotic activities of the interferon-inducible 2-5A system. Although the relationship between RNASEL gene polymorphisms and prostate cancer (PCa) risk has been widely reported, results were somewhat controversial and underpowered. Now, we performed an update analysis of 14 publications evaluating the association between RNASEL R462Q and D541E polymorphisms and PCa risk. We conducted a literature search of PubMed database to identify all eligible articles that examined the association of RNASEL R462Q and D541E polymorphisms with PCa. Odds ratios (OR) with 95% confidence intervals (CI) were estimated to assess these association. R462Q showed a significantly elevated effect on Africans (QQ vs. RR: OR = 2.50, 95% CI = 1.28–4.87, P_{heterogeneity} = 0.231). In addition, PCa men who contain 462Q genotype had a higher Gleason score ≥ 7 (OR = 1.16, 95% CI = 1.05–1.28, P_{heterogeneity} = 0.906). On the other hand, D541E was associated with increased total PCa. In the stratified analysis by race, there was also significantly increased PCa in Africans and Caucasians, as well as in sporadic PCa studies (OR = 1.09, 95% CI = 1.04–1.15, P_{heterogeneity} = 0.078). Our update analysis showed evidence that RNASEL R462Q and D541E polymorphisms were associated with PCa risk. Still more well-designed studies should be performed to clarify the role of these two polymorphisms in the development of PCa.     

Liana co‐occurrence patterns in a temperate rainforest

Questions: Are liana–host interactions structured at the community level? Do liana–host interactions differ between species, growth form guilds or habitats? Location: Otari‐Wilton's Bush, on the southern tip of North Island, New Zealand. The forest contains 75 ha of mature and regenerating conifer–broadleaf forest. Methods: Nine liana species were quantified among 217 trees to test for negative co‐occurrence patterns. We also conducted additional analyses within and among compartments embedded in the community‐level matrix. Liana and host abundance distributions were assessed across two contrasting habitats. Results: Community‐level analyses revealed negative co‐occurrence patterns. Positive, neutral and negative co‐occurrence patterns were found among compartments within the community‐level matrix. Host species compartments were consistent with randomized expectations, while positive co‐occurrence patterns were found within the host species matrix. Negative co‐occurrence patterns were found inconsistently among lianas that share the same region of host space, and those that do not. Conclusions: Overall, results indicate the liana community is structured non‐randomly. Liana–host interactions appear to follow an opportunistic growth strategy and interactions are due mostly to habitat partitioning.