Isolation-induced social behavioral deficit: a proposed model of hyperreactivity with a behavioral inhibition

The behavior of mice isolated for 7-9 days (isolated mice) was compared to that of mice reared in groups (grouped mice). The method consisted of counting the number of escape attempts of the mice placed under an inverted beaker. When individually observed the isolated mice attempted to escape slightly but significantly more often than the grouped mice. When a pair of mice (one isolated + one grouped) were tested together, the number of escape attempts of the isolated mice was half of that of the grouped mice: this phenomenon was named the isolation-induced social behavioral deficit. These opposed behaviors may mean the same thing: an hyperreactivity to the novelty. In a variety of new situations under the beaker (presence of a lifeless object, of a grouped mouse or of an isolated mouse), the isolated mice were more reactive than the grouped mice. In conclusion, the social behavioral deficit test may be seen as a model of hyperreactivity with a behavioral inhibition.     

基于抗氧化反应元件的药物筛选模型的建立

目的建立基于抗氧化反应元件(antioxident responseelement,ARE)和SEAP报告基因的细胞筛选模型,用此模型对金雀异黄素、芹菜苷配基、儿茶素、茨非醇4种化合物进行活性比较,观察上述化合物拮抗过氧化氢损伤的作用,寻找具有强抗氧化活性作用的黄酮类化合物。方法构建重组报告基因表达载体pARE-TAL-SEAP与对照载体分别转染HEK-293细胞,检测上述黄酮类化合物作用后对SEAP的活性和抗氧化作用的影响。结果在加入25μmol.L-1H2O2进行氧化损伤的HEK-293细胞中,加入100μmol.L-1的4种化合物进行比较时金雀异黄素的抗氧化作用最强,金雀异黄素诱导SEAP的最大表达水平较对照孔升高1.3倍;加入25μmol.L-14种化合物的抗氧化作用时茨非醇的抗氧化作用最强,茨非醇诱导SEAP的最大表达水平较对照孔升高1.5倍。结论利用此模型可以检测H2O2的氧化应激反应并可筛选到抗氧化活性强的黄酮类化合物。     

Monitoring urinary excretion of cannabinoids by fluorescence-polarization immunoassay: a cannabinoid-to-creatinine ratio study

Drug testing in substance abuse treatment programs is focused on urine analysis of parent drugs and major metabolites. Huestis reported that serial monitoring of the major urinary cannabinoid metabolite (delta9-THC-COOH)-to-creatinine ratios in paired urine specimens (collected at least 24 hours apart) could differentiate new marijuana or hashish use from residual cannabinoid metabolite excretion in urine after previous drug use. Subjects with a history of chronic marijuana use were screened for cannabinoids in urine over several months by an enzyme immunoassay (EMIT) with a cut-off value of 50 ng/mL. Presumptive positive specimens were confirmed by gas chromatography-mass spectrometry (GC-MS) for delta9-THC-COOH with a cut-off value of 15 ng/mL. The objective of this study was to determine whether a semiquantitative cannabinoids immunoassay (corrected for creatinine concentration) could differentiate new marijuana use from residual cannabinoid excretion in chronic users of marijuana or hashish compared with GC-MS. The criterion for new marijuana use was a cannabinoid-to-creatinine ratio > or =0.5 (dividing the immunoassay quantitative result to creatinine ratio of specimen 2 by the specimen 1 ratio, specimen 3 by the specimen 2 ratio, etc.). Urine specimens were analyzed by fluorescence-polarization immunoassay (FPIA) on an Abbott TDxFLx analyzer after analysis by GC-MS. In 90 urine specimens (group A) with delta9-THC-COOH values determined by GC-MS, the mean delta9-THC-COOH concentration was 44.4 ng/mL (range, 16-100), and the mean FPIA total cannabinoids value was 91.7 ng/mL (range, 21-204 ng/mL) with a correlation coefficient of 0.993 (group A). In 111 specimens (group B), the mean delta9-THC-COOH concentration was 361 ng/mL (range, 101-960 ng/mL). The mean FPIA value was 657 ng/mL (range, 211-1,270 ng/mL), and the correlation coefficient of the B series was 0.975. Percent cross-reactivity for delta9-THC-COOH standards prepared in drug-free urine by FPIA was 82% at 25 ng/mL, 45% at 50 ng/mL, and 50% at 100 ng/mL. Overall, there was 89% agreement (132 of 148 specimens) between FPIA and GC-MS. In 16 of 148 specimens, however, the FPIA and GC-MS paired urine data did not agree. The sensitivity of the FPIA assay was 95.3%, and the specificity was 44.4%. The authors conclude that FPIA cannabinoid analysis should be further evaluated as an alternative to GC-MS quantitation to help distinguish new marijuana use from residual marijuana metabolite excretion in clinical drug treatment programs.     

RCAM: a proposed model of recovery capital for adolescents

Problematic substance use is a challenge worldwide among adolescents. The recovery process requires holistic support addressing multiple and intersecting substance use risk factors; yet, there remains a lack of evidence on how to best understand and support adolescents in recovery. Recovery capital (RC) is a model that can be used to identify areas of assets that could be enhanced and barriers to address in one’s recovery process; however, this construct was generated through a study of adults who achieved natural recovery and it has since been used to frame adult recovery-related literature across the world. The primary aim of this article is to outline the rationale for and present a Recovery Capital for Adolescents Model (RCAM). The article will discuss the original recovery capital model, describe adolescent development, substance use, and recovery, and detail proposed developmental adaptations. Future qualitative and quantitative research should explore the RCAM to assess whether the proposed dimensions are complete as well as to assess its utility in clinical settings for identifying strengths and barriers for adolescents in or seeking recovery.     

Patent portfolio management: literature review and a proposed model

Introduction: Patents and patent portfolios are gaining attention in the last decades, from the called ‘pro-patent era’ to the recent billionaire transactions involving patent portfolios. The field is growing in importance, both theoretically and practically and despite having substantial literature on new product development portfolio management, we have not found an article relating this theory to patent portfolios.

Areas covered: The paper develops a systematic literature review on patent portfolio management to organize the evolution and tendencies of patent portfolio management, highlighting distinctive features of patent portfolio management. Interview with IP manager of three life sciences companies, including a leading multinational group provided relevant information about patent portfolio management.

Expert opinion: Based on the systematic literature review on portfolio management, more specifically, on new product development portfolio theory, and interview the paper proposes the paper proposes a reference model to manage patent portfolios. The model comprises four stages aligned with the three goals of the NPD portfolio management: 1 – Linking strategy of the Company’s NPD Portfolio to Patent Portfolio; 2 – Balancing the portfolio in buckets; 3 – Patent Valuation (maximizing valuation); 4 – Regularly reviewing the patent portfolio.     

基于STAT3转录调节的筛药模型的建立

目的　依据造血生长因子信号转导途径中重要转录因子STAT3的转录调节作用建立基于报告基因的靶向STAT3转录调节的筛药模型 ,用此模型筛选具有G CSF样活性的化合物。方法　构建诱导性表达载体 pTKS3 CAT并转染入表达G CSF受体的NFS 6 0不依赖细胞 ,筛选报告基因CAT表达受rhG CSF诱导的阳性克隆 ,采用ELISA法检测化合物对CAT表达活性的影响。同时 ,对模型的特异性和灵敏性进行检测。结果　在转染有重组质粒的NFS 6 0不依赖细胞中 ,CAT表达受rhG CSF诱导并呈剂量依赖关系 ,EC50 等于 0 0 44nmol·L-1,而rhEPO不能诱导CAT表达。结论　以上模型的CAT基因表达活性能够被其特异性配体强诱导表达 ,利用此模型在 96孔板上用ELISA法测定CAT基因的诱导表达水平可筛选具有G CSF样活性的化合物。     

Two-stage sample size re-estimation based on a nuisance parameter: a review

Sample size calculations are important and difficult in clinical trails because they depend on the nuisance parameter and treatment effect. Recently, much attention has been focused on two-stage methods whereby the first stage constitutes an internal pilot study used to estimate parameters and revise the final sample size. This paper reviews two-stage methods based on estimation of nuisance parameters in either a continuous or dichotomous outcome setting.     

Lead identification for modulators of multidrug resistance based on in silico screening with a pharmacophoric feature model

Considerable effort has been devoted to the characterization of P-glycoprotein - drug interaction in the past. Systematic quantitative structure-activity relationship (QSAR) studies identified both predictive physicochemical parameters and pharmacophoric substructures within homologous series of compounds. Comparative molecular field analysis (CoMFA) led to distinct 3D-QSAR models for propafenone and phenothiazine analogs. Recently, several pharmacophore models have been generated for diverse sets of ligands. Starting from a training set of 15 propafenone-type MDR-modulators, we established a chemical function-based pharmacophore model. The pharmacophoric features identified by this model were (i) one hydrogen bond acceptor, (ii) one hydrophobic area, (iii) two aromatic hydrophobic areas, and (iv) one positive ionizable group. In silico screening of the Derwent World Drug Index using the model led to identification of 28 compounds. Substances retrieved by database screening are diverse in structure and include dihydropyridines, chloroquine analogs, phenothiazines, and terfenadine. On the basis of its general applicability, the presented 3DQSAR model allows in silico screening of virtual compound libraries to identify new potential lead compounds.     

Management of urinary tract infections in the nursing home elderly: a proposed algorithmic approach

The objective of this paper is to review the microbiology, clinical presentation, diagnosis, and treatment of urinary tract infections (UTIs) in the nursing home elderly, and recommend an algorithmic approach to the management of UTIs in this population.     

Comparison of urinary on-site immunoassay screening and gas chromatography-mass spectrometry results of 111 patients with suspected poisoning presenting at an emergency department

On-site tests based on immunoassay techniques are widely used for toxicologic screening analysis in patients with suspected poisoning. However, such assays usually have been validated using urine samples with known concentrations of the investigated substances. In the present investigation, on-site screening results were evaluated in a clinical setting. This was a retrospective study of patients with suspected poisoning from January to December 2003 in the emergency department of a tertiary urban hospital. Urine samples were analyzed using the Triage 8 panel and gas chromatography-mass spectrometry (GC-MS). A total of 111 patients were included (54 female, 57 male; average age 37.8 +/- 19.7 years). A total of 3.8% of the patients showed no symptoms, 45.2% minor, 24.0% moderate, and 26.9% serious symptoms. In 50 patients (45.0%), Triage 8 results corresponded well with GC-MS results. In 17 patients (15.3%), the Triage 8 results were confirmed by GC-MS, but additional substances were determined that could not be detected by the Triage 8 panel. A completely negative Triage 8 screening result was obtained in 23 patients (20.7%) who showed toxicologically relevant findings in GC-MS. In 21 patients (18.9%), Triage 8 results could not be confirmed by GC-MS. The analysis of the results in view of the patients' medical histories revealed that in 20 patients (18.0%), no relevant toxic substance could be detected. Additionally, 8 patients (7.2%) showed intoxication with alcohol, which could not be detected by the presently applied toxicologic screening investigations. On-site screening results in suspected poisoning were not very helpful in the present study because practically every second patient ingested substances that were not detectable by the Triage 8 device. In addition, every fifth result was not in line with GC-MS findings. On-site test findings should be interpreted very carefully, and in critical cases, a GC-MS screening should be performed.     

全自动微粒子发光酶免疫分析仪在孕中期产前筛查的应用

目的探讨孕中期筛查先先天缺陷的临床意义。方法用微粒子发光酶免疫分析仪（Access）检测1738例孕中期孕妇血清标志物AFP,β-HCG和uE3三项指标的筛查．结果：在1738例孕妇中,按Access仪提供的中位数和本组孕妇的中位数计算,唐氏综合症（Down Syndrome,DS）筛查阳性率分别为2．35％,5．46％,18三体筛查阳性率分别为0．35％,0．58％,神经管缺陷（neural tube defects NTD）筛查阳性率均为1．09％。共检出先天缺陷8例,检出率为0．46％。结论对孕中期母血清标记物筛查是预防先天缺陷患儿出生的重要途径。     

Osteoporosis screening and treatment in women with schizophrenia: a controlled study

STUDY OBJECTIVE: As patients with a major psychiatric disorder such as schizophrenia generally are less likely to have their medical illnesses diagnosed and medically managed, we investigated whether osteoporosis screening, prevention management, and/or drug therapy (i.e., clinical services for osteoporosis) are provided consistently to both women with schizophrenia and those without the disease. DESIGN: Retrospective medical record review. SETTING: Three Midwest Veterans Affairs medical centers and clinics. PATIENTS: Forty-six women aged 45 years or older who had schizophrenia and 46 female control subjects who were frequency matched on age. MEASUREMENTS AND MAIN RESULTS: Twelve months of progress notes were reviewed for osteoporosis clinical services. In addition, smoking status, smoking cessation counseling, alcohol consumption, and fracture rates were compared between the groups. Overall, significantly fewer patients with schizophrenia (28 patients [61%]) received a clinical service for osteoporosis compared with the control group (37 patients [80%]). This difference was due to a significantly fewer number of patients with schizophrenia who received any osteoporosis agent (22 patients [48%]) compared with the control group (36 patients [78%]). Only 13 patients (28%) with schizophrenia received hormone replacement therapy compared with 25 control patients (54%). CONCLUSION: Women with schizophrenia in three Midwest Veterans Affairs medical centers did not receive the same level of osteoporosis care as that of age-matched control patients. This was primarily due to a lower utilization of osteoporosis agents, specifically hormone replacement therapy. Further research is necessary to determine the reason for this difference. Clinicians should be aware of medical management issues in patients with major psychiatric diagnoses and, specifically, osteoporosis care of women with schizophrenia.     

Successful virtual screening for a submicromolar antagonist of the neurokinin-1 receptor based on a ligand-supported homology model

The neurokinin-1 (NK1) receptor belongs to the family of G-protein-coupled receptors (GPCRs), which represents one of the most relevant target families in small-molecule drug design. In this paper, we describe a homology modeling of the NK1 receptor based on the high-resolution X-ray structure of rhodopsin and the successful virtual screening based on this protein model. The NK1 receptor model has been generated using our new MOBILE (modeling binding sites including ligand information explicitly) approach. Starting with preliminary homology models, it generates improved models of the protein binding pocket together with bound ligands. Ligand information is used as an integral part in the homology modeling process. For the construction of the NK1 receptor, antagonist CP-96345 was used to restrain the modeling. The quality of the obtained model was validated by probing its ability to accommodate additional known NK1 antagonists from structurally diverse classes. On the basis of the generated model and on the analysis of known NK1 antagonists, a pharmacophore model was deduced, which subsequently guided the 2D and 3D database search with UNITY. As a following step, the remaining hits were docked into the modeled binding pocket of the NK1 receptor. Finally, seven compounds were selected for biochemical testing, from which one showed affinity in the submicromolar range. Our results suggest that ligand-supported homology models of GPCRs may be used as effective platforms for structure-based drug design.     

以酵母病毒杀伤系统为基础的抗病毒药物筛选模型

许多病毒利用程序性-1核糖体移码作为翻译调节机制进行繁殖。程序性酵母的病毒杀伤系统由L-A病毒和M1卫星病毒组成。M1病毒编码一种分泌型毒素K1，能杀死不含病毒的酵母细胞，但有自身免疫功能。L-A通过一定频率-1移码事件进行繁殖，-1移码效率的改变影响L-A病毒的存活，使M1数量快速下降。因此以程序性-1核糖体移码为靶位，建立以酵母病毒杀伤系统为基础的筛选模型，在抗病毒药物的高通量筛选方面有良好的应用前景。     

Adaptive clinical endpoint bioequivalence studies with sample size re-estimation based on a nuisance parameter

ABSTRACT

A clinical endpoint bioequivalence (BE) study is often used to establish bioequivalence (BE) between a locally acting generic drug (T) and an innovator drug (R), which is a double-blind, randomized three-arm (T, R and placebo: P) parallel clinical trial. BE is established if two superiority tests (T vs. P, R vs. P) and one equivalence test (T vs. R) all pass. An accurate estimate of the nuisance parameter (e.g. variance) is vital in determining an accurate sample size to attain sufficient power. However, due to potential study design variations between NDA and Abbreviated NDA (ANDA) studies and high variability of clinical endpoints, variance may be over- or under-estimated, resulting in unnecessary extra costs or underpowered studies. Traditionally, clinical endpoint BE studies use a fixed study design. In this work, we propose four sample size re-estimation approaches based on a nuisance parameter and recommend one approach after comparing various operating characteristics by simulation.

The proposed adaptive design with sample size re-estimation provides a more accurate estimate of sample size without wasting resources or under-powering the study and controls the Type 1 error rate under a negligible level, both for the family-wise alpha and individual alpha for superiority and equivalence tests.     

Criminal justice and alcohol treatment: Results from a national sample

This study investigates the associations of recent criminal justice involvement with perceived need for alcohol treatment and alcohol treatment utilization, adjusting for demographic and clinical characteristics. We examined a national sample of adults with alcohol use disorders (N=4390) from the 2006 National Survey on Drug Use and Health. Almost 15% reported criminal justice involvement in the past year. Generalized logit models regressed perceived need for alcohol or drug treatment and past year treatment utilization (versus neither) on past year legal involvement, demographic, and clinical information. In general, results found stronger associations between frequency of criminal justice involvement for treatment utilization compared to perceived need for treatment alone. Treatment utilization was also associated with being on probation, arrests for drug possession/sale and driving under the influence but perceived need was not. Study results suggest opportunities for interventions to increase treatment rates or treatment need, a major correlate of treatment utilization.