Prolonged treatment of genetically obese mice with conjugated linoleic acid improves glucose tolerance and lowers plasma insulin concentration: possible involvement of PPAR activation

Background

Studies in rodents and some studies in humans have shown that conjugated linoleic acid (CLA), especially its trans -10, cis -12 isomer, reduces body fat content. However, some but not all studies in mice and humans (though none in rats) have found that CLA promotes insulin resistance. The molecular mechanisms responsible for these effects are unclear, and there are conflicting reports on the effects of CLA on peroxisomal proliferator-activated receptor-γ (PPARγ) activation and expression. We have conducted three experiments with CLA in obese mice over three weeks, and one over eleven weeks. We have also investigated the effects of CLA isomers in PPARγ and PPARα reporter gene assays.

Results

Inclusion of CLA or CLA enriched with its trans -10, cis -12 isomer in the diet of female genetically obese (lep ^ob /lep ^ob ) mice for up to eleven weeks reduced body weight gain and white fat pad weight. After two weeks, in contrast to beneficial effects obtained with the PPARγ agonist rosiglitazone, CLA or CLA enriched with its trans -10, cis -12 isomer raised fasting blood glucose and plasma insulin concentrations, and exacerbated glucose tolerance. After 10 weeks, however, CLA had beneficial effects on glucose and insulin concentrations. At this time, CLA had no effect on the plasma TNFα concentration, but it markedly reduced the plasma adiponectin concentration. CLA and CLA enriched with either isomer raised the plasma triglyceride concentration during the first three weeks, but not subsequently. CLA enriched with its trans -10, cis -12 isomer, but not with its cis -9, trans -11 isomer, stimulated PPARγ-mediated reporter gene activity; both isomers stimulated PPARα-mediated reporter gene activity.

Conclusions

CLA initially decreased but subsequently increased insulin sensitivity in lep ^ob /lep ^ob mice. Activation of both PPARγ and PPARα may contribute to the improvement in insulin sensitivity. In the short term, however, another mechanism, activated primarily by trans -10, cis -12-CLA, which probably leads to reduced adipocyte number and consequently reduced plasma adiponectin concentration, may decrease insulin sensitivity.     

Sodium/myo‐inositol cotransporter 1 and myo‐inositol are essential for osteogenesis and bone formation

myo‐Inositol (MI) plays an essential role in several important processes of cell physiology, is involved in the neural system, and provides an effective treatment for some psychiatric disorders. Its role in osteogenesis and bone formation nonetheless is unclear. Sodium/MI cotransporter 1 (SMIT1, the major cotransporter of MI) knockout (SMIT1^?/?) mice with markedly reduced tissue MI levels were used to characterize the essential roles of MI and SMIT1 in osteogenesis. SMIT1^?/? embryos had a dramatic delay in prenatal mineralization and died soon after birth owing to respiratory failure, but this could be rescued by maternal MI supplementation. The rescued SMIT1^?/? mice had shorter limbs, decreased bone density, and abnormal bone architecture in adulthood. Deletion of SMIT1 resulted in retarded postnatal osteoblastic differentiation and bone formation in vivo and in vitro. Continuous MI supplementation partially restored the abnormal bone phenotypes in adult SMIT1^?/? mice and strengthened bone structure in SMIT1^+/+ mice. Although MI content was much lower in SMIT1^?/? mesenchymal cells (MSCs), the I(1,4,5)P₃ signaling pathway was excluded as the means by which SMIT1 and MI affected osteogenesis. PCR expression array revealed Fgf4, leptin, Sele, Selp, and Nos2 as novel target genes of SMIT1 and MI. SMIT1 was constitutively expressed in multipotential C3H10T1/2 and preosteoblastic MC3T3‐E1 cells and could be upregulated during bone morphogenetic protein 2 (BMP‐2)–induced osteogenesis. Collectively, this study demonstrated that deficiency in SMIT1 and MI has a detrimental impact on prenatal skeletal development and postnatal bone remodeling and confirmed their essential roles in osteogenesis, bone formation, and bone mineral density (BMD) determination. © 2011 American Society for Bone and Mineral Research.     

Mastery learning of advanced cardiac life support skills by internal medicine residents using simulation technology and deliberate practice

BACKGROUND: Internal medicine residents must be competent in advanced cardiac life support (ACLS) for board certification. OBJECTIVE: To use a medical simulator to assess postgraduate year 2 (PGY-2) residents' baseline proficiency in ACLS scenarios and evaluate the impact of an educational intervention grounded in deliberate practice on skill development to mastery standards. DESIGN: Pretest-posttest design without control group. After baseline evaluation, residents received 4, 2-hour ACLS education sessions using a medical simulator. Residents were then retested. Residents who did not achieve a research-derived minimum passing score (MPS) on each ACLS problem had more deliberate practice and were retested until the MPS was reached. PARTICIPANTS: Forty-one PGY-2 internal medicine residents in a university-affiliated program. MEASUREMENTS: Observational checklists based on American Heart Association (AHA) guidelines with interrater and internal consistency reliability estimates; deliberate practice time needed for residents to achieve minimum competency standards; demographics; United States Medical Licensing Examination Step 1 and Step 2 scores; and resident ratings of program quality and utility. RESULTS: Performance improved significantly after simulator training. All residents met or exceeded the mastery competency standard. The amount of practice time needed to reach the MPS was a powerful (negative) predictor of posttest performance. The education program was rated highly. CONCLUSIONS: A curriculum featuring deliberate practice dramatically increased the skills of residents in ACLS scenarios. Residents needed different amounts of training time to achieve minimum competency standards. Residents enjoy training, evaluation, and feedback in a simulated clinical environment. This mastery learning program and other competency-based efforts illustrate outcome-based medical education that is now prominent in accreditation reform of residency education.     

Medical and veterinary students' structural knowledge of pulmonary physiology concepts.

PURPOSE: The goal of this study was to assess quantitatively medical and veterinary students' knowledge structures of 12 pulmonary physiology concepts before and after receiving a focused instructional block. The "goodness of fit" and internal consistency reliability of the students' knowledge structures were evaluated. Indexes of the students' structural knowledge were correlated with customary measures of student learning of the same concepts. METHOD: Knowledge structures were assessed using a questionnaire that requested similarity judgments about all possible pairs of the concepts: n(n - 1)/2 = 66 pairs. The similarity judgment data were analyzed using the individual differences (INDSCAL) model of multidimensional scaling (MDS). Dimension weights for individual students were then correlated with their final examination scores. RESULTS: A four-dimensional MDS solution provided the best structural fit to the pairwise concept-similarity data. Dimension 1 ranges from control of breathing to lung gas exchange. Dimension 2 ranges from control of breathing to respiratory mechanics. Dimension 3 separates perfusion from diffusion. Dimension 4 addresses ventilatory control. Hierarchical concept clusters are located within this framework. However, indexes of structural learning did not correlate with other measures of knowledge about the same concepts. CONCLUSION: The study outcomes, in contrast to research in other fields, suggest that structural knowledge in this domain differs from knowledge assessed by standard examinations. Further research involving other basic science or clinical concept sets is needed to verify or refute this finding.     

The contribution of employer characteristics to continued employment of employees with residual work capacity: evidence from register data in The Netherlands

Objectives:This study aimed to examine the contribution of employer characteristics to continued employment of employees with residual work capacity. Moreover, we examined whether the contribution of employer characteristics differs across types of employers and employees’ types of diseases.Methods:Register data on disability assessments and employment status of N=84 394 long-term sick-listed employees with residual work capacity were obtained from the Dutch Employee Insurance Agency between 2010 and 2017. The dependent variable was continued employment four months after the assessment. We linked employees to their (former) employer to measure sector, firm size, and workforce composition. The average employment outcome of all employees assessed in the same firm and year served as a proxy measure for the extent of implemented disability-related policies and practices. Using multilevel multiple regression analysis, we compared the relative contribution of employer characteristics with employees’ characteristics.Results:Employer characteristics accounted for 10% of the variability in employment outcomes. In comparison, employees’ socio-demographic and disease characteristics accounted for 13% of the variability. The prevalence of continued employment was lowest in smaller firms and construction and low-wage service-orientated sectors. Furthermore, there were sizeable differences in employment outcomes between similar employers in terms of size, sector and workforce-composition, particularly between larger firms and among employees with mental or musculoskeletal disorders compared to other diseases.Conclusions:This study shows substantial differences between employers in facilitating continued employment of employees with residual work capacity. Encouraging firms to invest more in disability-related policies and practices may result in better employment opportunities for these employees.     

1-取代吡唑烷酮类抗惊构效关系的研究

1-正癸基吡唑烷-3-酮(Ⅱ结构式见表1)是欧洲专利报道的一种新型减肥剂。White等报道该化合物可通过血脑屏障,并对γ-氨基丁酸氨基转移酶(GABA-T)有强烈的抑制活性,但对谷氨酸脱羧酶的抑制作用较弱,因此可引起脑内γ-氨基丁酸(GABA)水平的升高,故我们相信应有抗惊活性。经我们合成后,发现Ⅱ确有良好的抗癲痫活性,抗小鼠最大电