Soluble Epoxide Hydrolase Gene Deficiency or Inhibition Attenuates Chronic Active Inflammatory Bowel Disease in IL-10(?/?) Mice

Background

Soluble epoxide hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids (EETs) into their much less active dihydroxy derivatives dihydroxyeicosatrienoic acids. Thus, targeting sEH would be important for inflammation.

Aims

To determine whether knockout or inhibition of sEH would attenuate the development of inflammatory bowel disease (IBD) in a mouse model of IBD in IL-10(?/?) mice.

Methods

Either the small molecule sEH inhibitor trans/-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) or sEH knockout mice were used in combination with IL-10(?/?) mice. t-AUCB was administered to mice in drinking fluid. Extensive histopathologic, immunochemical, and biochemical analyses were performed to evaluate effect of sEH inhibition or deficiency on chronic active inflammation and related mechanism in the bowel.

Results

Compared to IL-10 (?/?) mice, sEH inhibition or sEH deficiency in IL-10(?/?) mice resulted in significantly lower incidence of active ulcer formation and transmural inflammation, along with a significant decrease in myeloperoxidase-labeled neutrophil infiltration in the inflamed bowel. The levels of IFN-γ, TNF-α, and MCP-1, as well VCAM-1 and NF-kB/IKK-α signals were significantly decreased as compared to control animals. Moreover, an eicosanoid profile analysis revealed a significant increase in the ratio of EETs/DHET and EpOME/DiOME, and a slightly down-regulation of inflammatory mediators LTB₄ and 5-HETE.

Conclusion

These results indicate that sEH gene deficiency or inhibition reduces inflammatory activities in the IL-10 (?/?) mouse model of IBD, and that sEH inhibitor could be a highly potential in the treatment of IBD.     

Lifestyle risk factors predict disability and death in healthy aging adults

BackgroundAssociations between modifiable health risk factors during middle age with disability and mortality in later life are critical to maximizing longevity while preserving function. Positive health effects of maintenance of normal weight, routine exercise, and nonsmoking are known for the short and intermediate term. We studied the effects of these risk factors into advanced age.MethodsA cohort of 2327 college alumnae aged 60 years or more was followed annually (1986-2005) by questionnaires addressing health risk factors, history, and Health Assessment Questionnaire disability. Mortality data were ascertained from the National Death Index. Low-, medium-, and high-risk groups were created on the basis of the number (0, 1, ≥2) of health risk factors (overweight, smoking, inactivity) at baseline. Disability and mortality for each group were estimated from unadjusted data and regression analyses. Multivariable survival analyses estimated time to disability or death.ResultsThe medium- and high-risk groups had higher disability than the low-risk group throughout the study (P < .001). Low-risk subjects had onset of moderate disability delayed 8.3 years compared with high-risk subjects. Mortality rates were higher in the high-risk group (384 vs 247 per 10,000 person-years). Multivariable survival analyses showed the number of risk factors to be associated with cumulative disability and increased mortality.ConclusionSeniors with fewer behavioral risk factors during middle age have lower disability and improved survival. These data document that the associations of lifestyle risk factors on health continue into the ninth decade.     

Osteogenic potential of mesenchymal cells embedded in the provisional matrix after a 6-week healing period in augmented and non-augmented extraction sockets: an immunohistochemical prospective pilot study in humans

Purpose: The aim of the present clinical study was the evaluation of the osteogenic potential of mesenchymal cells embedded in the provisional matrix of non‐augmented and with Bio‐Oss collagen‐augmented human extraction sockets after 6 weeks of healing time. Methods: Twenty‐five patients with 47 extraction sites participated in the present study. After tooth removal, the extraction sockets were augmented with Bio‐Oss collagen or not augmented. At implant placement, bone biopsies of the extraction sockets were obtained. The immunohistochemical analysis of the osteogenic potential of the mesenchymal cells in the provisional matrix was performed using three monoclonal antibodies: core‐binding factor α1 (Cbfa1)/runt‐related protein (Runx)2, osteonectin (OSN/secreted protein acidic and rich in cyst [SPARC]) and osteocalcin (OC). The statistical analysis was performed using two‐factorial analysis for repeated measures, Mann–Whitney U‐test and Spearman's rank‐order correlation coefficient. Results: Of 47 extraction sockets examined, 17 sockets demonstrated an almost complete ossification. Hence, the provisional matrix of the 30 remaining extraction sockets (21 non‐augmented, 9 augmented) was immunohistochemically investigated. No evidence of acute or chronic inflammation was noted in any of the specimens. In the provisional matrix of the non‐grafted socket, the median amount of Cbfa1/Runx2‐positive cells was 72.3%, of OSN (SPARC) 66.9% and of OC 23.4%, whereas in the grafted sockets the median rate of immunopositive cells staining with Cbfa1/Runx2 was 73.3%, of OSN (SPARC) 61.4% and of OC 20.1%. There was no significant difference in the proportion of positive cells expressed by Cbfa1/Runx2, OSN/SPARC and OC between the grafted and non‐grafted socket. Furthermore, the cell density did not correlate to the quantity of stained cells independent of the used proteins. Discussion: After a 6‐week healing period, the provisional matrix was demonstrated to have a high proportion of cells displaying a maturation of mature osteoprogenitor cells to osteoblasts. The grafting procedure did not influence the quantity of osteogenic cells in the extraction socket. To cite this article:
Heberer S, Wustlich A, Lage H, Nelson JJ, Nelson K. Osteogenic potential of mesenchymal cells embedded in the provisional matrix after a 6‐week healing period in augmented and non‐augmented extraction sockets: an immunohistochemical prospective pilot study in humans.
Clin. Oral Impl. Res. 23 , 2012; 19–27.
doi: 10.1111/j.1600‐0501.2010.02148.x     

Randomized controlled trials: what are they and who needs them?

Dentistry is rapidly entering a new era of evidence-based practice, and society is demanding prevention and treatment that has been proven to be effective in terms of meaningful health outcomes. Practitioners, individual patients and the public need randomized controlled trials because they provide the highest level of scientific evidence to change clinical practice and inform public health policy. Well-designed randomized controlled trials are conceptually simple but deceptively complex to design, implement and translate into clinical practice. Randomized controlled trials are fundamentally different from observational clinical research because they randomly assign volunteers to receive test or control interventions, they are prospective and the success of the test intervention is based on a meaningful clinical outcome that is specified before the trial begins. To be successful, randomized controlled trials must be carefully designed and powered to answer a specific question that will be generalizable to the population under study. Randomized controlled trials can be designed to evaluate efficacy, effectiveness, superiority, equivalence or noninferiority. Prominent issues and challenges in designing and conducting randomized controlled trials include carefully defining enrollment criteria, establishing an organizational infrastructure, use of a data-coordinating center, developing a manual of procedures, obtaining informed consent, recruiting and ensuring the safety of volunteer subjects, ensuring data quality, analysis and publication of trial outcomes, and translating results into clinical practice.     

Early postnatal development of the mandibular permanent first molar in infants with isolated cleft palate

International Journal of Paediatric Dentistry 2012; 22: 280–285 Background. Based on measurements on dental casts, smaller permanent teeth in children with cleft palate have previously been reported in the literature; however, the early maturation of teeth and the size of the follicles and crowns have not been investigated. Hypothesis. The maturation of the mandibular permanent first molar (M1_inf) is delayed, and the mesiodistal diameters of the follicle and crown of M1_inf, respectively, are reduced in children with isolated cleft palate (ICP). Design. Retrospective, longitudinal. Cephalometric X‐rays were available for 2 and 22 months old children with clefts (64 children with ICP, and a control group of 38 children with unilateral incomplete cleft lip). The width of the follicle and the crown of M1_inf, and the maturation of M1_inf were assessed. Intra‐observer error was acceptable. Results. M1_inf maturation was delayed in children with ICP at both 2 and 22 months of age. The mesiodistal diameter of the crown of M1_inf in the ICP group was reduced. Thus, the two hypotheses could not be refuted. Conclusions. Children with ICP showed smaller dimensions of the M1_inf, and in addition, the maturation of M1_inf was delayed.