Synthesis and structure-activity relationships of thieno[2,3-d]pyrimidines as atypical protein kinase C inhibitors to control retinal vascular permeability and cytokine-induced edema.

Studies demonstrate that small molecule targeting of atypical protein kinase C (aPKC) may provide an effective means to control vascular permeability, prevent edema, and reduce inflammation providing novel and important alternatives to anti-VEGF therapies for certain blinding eye diseases. Based on a literature tricyclic thieno[2,3-d]pyrimidine lead (1), an ATP-competitive inhibitor of the aPKC iota (ι) and aPKC zeta (ζ) isoforms, we have synthesized a small series of compounds in 1-2 steps from a readily available chloro intermediate. A single pyridine congener was also made using 2D NMR to assign regiochemistry. Within the parent pyrimidine series, a range of potencies was observed against aPKCζ whereas the pyridine congener was inactive. Selected compounds were also tested for their effect toward VEGF-induced permeability in BREC cells. The most potent of these (7l) was further assayed against the aPKCι isoform and showed a favorable selectivity profile against a panel of 31 kinases, including kinases from the AGC superfamily, with a focus on PKC isoforms and kinases previously shown to affect permeability. Further testing of 7l in a luciferase assay in HEK293 cells showed an ability to prevent TNF-α induced NFκB activation while not having any effect on cell survival. Intravitreal administration of 7l to the eye yielded a complete reduction in permeability in a test to determine whether the compound could block VEGF- and TNFα-induced permeability across the retinal vasculature in a rat model. The compound in mice displayed good microsomal stability and in plasma moderate exposure (AUC and Cmax), low clearance, a long half-life and high oral bioavailability. With IV dosing, higher levels were observed in the brain and eye relative to plasma, with highest levels in the eye by either IV or PO dosing. With a slow oral absorption profile, 7l accumulates in the eye to maintain a high concentration after dosing with higher levels than in plasma. Compound 7l may represent a class of aPKC inhibitors for further investigation.

Synthesis of CID-cleavable protein crosslinking agents containing quaternary amines for structural mass spectrometry.

Two novel cyclic quaternary amine crosslinking probes are synthesized for structural mass spectrometry of protein complexes in solution and for analysis of protein interactions in organellar and whole cell extracts. Each exhibits high aqueous solubility, excellent protein crosslinking efficiencies, low collision induced dissociation (CID) energy fragmentation efficiencies, high stoichiometries of reaction, increased charges of crosslinked peptide ions, and maintenance of overall surface charge balance of crosslinked proteins.

Perturbation of ubiquitin homeostasis promotes macrophage oxidative defenses.

The innate immune system senses microbial ligands through pattern recognition and triggers downstream signaling cascades to promote inflammation and immune defense mechanisms. Emerging evidence suggests that cells also recognize alterations in host processes induced by infection as triggers. Protein ubiquitination and deubiquitination are post-translational modification processes essential for signaling and maintenance of cellular homeostasis, and infections can cause global alterations in the host ubiquitin proteome. Here we used a chemical biology approach to perturb the cellular ubiquitin proteome as a simplified model to study the impact of ubiquitin homeostasis alteration on macrophage function. Perturbation of ubiquitin homeostasis led to a rapid and transient burst of reactive oxygen species (ROS) that promoted macrophage inflammatory and anti-infective capacity. Moreover, we found that ROS production was dependent on the NOX2 phagocyte NADPH oxidase. Global alteration of the ubiquitin proteome also enhanced proinflammatory cytokine production in mice stimulated with a sub-lethal dose of LPS. Collectively, our findings suggest that major changes in the host ubiquitin landscape may be a potent signal to rapidly deploy innate immune defenses.

Impact of compliance to oral hypoglycemic agents on short-term disability costs in an employer population.

This study evaluated the relationships between compliance with oral hypoglycemic agents and health care/short-term disability costs in a large manufacturing company. The retrospective analysis used an observational cohort drawn from active employees of Ford Motor Company. The study population consisted of 4978 individuals who were continuously eligible for 3 years (between 2001-2007) and who received a prescription for an oral hypoglycemic agent during that time. Medical, pharmacy, and short-term disability claims data were obtained from the University of Michigan Health Management Research Center data warehouse. Pharmacy claims/refill data were used to calculate the proportion of days covered (PDC); an individual was classified as compliant if his/her PDC was ≥80%. Model covariates included age, sex, work type, and Charlson comorbidity scores. The impact of compliance on disability and health care costs was measured by comparing the costs of the compliant with those of the noncompliant during a 1-year follow-up. Among these employees, compliant patients had lower medical, higher pharmacy, and lower short-term disability costs than did the noncompliant. After adjusting for demographics and comorbidity, noncompliance was associated with statistically higher short-term disability costs ($1840 vs. $1161, P<0.0001), longer short-term disability duration, and an increase in short-term disability incidence (21.5% of the noncompliant had a claim compared to 16.0% of the compliant, P<0.0001). These results suggest that medication compliance may be important in curtailing the rise of health care/disability costs in the workplace. Employers concerned with the total costs associated with diabetes should not overlook the impact of compliance on short-term disability.

Multilevel analysis of the physical health perception of employees: community and individual factors.

PURPOSE: To investigate whether the communities where employees reside are associated with employee perception of overall physical health after adjusting for individual factors. DESIGN: Retrospective cross-sectional. SETTING: Active employees from a large manufacturing company representing 157 zip code tabulation areas (ZCTAs) in Michigan. PARTICIPANTS: 22,012 active employees who completed at least one voluntary health risk appraisal (HRA) during 1999-2001. METHOD: Community deprivation and racial segregation at the ZCTA level were obtained using indices created from 2000 U.S. Census data. Demographics and HRA-related data (health-related behaviors, medical history, and quality of life indicators) at the individual level were used as independent variables. A two-level logistic regression model (employees nested in ZCTA) was used to model the probability of better self-rated health perception (SRH) (better health: 89.1% versus poor health: 10.9%). RESULTS: Relative to those living in highly deprived communities, employees residing in less-deprived communities showed 2.06 (95% confidence interval [CI], 1.57-2.72) and those living in moderately deprived communities showed 1.83 (95% CI, 1.42-2.35) increased odds of better SRH. After adjusting for individual-level variables, employees living in less-deprived communities had increased odds (1.31 [95% CI, 1.07-1.60]) and those living in moderately deprived communities had increased odds (1.33 [95% CI, 1.11-1.59]) of better SRH compared with individuals from highly deprived communities. The association of racial segregation with employees' SRH was mediated after adjusting for other variables. Individual-level variables showed significant statistical associations with SRH. CONCLUSION: Communities do have a modest association with SRH of the employees living there. After adjusting for individual-level and demographic variables, employees living in less/moderately deprived communities are more likely to perceive better physical health relative to those who live in highly deprived communities.

Presenteeism: critical issues.

OBJECTIVE: The objective of this commentary is to discuss the issues surrounding the concept of presenteeism, including the measurement of lost work time per individual, the conversion of the scores attained by the instruments into expressions of productivity loss, and the translation of productivity losses into economic outcomes. METHODS: Literature searches using PubMed and MEDLINE were conducted using "presenteeism" and "productivity" as keywords and combined with other studies known to the authors. Publications on presenteeism instruments and their applications were included. RESULTS: Substantive questions remain about the measurement of presenteeism, its conversion into lost productivity, and the translation of presenteeism into financial equivalents. CONCLUSIONS: Many aspects of presenteeism still warrant caution, especially when using presenteeism measurements to quantify economic outcomes. Focusing on productivity at the population level, rather than the individual level, may be more appropriate.

Effect of health risk appraisal frequency on change in health status.

OBJECTIVE: To examine the association between repeat participation in health risk appraisal (HRA) and change in health status. If low-risk individuals get worse in their health status, the amount of cost increase tends to be greater than the amount of cost reduction when high-risk individuals improve their health status. Thus, "no change" in health status was considered a desired change along with "getting better" in this study. METHODS: Longitudinal data (1997 to 2004) were used to measure change in health status and participation in HRAs and wellness programs. RESULTS: Taking an HRA more than once between 2002 and 2004 was associated with a desired change in health status (staying no change or getting better) (P < 0.0001). Additionally, participation in wellness programs during the same time period was also positively associated with a desired change (P < 0.05). CONCLUSIONS: These results highlight the effect of continued engagement in health promotion activities on health status change. Combined with other education and intervention programs, HRAs can be useful tools in promoting and maintaining healthy lifestyles.

Synthesis and structure-activity studies of novel benzocycloheptanone oxazolidinone antibacterial agents.

We describe a novel class of benzocycloheptanone derived oxazolidinone antibacterial agents. The synthesis and antibacterial activities with structure variation is discussed.

Novel benzthiodiazepinones as antiherpetic agents: SAR improvement of therapeutic index by alterations of the seven-membered ring.

A series of novel benzthiodiazepinones was studied as antiherpetic agents. Significant improvements in potency and therapeutic index in a viral replication assay were realized over the starting molecule. The role of stereospecific substitution on the diazepine ring and optimal nitrogen substitution were investigated.