The Establishment of Ontario's Local Health Integration Networks: A Conflation of Regionalization with Integration of Health Services

In 2006, Ontario became the last Canadian province to implement health services regionalization with the establishment of Local Health Integration Networks (LHINs). Facing a large health reform agenda to be implemented in a "system" of disconnected health service silos, the Ontario government created the LHINs as a recognition of the need for system change to achieve health reform. As a component of greater provincial health reform goals, the LHINs were specifically designed to integrate health services; however, they may have been implicitly created to shift accountability away from the central government. While some stakeholders supported reform goals of increased health system integration and responsiveness, others opposed the reform stating concern about increased bureaucracy and lack of stakeholder input. Nevertheless, the reform was achieved with the policy framework developed by a government-mandated team and the creation of legislation called the Local Health System Integration Act. To date, no robust evaluations have assessed the causal impact of the LHINs on the integration of the health system in Ontario. The lack of primary care integration and the retention of local health organization boards may have prevented the LHINs from realizing their potential. The decade long experience of the LHINs is a lesson for the Patients First Act enacted in 2016, the next phase of Ontario health care reform involving LHINs as key players

FBXW7-mediated ERK3 degradation regulates the proliferation of lung cancer cells

Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the mitogen-activated protein kinase (MAPK) family, members of which play essential roles in diverse cellular processes during carcinogenesis, including cell proliferation, differentiation, migration, and invasion. Unlike other MAPKs, ERK3 is an unstable protein with a short half-life. Although deubiquitination of ERK3 has been suggested to regulate the activity, its ubiquitination has not been described in the literature. Here, we report that FBXW7 (F-box and WD repeat domain-containing 7) acts as a ubiquitination E3 ligase for ERK3. Mammalian two-hybrid assay and immunoprecipitation results demonstrated that ERK3 is a novel binding partner of FBXW7. Furthermore, complex formation between ERK3 and the S-phase kinase-associated protein 1 (SKP1)-cullin 1-F-box protein (SCF) E3 ligase resulted in the destabilization of ERK3 via a ubiquitination-mediated proteasomal degradation pathway, and FBXW7 depletion restored ERK3 protein levels by inhibiting this ubiquitination. The interaction between ERK3 and FBXW7 was driven by binding between the C34D of ERK3, especially at Thr417 and Thr421, and the WD40 domain of FBXW7. A double mutant of ERK3 (Thr417 and Thr421 to alanine) abrogated FBXW7-mediated ubiquitination. Importantly, ERK3 knockdown inhibited the proliferation of lung cancer cells by regulating the G1/S-phase transition of the cell cycle. These results show that FBXW7-mediated ERK3 destabilization suppresses lung cancer cell proliferation in vitro

Fargesin Inhibits EGF-Induced Cell Transformation and Colon Cancer Cell Growth by Suppression of CDK2/Cyclin E Signaling Pathway

Although the lignan compound fargesin is a major ingredient in Shin-Yi, the roles of fargesin in carcinogenesis and cancer cell growth have not been elucidated. In this study, we observed that fargesin inhibited cell proliferation and transformation by suppression of epidermal growth factor (EGF)-stimulated G1/S-phase cell cycle transition in premalignant JB6 Cl41 and HaCaT cells. Unexpectedly, we found that signaling pathway analyses showed different regulation patterns in which fargesin inhibited phosphatidylinositol 3-kinase/AKT signaling without an alteration of or increase in mitogen activated protein kinase (MAPK) in JB6 Cl41 and HaCaT cells, while both signaling pathways were abrogated by fargesin treatment in colon cancer cells. We further found that fargesin-induced colony growth inhibition of colon cancer cells was mediated by suppression of the cyclin dependent kinase 2 (CDK2)/cyclin E signaling axis by upregulation of p21WAF1/Cip1, resulting in G1-phase cell cycle accumulation in a dose-dependent manner. Simultaneously, the suppression of CDK2/cyclin E and induction of p21WAF1/Cip1 were correlated with Rb phosphorylation and c-Myc suppression. Taken together, we conclude that fargesin-mediated c-Myc suppression inhibits EGF-induced cell transformation and colon cancer cell colony growth by the suppression of retinoblastoma (Rb)-E2F and CDK/cyclin signaling pathways, which are mainly regulated by MAPK and PKB signaling pathways

Atrophic Gastritis: A Related Factor for Osteoporosis in Elderly Women

Purpose Osteoporosis poses a great threat to the aging society. Hypochlorhydric or achlorhydric conditions are risk factors for osteoporosis. Atrophic gastritis also decreases gastric acid production; however, the role of atrophic gastritis as a related factor for osteoporosis is unclear. We investigated the relationship between atrophic gastritis and osteoporosis in postmenopausal women over 60 years of age. Subjects and Methods A total of 401 postmenopausal women were included in this cross-sectional study, which was conducted during their medical check-ups. Bone mineral densitometry was measured using a dual energy X-ray absorptiometry. Atrophic gastritis was defined endoscopically if gastric mucosa in the antrum and the body were found to be atrophied and thinned and submucosal vessels could be well visualized. Results: The proportion of people with atrophic gastritis was higher in the osteoporotic group than in the group without osteoporosis. A linear relationship was observed in the proportion of atrophic gastritis according to the categories of normal, osteopenia, and osteoporosis at the lumbar spine (p for trend = 0.039) and femur (p for trend = 0.001). A multiple logistic regression analysis revealed that the presence of atrophic gastritis was associated with an increased odds of osteoporosis after adjusting for age, body mass index, triglyceride, high-density lipoprotein cholesterol, alcohol consumption, and smoking status (odds ratio 1.89, 95% confidence interval 1.15–3.11). Conclusions: Atrophic gastritis is associated with an increased likelihood of osteoporosis in Korean elderly women

Differential Impact of Obesity on the Risk of Diabetes Development in Two Age Groups: Analysis from the National Health Screening Program

Background The effect of obesity on the development of type 2 diabetes mellitus (DM) in different age groups remains unclear. We assessed the impact of obesity on the development of DM for two age groups (40-year-old, middle age; 66-year-old, older adults) in the Korean population. Methods We analyzed Korean National Health Insurance Service data of 4,145,321 Korean adults with 40- and 66-year-old age without DM, between 2009 and 2014. Participants were followed up until 2017 or until the diagnosis of DM. We assessed the risk of DM based on the body mass index and waist circumference of the participants. Multiple confounding factors were adjusted. Results The median follow-up duration was 5.6 years. The association of general and abdominal obesity with the risk of DM development was stronger in the 40-year-old group (general obesity: hazard ratio [HR], 3.566, 95% confidence interval [CI], 3.512 to 3.622; abdominal obesity: HR, 3.231; 95% CI, 3.184 to 3.278) than in the 66-year-old group (general obesity: HR, 1.739; 95% CI, 1.719 to 1.759; abdominal obesity: HR, 1.799; 95% CI, 1.778 to 1.820). In the 66-year-old group, abdominal obesity had a stronger association with the development of DM as compared to general obesity. In the 40-year-old group, general obesity had a stronger association with the risk of DM development than abdominal obesity. Conclusion The influence of general and abdominal obesity on the development of DM differed according to age. In older adults, abdominal obesity had a stronger association with DM development than general obesity

Electrophysiological Characterization of Benzofuroindole- Induced Potentiation of Large-Conductance Ca 2ϩ -Activated K ϩ Channels

ABSTRACT Large-conductance Ca 2ϩ -activated K ϩ (BK Ca ) channels are widely distributed and play key roles in various cell functions. We previously reported the chemical synthesis of several benzofuroindole compounds that act as potent openers of BK Ca channels. In this study, we investigated the mechanism of channel potentiation by one of the compounds, 7-trifluoromethyl-10H-benzo [4,5]furo[3,2-b]indole-1-carboxylic acid (TBIC), using electrophysiological means. This chemical highly activated cloned BK Ca channels from extracellular side independent of ␤ subunits and regardless of the presence of intracellular Ca 2ϩ . The EC 50 and Hill coefficient for rat BK Ca channel ␣ subunit, rSlo, were estimated as 8.9 Ϯ 1.5 M and 0.9, respectively. TBIC shifted the conductance-voltage curve of rSlo channels to more hyperpolarized potentials without altering its voltage dependence. Single-channel recording revealed that TBIC increased the open probability of the channel in a dosedependent manner without any changes in single-channel conductance. Strong potentiation by TBIC was also observed for native BK Ca channels from rat hippocampus pyramidal neurons. Thus, TBIC and the related benzofuroindole compounds can be useful tools to unravel the mechanism of this novel allosteric activation of BK Ca channels

A Review of Suicide Risk Assessment Tools and Their Measured Psychometric Properties in Korea

While there has been a slew of review studies on suicide measurement tools until now, there were not any reviews focusing on suicide assessment tools available in Korea. This review aimed to examine the psychometric properties of tools developed in Korea or the translated versions from the original tools in their foreign language and to identify potential improvements and supplements for these tools. A literature search was done using the Korean academic information search service, Research Information Service System, to identify the suicide measures to be included in this review. Abstracts were screened to identify which measures were used to assess suicide-related factors. Based on the established inclusion and exclusion criteria, 18 tools remained and we assessed their psychometric properties. The current review indicated several major findings. First, many of the tools did not report predictive validity and even those with predictive validity were based on past suicide attempts. Second, some of the tools overlooked the interactive component for the cause of suicide. In addition, information to supplement the self-reported and clinician-administered reports by collecting reports from the subjects' families and acquaintances is needed. It is also important to develop a screening tool that examines other aspects of an individual's personal life, including unemployment, bereavement, divorce, and childhood trauma. Moreover, tools that have been studied in more diverse groups of the population are needed to increase external validity. Finally, the linguistic translation of the tools into Korean needs to consider other cultural, social, and psychological factors of the sample of interest

Topical administration of EGF suppresses immune response and protects skin barrier in DNCB-induced atopic dermatitis in NC/Nga mice

Atopic dermatitis (AD) is a common inflammatory skin disease characterized by a complex, heterogeneous pathogenesis including skin barrier dysfunction, immunology, and pruritus. Although epidermal growth factor (EGF) is essential for epithelial homeostasis and wound healing, the effect of EGF on AD remains to be explored. To develop a new therapy for AD, the anti-AD potential of EGF was investigated by inducing AD-like skin lesions in NC/Nga mice using 2,4-dinitrochlorobenzene (DNCB). EGF was administrated to NC/Nga mice to evaluate its therapeutic effect on DNCB-induced AD. EGF treatment improved dermatitis score, ear thickness, epidermal hyperplasia, serum total immunoglobulin E level, and transepidermal water loss in NC/Nga mice with DNCB-induced AD. In addition, levels of skin barrier-related proteins such as filaggrin, involucrin, loricrin, occludin, and zonula occludens-1 (ZO-1) were increased by EGF treatment. These beneficial effects of EGF on AD may be mediated by EGF regulation of Th1/Th2-mediated cytokines, mast cell hyperplasia, and protease activated receptor-2 (PAR-2) and thymic stromal lymphopoietin (TSLP), which are triggers of AD. Taken together, our findings suggest that EGF may potentially protect against AD lesional skin via regulation of skin barrier function and immune response