[Expanding Pharmacy Services for Sustainable Universal Health Coverage: Lessons from the Canadian Health Care System].

Japan's health care system can be regarded as one of the best worldwide, provided it remains sustainable. It has relatively low costs, short wait times, low disease incidence, and high life expectancy. However, universal coverage in Japan faces financial challenges due to the country's rapidly aging population. Canada is another of the few developed countries that have universal health coverage. In contrast to Japan, Canada's health care spending is still sustainable according to recent studies. Effective cost control by payers has played a major role, with providers being steered toward evidence-based and cost-effective drug therapies. Furthermore, expanded pharmacy services have been important in suppressing spending on prescription drugs and minor health care services such as vaccination, government-funded smoking cessation, and medication review programs. This article outlines the services provided by Canadian pharmacists with expanded scope of practice. The pharmaceutical profession and its advocacy body in Canada have not only played a role in regulatory changes, but also put in place technological infrastructure called PharmaNet and contributed to appropriate prescribing. Given the current economic situation and demographic trends in Japan, more options should be explored in order to maintain universal health coverage by meeting the funding gap. Utilizing community pharmacies and pharmacists is proposed as one option.

[Paradigm Shift in the Quality of Regional Medical Care: Cooperative Treatment of Onychomycosis].

　In a superaging society, the medical paradigm should include both less coverage of medical-care work flow by human resources and high-quality care for patients. Strategies such as establishing medical-care teams and community medicine systems mainly for home medical care should be implemented. However, a well-organized system for home-based medical treatment of elderly patients is not yet in place, as evidenced by the lack of care, problems with long-term polypharmacy resulting from visits to multiple healthcare providers, and declines in their physical strength. It is assumed that care might not be provided in association with treatment because planning based on the paradigm of "home medical care" has not been fully established. Therefore, in this study, we aimed to determine the "paradigm shift in home medical care" based on the treatment of onychomycosis. We also hoped to identify the types of medical support required to improve the general well-being of individuals and what needs to be done to ensure a high quality of life for patients. All those (including patients themselves) involved in patient care should together formulate a protocol for medical treatment and cooperate based on the role each can play. Although it may be difficult to maintain cooperation among healthcare workers, improvements in the medical quality of an entire region can be achieved by planning a life design including medical treatment for each patient.

Effect of enhanced expression of connexin 43 on sunitinib-induced cytotoxicity in mesothelioma cells.

Connexin (Cx) makes up a type of intercellular channel called gap junction (GJ). GJ plays a regulatory role in cellular physiology. The Cx expression level is often decreased in cancer cells compared to that in healthy ones, and the restoration of its expression has been shown to exert antiproliferative effects. This work aims to evaluate the effect of the restoration of connexin 43 (Cx43) (the most ubiquitous Cx subtype) expression on sunitinib (SU)-induced cytotoxicity in malignant mesothelioma (MM) cells. Increased Cx43 expression in an MM cell line (H28) improved the ability of SU to inhibit receptor tyrosine kinase (RTK) signaling. Moreover, higher Cx43 expression promoted SU-induced apoptosis. The cell viability test revealed that Cx43 enhanced the cytotoxic effect of SU in a GJ-independent manner. The effect of Cx43 on a proapoptotic factor, Bax, was then investigated. The interaction between Cx43 and Bax was confirmed by immunoprecipitation. Furthermore, higher Cx43 expression increased the production of a cleaved (active) form of Bax during SU-induced apoptosis with no alteration in total Bax expression. These findings indicate that Cx43 most likely increases sensitivity to SU in H28 through direct interaction with Bax. In conclusion, we found that Cx43 overcame the chemoresistance of MM cells.

Elacridar enhances the cytotoxic effects of sunitinib and prevents multidrug resistance in renal carcinoma cells.

Intrinsic drug resistance occurs in many renal carcinomas and is associated with increased expression of multidrug resistant proteins, which inhibits intracellular drug accumulation. Multidrug resistant protein 1, also known as P-glycoprotein, is a membrane drug efflux pump belonging to the ATP-binding cassette (ABC) transporter superfamily. ABC Sub-family B Member 2 (ABCG2) is widely distributed and is involved in the multidrug resistant phenotype. Sunitinib is a tyrosine kinase inhibitor used to treat kidney cancer that disrupts signaling pathways responsible for abnormal cancer cell proliferation and tumor angiogenesis. Multiple drug resistance is important in tyrosine kinase inhibitor-induced resistance. We hypothesized that inhibition of multidrug resistant transporters by elacridar (dual inhibitor of P-glycoprotein and ABCG 2) might overcome sunitinib resistance in experimental renal cell carcinoma. Human renal carcinoma cell lines 786-O, ACHN, and Caki-1 were treated with sunitinib or elacridar alone, or in combination. We showed that elacridar significantly enhanced sunitinib cytotoxicity in 786-O cells. P-glycoprotein activity, confirmed by P-glycoprotein function assay, was found to be inhibited by elacridar. ABCG2 expression was low in all renal carcinoma cell lines, and was suppressed only by combination treatment in 786-O cells. ABCG2 function was inhibited by sunitinib alone or combination with elacridar but not elacridar alone. These findings suggest that sunitinib resistance involves multidrug resistance transporters, and in combination with elacridar, can be reversed in renal carcinoma cells by P-glycoprotein inhibition.

Increased expression of the histamine H4 receptor following differentiation and mediation of the H4 receptor on interleukin-8 mRNA expression in HaCaT keratinocytes.

Recent in vivo studies have demonstrated involvement of the histamine H4 receptor in pruritus and skin inflammation. We previously reported that an H4 receptor antagonist attenuated scratching behaviour and improved skin lesions in an experimental model of atopic dermatitis. We also reported the expression of the H4 receptor in human epidermal tissues. In this study, we investigated the expression of H4 receptor mRNA and the function of the receptor in a culture system that mimics in vivo inflammation on the HaCaT human keratinocyte cell line. Increased expression of the H4 receptor was observed in HaCaT cells following differentiation. Treatment of HaCaT cells with histamine and TNFα enhanced the mRNA expression of interleukin (IL)-8. These increases in expression were significantly inhibited by the H4 receptor antagonist JNJ7777120. Our results indicate that IL-8 mRNA expression might be enhanced by histamine and TNFα via H4 receptor stimulation in keratinocytes.

Sex differences in stress reactivity of hippocampal BDNF in mice are associated with the female preponderance of decreased locomotor activity in response to restraint stress.

The incidence and prevalence of depression is higher in women than in men, but the cause of this sex discrepancy remains unknown. Brain-derived neurotrophic factor (BDNF) is a key protein for maintaining neuronal integrity. The purpose of this study was to investigate the female preponderance in behavioral responsivity to restraint stress focusing on the stress reactivity of BDNF in the hippocampus. Male and female ICR mice were exposed to a 3-h session of restraint stress. Plasma corticosterone was measured by high-performance liquid chromatography. BDNF mRNA expression in the whole hippocampus was measured by quantitative real-time reverse transcription-polymerase chain reaction. Wheel-running activity was monitored during the dark period. In response to restraint stress, the increase in levels of serum corticosterone was higher in female than in male mice. Restraint stress resulted in decreased voluntary wheel-running behavior that was greater in female than male animals. In addition to these sex differences in stress reactivity, we found a significant sex difference in BDNF levels in the hippocampus of restraint-stressed mice; total BDNF levels significantly decreased in female mice, but not in male mice in response to the stress. Furthermore, BDNF exon I and IV mRNA expression also showed the same tendency. These data indicate that the reduction in levels of voluntary wheel-running activity in response to stress can be significantly influenced by sex. Moreover, our findings suggest a link between the sex differences in this behavioral response to stress and differential stress reactivity in the production of BDNF in the hippocampus.

Expression of the histamine H4 receptor in dermal and articular tissues.

Histamine H(4) receptor was identified in 2000 and is the most recently identified of the four histamine receptors. It is expressed primarily in immune cells and is involved in physiologic functions related to inflammation and allergy. Recently, the H(4) receptor was highlighted as a promising therapeutic target in atopic dermatitis, asthma, and chronic arthritis. In fact, some H(4) receptor antagonists have reached clinical trials for the treatment of asthma, atopic dermatitis, and allergic rhinitis. Based on an initial assessment of distribution, the H(4) receptor has been referred to as the histamine receptor of the hematopoietic system. However, the H(4) receptor has also been implicated in the regulation of other non-hematopoietic systems. Here, we review the expression and function of the H(4) receptor with a focus on dermal and articular tissues. In skin, the H(4) receptor is expressed in both the epidermis and dermis, with stronger receptor expression in the epidermis. In articular tissue, H(4) receptor expression has been detected in synovial cells. Chondrocytes, a major cell sources for cartilage tissue engineering, also express the H(4) receptor. Further understanding of the functions of H(4) receptors in non-hematopoietic cells might lead to novel treatments for diseases with unmet needs.

Anthocyanins from bilberry (Vaccinium myrtillus L.) alleviate pruritus in a mouse model of chronic allergic contact dermatitis.

BACKGROUND: Bilberry (Vaccinium myrtillus L.) is one of the richest sources of anthocyanins which are known to have anticancer, wound healing and anti-allergic effects. Here, we examined whether bilberry extract (Bilberon-25) alleviates pruritus in a mouse model of chronic allergic contact dermatitis. MATERIALS AND METHODS: BALB/c mice with chronic allergic contact dermatitis induced by 3 weeks of repeated application of 2,4,6-trinitro-1-chlorobenzene (TNCB) were administered Bilberon-25 orally for 3 weeks after sensitization with TNCB. The effects of Bilberon-25 on pruritus and inflammation were evaluated by measurement of scratching behaviour and ear swelling, respectively. RESULTS: Treatment with Bilberon-25 significantly attenuated the TNCB-induced increase in scratching behaviour, but dexamethasone did not. In contrast, ear swelling was ameliorated by dexamethasone treatment, and significantly decreased by Bilberon-25. Repeated application of TNCB induced a shift in the cutaneous cytokine milieu from a T helper cell type (Th)1 to a Th2 profile; Bilberon-25 and dexamethasone alleviated this Th2 predominance of the lesional skin. CONCLUSION: Anthocyanins from bilberry might be beneficial for the treatment of chronic pruritus which can occur in patients with inflammatory skin diseases such as atopic dermatitis.

Enhanced effect of connexin 43 on cisplatin-induced cytotoxicity in mesothelioma cells.

The expression levels of connexin (Cx) proteins, which are gap junction (GJ) components, are often decreased in many cancers, and restoring their levels has been shown to have antitumor effects. Previously, dysfunctional gap junctional intercellular communication (GJIC) has been observed in several malignant mesotheliomas (MMs), and among the many Cx proteins, Cx43 is prominently expressed in nontumorigenic mesothelial tissues. Therefore, we investigated whether Cx43 upregulation has an antitumor effect on an MM cell line (H28 cell), especially with regard to drug resistance. After treatment with the chemotherapeutic agent cisplatin (CDDP), MM cell viability significantly decreased, and apoptosis induction was observed in Cx43-transfected clones. A specific GJIC inhibitor could not abrogate this effect. On the other hand, the Src protein is known to phosphorylate Cx43, which results in GJIC inhibition. This suggests that Src activity might also be regulated by the hyperexpression of Cx43. In fact, the Src protein level was decreased in Cx43-transfected clones. Moreover, Src inhibition reinforced CDDP cytotoxicity in parental H28 cells. These data suggest that Cx43 could improve the resistance to CDDP in a GJIC-independent manner, which may be partly mediated by the suppression of Src activity.