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.

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-related differences regarding headache triggered by low barometric pressure in Japan.

PURPOSE: The prevalence of migraine headache is higher in women. Low barometric pressure is a factor in headache triggering, but sex-related differences have not been identified. The purpose of this study was to examine sex-related differences in headache triggered by low barometric pressure. METHODS: Study subjects aged 20-49 years were randomly selected from a research company's (Macromill, Inc.) web panel. Those with chronic migraine or tension-type headache invited to complete a web-based self-administered questionnaire. Logistic regression analysis was performed with the objective variable as the Headache Impact Test-6 (HIT-6) high scores (56 or more) or headache triggered by low barometric pressure. RESULTS: Participants were 332 women and 337 men in the headache population. HIT-6 high scores were associated with age at headache occurrence 20 years or younger (OR: odds ratio 1.85, 95% CI: confidence interval 1.15-2.99, p = 0.012) and headache triggered by low barometric pressure (OR 2.11, 95%CI 1.51-2.94, p < 0.001). Headache triggered by low barometric pressure was significantly associated with women (OR 2.92, 95%CI 2.12-4.02, p < 0.001). CONCLUSIONS: Headache triggered by low barometric pressure were related to sex-related differences. It was suggested that a sex-specific treatment approach for headache triggering is needed.

Lack of information on gender differences in the package inserts of prescription drugs in Japan.

The package inserts of prescription drugs provide essential information for the proper administration of pharmacotherapy. The incidence of adverse reactions for several drugs is known to be higher in women than in men. However, no studies have examined whether information on gender differences is included in Japanese package inserts. Therefore, this study investigated information on gender differences in the package inserts of Japanese prescription drugs, using the drug information database JAMES provided by the Medical Information System Development Center and the Japan Pharmaceutical Information Center. Non-proprietary names of prescription drugs were yielded 1,679 in Japan. Of the 1,679 ingredients in package inserts of prescription drugs, 76 (4.5%) included information on gender differences. The number of inserts that contained information on gender differences in the "DOSAGE AND ADMINISTRATION," "ADVERSE REACTIONS," and "PHARMACOKINETICS" sections was 3, 16, and 62, respectively. Furthermore, in the "ADVERSE REACTIONS" section, 15 of the 16 inserts mentioned a higher frequency of adverse reactions in women compared with men. Importantly, most of the inserts with information on gender differences in the "PHARMACOKINETICS" section mentioned a higher area under the curve for women than for men. Most of the package inserts of prescription drugs with information on gender differences provide useful information aimed at preventing risks in women. However, there is an extreme lack of information on gender differences in the package inserts of prescription drugs in Japan, and we consider enhancing information on gender difference as an urgent issue.

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.

Inhibition of the dorsomedial striatal direct pathway is essential for the execution of action sequences.

Contrary to the previous notion that the dorsomedial striatum (DMS) is crucial for acquiring new learning, accumulated evidence has suggested that the DMS also plays a role in the execution of already learned action sequences. Here, we examined how the direct and indirect pathways in the DMS regulate action sequences using a task that requires animals to press a lever consecutively. Cell-type-specific bulk Ca2+ recording revealed that the direct pathway was inhibited at the time of sequence execution. The sequence-related response was blunted in trials where the sequential behaviors were disrupted. Optogenetic activation at the sequence start caused distraction of action sequences without affecting motor function or memory of the task structure. By contrast with the direct pathway, the indirect pathway was slightly activated at the start of the sequence, but the optogenetic suppression of such sequence-related signaling did not impact the behaviors. These results suggest that the inhibition of the DMS direct pathway promotes sequence execution potentially by suppressing the formation of a new association.

Increased expression of the histamine H4 receptor subtype in hypertrophic differentiation of chondrogenic ATDC5 cells.

Histamine has been regarded as an inflammatory mediator of arthritic disorders. We have previously reported that the expression of histamine H(4) receptor (H(4)R) mRNA in synovial tissues was significantly higher in patients with osteoarthritis (OA) compared to those with rheumatoid arthritis. Chondrocyte hypertrophy and endochondral ossification are essential processes in pathologic disorders such as osteophyte formation during OA progression. In the present study, we examined the expression of H(4) R during differentiation into hypertrophic chondrocytes in the ATDC5 cells, a widely used in vitro model of chondrogenic differentiation. Quantitative reverse transcription polymerase chain reaction showed that the levels of histidine decarboxylase and H(4)R mRNA on ATDC5 cells were increased in a time-dependent manner during the culture period. By contrast, the expressions of H(1)R and H(2)R were not increased from day 7 onwards. The mRNA expression of the hypertrophic chondrocyte marker type X collagen (COL X) was increased markedly from 14 to 21. Immunocytochemical analysis indicated that H(4)R staining was strongly immunoreactive on the plasma membrane of ATDC5 cells. Flow cytometry showed increased expression of H(4)R and COL X protein in ATDC5 chondrocytes. Furthermore, the majority of the COL X-positive cells expressed H(4) R throughout the culture period. In summary, we showed for the first time that H(4)R is expressed in ATDC5 chondrocytes. Moreover, we found that most hypertrophic chondrocytes express H(4)R, suggesting that this receptor might be associated with the differentiation of chondrocytes into hypertrophic cells, which are abnormally observed in joint lesions in OA.

Lower expression of histamine H4 receptor in synovial tissues from patients with rheumatoid arthritis compared to those with osteoarthritis.

The aim of this study is to compare the expression level of histamine H(4) receptor (H(4)R) mRNA in synovial tissues of rheumatoid arthritis (RA) and osteoarthritis (OA) patients, and to study correlation of results with clinical characteristics of patients with RA. Synovial tissues were obtained from 7 RA and 7 OA patients undergoing artificial arthroplasty. Serum levels of erythrocyte sedimentation rate, C-reactive protein, matrix metalloproteinase-3 (MMP-3), rheumatoid factors, and cyclic citrullinated peptide antibodies were determined. The expression of H(4)R mRNA in synovial tissues was determined by real-time polymerase chain reaction. Expression of H(1)R and H(4)R mRNA were significantly lower in RA compared with OA patients (P < 0.005), while expression of H(2)R mRNA was comparable in both. While a significant negative correlation was found between H(4)R expression and serum MMP-3 concentration (r = -0.70, P < 0.05), no correlation was found between MMP-3 and H(1)R (r = -0.52) or H(2)R (r = 0.23). This study supports the supposition that H(4)R in synovial tissue may play a role in cartilage and bone destruction by influencing the secretion of MMP-3 in patients with RA.

Most dentists approve of oral health check-ups for local residents at community pharmacies and desire collaboration with community pharmacists.

Community pharmacies are required to play a role in maintaining the health of local residents. Since September 2015, a national policy in Japan has allowed saliva tests to be used for oral health check-ups at community pharmacies. In the present study, we aimed to reveal dentists' perceptions and expectations for oral health check-ups provided at community pharmacies. A questionnaire survey was administered to dentists at 1,000 randomly selected dental clinics in Tokyo, Japan; 257 responses (25.7%) were included in the analysis and 85.2% of respondents approved of oral health check-ups at community pharmacies. Most respondents who approved of oral health check-ups expected that community pharmacists would recommend that local residents visit a dental clinic (85.8%) and provide a report to dentists (60.3%) after the check-up. Furthermore, 79.0% of respondents desired collaboration with community pharmacies. These findings suggested the potential for oral health check-ups to facilitate collaboration between community pharmacies and dental clinics aimed at maintaining and improving oral health of local residents.

Patient satisfaction with oral health check-ups at a community pharmacy and their effect on oral self-care habits and dental consultation behavior.

Maintaining good oral health is important because oral diseases are related to systemic diseases, and community pharmacies play a key role in maintaining the health of local residents. This study aimed to examine the effects of oral health check-ups and information provision at community pharmacies on oral health-associated behaviors as well as patient satisfaction. We conducted oral health check-ups and provided information about oral health self-care to 84 patients at a community pharmacy, and then asked them to complete a questionnaire survey. One month later, we sent them a follow-up questionnaire and received responses from 66.7% (56/84) of the participants. The large majority were satisfied with the salivary test (95.2%) and the information (96.4%) we provided. Most of the participants (89.3%) indicated that they wanted to use the oral health check-up service again in the future. Compared with baseline, the ratio of participants restricting their intake of sugar-rich foods and drinks significantly increased 1 month later (p = 0.021). About 60% of those who had not undergone a regular dental examination at baseline reported newly visiting or planning to visit a dental clinic. The results revealed high satisfaction with the oral health check-up and information about oral self-care they received at the community pharmacy. The results suggested that oral health check-ups had the potential to change both oral self-care habits and dental consultation behavior. Our findings indicate that community pharmacies can contribute to the maintenance and promotion of oral health by providing oral health check-ups to local residents.

[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.

[Topical Treatment of Pruritic Skin Disease and the Role of Community Pharmacists].

Itching, or pruritus, can be defined as an unpleasant sensation that evokes the desire to scratch. Pruritus is most commonly associated with a primary skin disorder such as atopic dermatitis (AD), psoriasis, etc., and can have a major impact on the quality of life of those patients. Itch-induced scratching can further damage the skin barrier, leading to a worsening of symptoms. For that reason, it is important to manage pruritus. Topical glucocorticoids are commonly the first-line therapy in the management of AD and psoriasis patients. We found that topical glucocorticoids induce pruritus in mice under certain conditions. Topical glucocorticoids may induce pruritus in a mouse model of allergic contact dermatitis via inhibition of prostaglandin (PG)D2 production in antigen-mediated activated mast cells in the skin. Additionally, topical glucocorticoids do not induce pruritus in healthy skin. These results indicate the importance of controlling skin inflammation to a healthy level by applying sufficient quantities of glucocorticoids to avoid glucocorticoid-induced pruritus. However, topical "steroid phobia" is common in Japan, and most patients apply inadequate amounts of topical glucocorticoids for this reason. This may cause glucocorticoid-induced pruritus in patients by prolonging the skin inflammation. We conducted a survey regarding community pharmacists' instructions on the application quantity of topical glucocorticoids and found that most community pharmacists have experienced inappropriate instructions concerning this point.

A survey on awareness of the "finger-tip unit" and medication guidance for the use of topical steroids among community pharmacists.

Atopic dermatitis (AD) is a common chronic, pruritic inflammatory skin condition. AD is most commonly treated with topical corticosteroids, and the finger-tip unit (FTU) should be used as a guideline for the amount to be used per application. In this study, we investigated the adequacy of pharmacists' instructions on the amount of topical steroids to be applied and the way in which they enhance the effect of pharmaceutical interventions. A self- administered anonymous questionnaire was distributed using QLifePro to 300 pharmacists working in insurance pharmacies that filled at least one dermatologist's prescription per month on average in Japan. Out of 300 pharmacists, 196 (65.3%) recognized the Japanese Dermatological Association's 2016 guidelines for the treatment AD, 107 (35.6%) gave instructions using the FTU as an index of external dose of topical steroids, 157 (52.3%) explained the amount of steroid application using an index other than FTU, and 61 (38.9% of 157) had inadequately instructed AD patients to apply steroids as a thin layer. Pharmacists who had read the guidelines for AD tended to give an appropriate instruction using FTU as an index of external dose of topical steroids (p < 0.001). We found that many pharmacists in pharmacies gave inadequate instructions on the amount of topical steroid application and deviated from the guidelines for AD, mainly because of inadequate knowledge of the guidelines.

Expression of precipitating factors of pruritus found in humans in an imiquimod-induced psoriasis mouse model.

AIMS: To use a mouse model of imiquimod-induced psoriasis to investigate the relationship between pruritus and mast cells, nerve growth factor (NGF) and endogenous pruritogenic peptides, which are highly expressed in the skin of psoriasis patients. MAIN METHODS: We developed a mouse model of imiquimod-induced psoriasis and measured the frequency and duration of the model animals' self-scratching behavior using the SCLABA®-Real real-time scratch counting system. We then harvested the ears and subjected them to toluidine blue staining and real-time PCR. KEY FINDINGS: Topical application of imiquimod increased the Psoriasis Area and Severity Index score as well as the frequency and duration of self-scratching. Regarding internal factors, increases in mast cells number and mRNA expression of NGF and endogenous pruritogenic peptide precursor were confirmed. SIGNIFICANCE: Self-scratching behavior is accompanied by increased number of mast cells and expression of NGF and endogenous pruritogenic peptides in our imiquimod-induced psoriasis model. The expression of these factors was consistent with the features in patients with pruritic psoriasis, suggesting that our model reflects at least some of the precipitating factors of pruritus found in humans.

[Current Status of Onychomycosis Topical Therapy Conducted at Home].

　Patients usually consult a dermatologist for the treatment of onychomycosis. However, in the case of home care, visiting nurses may assist with bathing, which offers the opportunity to observe patients' feet for possible signs of onychomycosis without causing anxiety. It is estimated that more than 30% of patients receiving home care have onychomycosis. Before the approval of efinaconazole, healthcare personnel hesitated to treat onychomycosis because of: 1) possible side effects, especially liver dysfunction and pain due to repeated blood collection, as a major goal of home care is to minimize pain; and 2) the questionable efficacy of previously available antifungal medications. In addition, many patients report fear of "transmitting athlete's foot to others" and "do not want to show my dirty toenails". On the other hand, caregivers reportedly worry about "athlete's foot being transmitted to them".

[Study of Home-based Ringworm Treatment and Follow-up by Visiting Nurses and Physicians: Interventional Effects].

　The aim of this study was to assess the effects of cooperation by visiting nurses and physicians experienced in general patient care, dermatology, and podiatry for the treatment of ringworm. Questionnaires were delivered to 1184 patients receiving home-based care by one of 14 participating visiting nursing establishments with a combined capacity of 3273 patients throughout five wards of the Tokyo metropolitan area. Responses were obtained from 691 patients (participation rate, 60.2%; average age, 80.2 years). The onychomycosis morbidity rate among home care patients was 22.7%. The results showed a significant reduction in the incidence of ringworm in the intervention group, from 79.5% to 54.5% (p=0.022), and in the incidence of "foot skin infection", from 100.0% to 31.6% (p<0.001). Although the level of care deteriorated in the control group (p=0.008), there was no significant change in the intervention group. The incidence of leg pain also remained unchanged in the control group (p=0.285) but decreased in the intervention group (p=0.003). While the "degree of satisfaction with foot cleanliness" did not change significantly in the control group (p=0.260), patients in the intervention group were generally satisfied with foot cleanliness. It is necessary to take into account foot care and the effect of onychomycosis treatment vearsusu no treatment and to ensure that visiting nurses and caregivers master foot care-related treatment regimens. We suggest the need to improve the maintenance of foot care and ringworm intervention/treatment performed by physicians, nurses, and caregivers.

[Role of Pharmacists in Topical Therapy for Onychomycosis in the Home-care Setting].

　There is an urgent need to promote home medical care in Japan because of the country's superaging society. Community pharmacists are expected to play an important role as part of home medical care teams. The prevalence of nail ringworm is high among home-care patients and can cause decreases in the quality of life, including difficulty in walking due to pain caused by nail deformation and inflammation around infected nails. Nail ringworm is typically treated with oral medication. However, the condition is left untreated in many elderly patients because of the risk of drug-drug interactions or concerns about severe liver damage. Efinaconazole, a novel triazole antifungal agent, has recently become available in Japan, enabling patients with nail ringworm to be treated with a topical medication. In topical treatment, the method of application is important because of its major impact on the therapeutic effect. Therefore, pharmacists should take special care to instruct patients and caregivers on the proper use of topical efinaconazole. Adherence to oral medication can be easily monitored by checking the number of tablets or capsules remaining, but adherence to topical medication regimens is more difficult to assess because the remaining amount cannot be determined precisely by checking the outer appearance of the container. The aim of this study was to determine and improve home-care patients' adherence to topical efinaconazole treatment regimens by measuring amounts remaining in the containers using a portable electronic scale. We found that this method is useful for determining the status of topical efinaconazole use.

[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.

[Evaluation of the efficacy of a medicine bag printed with a photograph of the medicine for the prevention of drug-dispensing errors].

In this study, a survey was conducted to determine the rate of drug-dispensing errors with the use of medicine bags printed with photographs of prescribed medicines (hereafter "medicine bag") for a 6-week period from June 20 to July 31, 2005. During this period, 393928 prescriptions were filled in 127 medical facilities that use the medicine bag. The efficacy of the medicine bag in the prevention of drug-dispensing errors was investigated. A total of 6550 (1.66%) drug-dispensing errors were identified: 70.6% were identified at the inspecting stage; 27.4% at the providing medicine and information stage; and 2% after the medication was dispensed. The drug-dispensing errors identified in the inspecting and providing stages included a) using the wrong contents, b) dispensing the wrong drugs, c) missing drugs, d) calculation errors, e) weighing/measuring errors, and f) others. No significant difference was observed in the error rates; thus it was assumed that the type of error was not dependent on the stage at which dispensing errors was discovered. However, it was found that approximately 25% of errors at the providing stage were discovered as a result of the medicine bag. Errors of types a), b), and c) were often discovered because the photograph was printed on the medicine bag. Therefore it was assumed that the photographs contributed to the discovery of drug-dispensing errors.

Whether Visual Information Loss of Expression by Community Pharmacist Masks to Effect a Change in Feeling of Trust among Help-seeker?

Pharmacy is required to shift toward human service such as hearing the complaints of health. But the study about help-seeking behavior to pharmacist is not really investigated. We hypothesized that a decrease in expression visibility, due to pharmacists' typical masks, may negatively impact help-seeker' trust in pharmacist. The sample included 100 drugstore customers aged ≥18 years. Participants were stratified by gender and randomly assigned to two groups: evaluation of clear-masked and normal-masked pharmacists. After viewing a video with either male or female pharmacists wearing either clear or normal masks, participants completed a questionnaire. The primary outcome was trust in pharmacist measured by the Trust Scale and the secondary outcome was impression of the pharmacist measured by nineteen pairs of adjectives. There were no differences by gender on trust scores. Results revealed that both male and female pharmacists who wore clear masks were rated as more trustworthy than normal-masked pharmacists (p<0.001, d=0.903, and p=0.001, d=0.716, respectively). Sixteen of nineteen adjectives reported for pharmacists wearing normal masks indicated greater negative intention than those with clear masks (d=0.431-1.469). In most cases, among pharmacists wearing clear masks, results showed positive correlations between trust and each impression adjective (r=0.279-0.710). Our findings indicate that pharmacists wearing normal masks, which partially hide facial expressions, may decrease customer's trust in pharmacist. Further, normal masks were associated with negative impression. To avoid the inhibition of help-seek behavior, we recommend that pharmacists wear a clear mask and increase non-verbal communication.