Adherence to and clinical utility of "quality indicators" for Staphylococcus aureus bacteremia: a retrospective, multicenter study.

BACKGROUND: We aimed to improve the prognosis, treatment, and management of Staphylococcus aureus bacteremia (SAB) by evaluating the association between adherence to quality indicators (QIs) and clinical outcomes in patients with their clinical outcomes. METHODS: We retrospectively collected clinical and microbiological data on hospitalized patients with SAB from 14 hospitals (three with > 600, two with 401-600, five with 201-400, and four with ≤ 200 beds) in Japan from January to December 2022. The SAB management quality was evaluated using the SAB-QI score (ranging from 0 to 13 points), which consists of 13 QIs (grouped into five categories) based on previous literature. RESULTS: Of the 4,448 positive blood culture episodes, 289 patients with SAB (6.5%) were enrolled. The SAB-QI scores ranged from 3 to 13, with a median score of 9 points. The SAB-QI score was highest in middle-sized hospitals with 401-600 beds. Adherence to each of the four QI categories (blood culture, echocardiography, source control, and antibiotic treatment) was significantly higher in survived cases than in fatal cases. Kaplan-Meier curves with log-rank tests demonstrated that higher adherence to SAB-QIs indicated a better prognosis. Logistic regression analysis revealed that age, methicillin resistance, multiple comorbidities (≥ 2), and low SAB-QI score were significantly associated with 30-day mortality in patients with SAB. CONCLUSIONS: Our study highlights that greater adherence to the SAB-QIs correlates with improved patient outcomes. Management of patients with SAB should follow these recommended indicators to maintain the quality of care, especially for patients with poor prognosticators.

Influence of the coronavirus disease 2019 pandemic on the post-graduate career paths of medical students: a cross-sectional study.

BACKGROUND: The World Health Organization first declared the coronavirus disease 2019 (COVID-19) pandemic in March 2020 and announced the end of the emergency in May 2023. Additionally, the COVID-19 pandemic significantly impacted individuals globally, including medical students. Although the COVID-19 pandemic increased online education, it restricted clinical training, extracurricular activities, and interprovincial travel. Therefore, this study aimed to examine whether the COVID-19 pandemic influenced the choice of training hospitals and career paths among 3rd- to 6th-year medical students in Japan. METHODS: We developed a questionnaire comprising 21 multiple-choice and 1 open-ended questions, which was administered anonymously via online platforms. The survey targeted Japanese medical students to obtain insights into their preferences for training hospitals and career paths during the COVID-19 pandemic. Participants included 4th- to 6th-year medical students from 51 medical schools in Japan. The survey was conducted through student networks from 8 February 2022 to 20 March 2022. RESULTS: Overall, 507 medical students participated in the survey, with representation from various academic years as follows: 102 (20.1%), 134 (26.4%), 121 (23.9%), and 150 (29.6%) students from the 3rd, 4th, 5th, and 6th year, respectively. Of these, 338 (66.6%) students reported that the COVID-19 pandemic had influenced their choice of training hospitals. The degree of the influence varied based on the university region and the student year. However, most of the students (473, 93.3%) did not change their course for clinical, basic research, or administrative pathways due to the COVID-19 pandemic. Among the clinically oriented students, 391 (77.2%) did not change their preferred speciality. CONCLUSIONS: The COVID-19 pandemic influenced medical students' choice of training hospitals. Although many students believed that the pandemic would not change their career choices, our results indicate a potential subconscious trend to avoid internal medicine, which is the speciality most directly involved in treating patients with COVID-19.

The effectiveness of simulation-based education combined with peer-assisted learning on clinical performance of first-year medical residents: a case-control study.

BACKGROUND: Simulation-based education and peer-assisted learning (PAL) are both known as useful educational methods. Previous research has reported that combining these two methods are effective for training medical residents in short-term evaluation. This study was aimed to evaluate the middle- to long-term effects of simulation-based education combined with PAL on the performance of medical residents during emergency department duties. METHODS: This study was designed as a case-control study and conducted over three years at Okayama University Hospital in Japan. Postgraduate-year-one medical residents were assigned to three groups: a simulation group that received simulation-based education, a lecture group that received traditional lecture-based education, and a control group that received no such prior trainings. Prior training in emergency department duties using PAL was performed as an educational intervention for the simulation and lecture groups during the clinical orientation period. The residents' medical knowledge was assessed by written examinations before and after the orientation. The performance of residents during their emergency department duties was assessed by self-evaluation questionnaires and objective-assessment checklists, following up with the residents for three months after the orientation period and collecting data on their 1st, 2nd, and 3rd emergency department duties. All the datasets collected were statistically analyzed and compared by their mean values among the three groups. RESULTS: A total of 75 residents were included in the comparative study: 27 in the simulation group, 24 in the lecture group, and 24 in the control group. The simulation and lecture groups obtained significantly higher written examination scores than the control group. From the self-evaluation questionnaires, the simulation group reported significantly higher satisfaction in their prior training than the lecture group. No significant differences were found in the emergency department performance of the residents among the three groups. However, when evaluating the improvement rate of performance over time, all three groups showed improvement in the subjective evaluation, and only the simulation and lecture groups showed improvement in the objective evaluation. CONCLUSION: Simulation-based education combined with PAL is effective in improving the knowledge and satisfaction of medical residents, suggesting the possibility of improving work performance during their emergency department duties.

Food allergy in nursery children of Kawasaki city, Japan.

BACKGROUND: Food allergies are often life threatening. In order to establish appropriate food allergy measures in nursery children, it is important to analyze local epidemiological data on the food allergy prevalence in nursery children. However, no such data are currently available for the city of Kawasaki, Japan. OBJECTIVE: The present study retrospectively evaluated food allergy prevalence among nursery children in Kawasaki city. METHODS: Data from children with food allergies requiring food avoidance in the nurseries of Kawasaki city between 2007 and 2016 were evaluated. RESULTS: From 2007 to 2016, the prevalence of food allergies among nursery children in Kawasaki city increased from 2.7% to 5.3%. The increase of food allergy prevalence was higher in 2-5 year-old children than in 0-1 year-old children (2.0% to 4.7% vs. 5.3% to 7.0%, respectively). The top five most common food allergies were hen's egg (73.0%), cow's milk (29.3%), nuts (9.7%), soy (8.9%), and wheat (6.5%). Hen's egg was consistently identified as a causative food of food allergy in more than 70% (73.0-89.1%) of food avoidance cases over the 10 year period. The increase of egg allergy prevalence was higher in 2-5 year-old children than in 0-1 year-old children (1.7% to 3.2% vs. 5.2% to 6.0%, respectively). CONCLUSIONS: Food allergies, to hen's egg in particular, have increased considerably among nursery children in the city of Kawasaki, Japan, and that increase was higher among older children.

Antibiotic literacy among Japanese medical students.

Antimicrobial resistance (AMR) is an urgent global issue. After the AMR action plan was introduced in 2016, a study on antibiotic literacy (i.e., awareness, knowledge, and attitude relating to antimicrobial use) among clinicians and lay people was conducted in Japan. However, no studies have hitherto targeted medical students who are expected to have a high level of antibiotic literacy. The present study was conducted between September 2019 and February 2020, enrolling undergraduate students at Okayama University Medical School. We collected data using a paper-based questionnaire form with 11 questions about antibiotic literacy. The response rate was 93.8% (661/705 students). Overall, 92.6% of the students knew that antibiotics inhibit the growth of bacteria. Student reporting that antibiotics could treat the common cold accounted for 77.0% (Year 1), 50.9% (Year 2), 48.2% (Year 3), 49.1% (Year 4), 23.8% (Year 5), and 26.2% (Year 6). Only 43 (6.5%) had heard about the AMR action plan. The study data suggested that medical students' level of literacy on antimicrobial use should be further enhanced to address AMR and promote antimicrobial stewardship.

Clinical Relevance of Serum Prolactin Levels to Inflammatory Reaction in Male Patients.

To clarify the relevance of prolactin (PRL) to clinical parameters in patients who visited our general medicine department, medical records of 353 patients in whom serum PRL levels were measured during the period from 2016 to 2018 were retrospectively reviewed. Data for 140 patients (M/F: 42/98) were analyzed after excluding patients lacking detailed records and patients taking dopaminergic agents. Median serum PRL levels were significantly lower in males than females: 6.5 ng/ml (IQR: 4.2-10.3) versus 8.1 ng/ml (5.9-12.9), respectively. Pain and general fatigue were the major symptoms at the first visit, and past histories of hypertension and dyslipidemia were frequent. Male patients with relatively high PRL levels (≥ 10 ng/ml) had significantly lower levels of serum albumin and significantly higher levels of serum LDH than those with low PRL (< 10 ng/ml). There were significant correlations of male PRL level with the erythrocyte sedimentation rate (R=0.62), serum LDH level (R=0.39) and serum albumin level (R=-0.52), while the level of serum CRP (R=0.33) showed an insignificant but weak positive correlation with PRL level. Collectively, these results show that PRL levels had gender-specific relevance to various clinical factors, with PRL levels in males being significantly related to inflammatory status.

Clinical and biochemical characteristics of patients having general symptoms with increased serum IgG4.

Objective: To differentiate patients with IgG4-related diseases (RD) from patients with other hyper IgG4 conditions who visit general medicine department.Methods: Fifty-six patients with high serum IgG4 levels (>135 mg/dL) were classified into three groups based on the final diagnosis: definite and possible IgG4-RD and others. Clinical and laboratory characteristics of the three groups of patients were retrospectively analyzed.Results: Major manifestations were renal dysfunction and general malaise, while thirst was the most frequent symptom in the definite group, in which submandibular glands and lymph nodes were likely to be affected. Biopsy of minor salivary glands was the least diagnostic for IgG4-RD despite the high frequency of biopsy. In the definite group, serum levels of IgG4 and IgG, IgG4/IgG ratio and basophil number were increased, while serum levels of CRP, IgA and complements were decreased. A negative correlation between serum levels of IgG4 and IgM was found in the definite group.Conclusion: The results indicated that in patients with renal dysfunction, malaise, thirst or weight loss, measurements of the levels of basophils, immunoglobulins and complements are helpful for diagnosing IgG4-RD. Considering distribution of affected tissues and localization of diagnostic biopsies, physical examination and laboratory workup are required for early diagnosis.

Effects on postgraduate-year-I residents of simulation-based learning compared to traditional lecture-style education led by postgraduate-year-II residents: a pilot study.

BACKGROUND: Simulation-based learning plays an important role in contemporary medical education, although there are problems providing tutors. Peer-assisted learning has begun being formally adopted in medical education. Although it is considered useful for simulation-based learning, its effectiveness remains unclear. This study was designed to compare the effect of simulation-based learning with that of traditional lectures conducted by postgraduate-year (PGY)-II residents on PGY-I residents. METHODS: This study was conducted at Okayama University Hospital over three years, for one week each year, before residents entered clinical practice. The study enrolled 76 PGY-I residents, who were randomized into two groups: simulation and lecture groups. PGY-II residents volunteered to conduct simulations and lectures. Knowledge evaluation was performed using pre- and post-tests, and self-evaluation of competence and behaviour-change and program evaluations were conducted using questionnaires. RESULTS: In both groups, knowledge test scores were found to improve significantly, and the score difference between pre- and post-tests in both the groups was not significant. Self-evaluation of competence and behaviour-change was found to be higher in the simulation group than the lecture group. The trainees in the simulation group valued the program and the PGY-II residents as teaching staff more than those in the lecture group. CONCLUSIONS: The combination of simulation-based learning and peer-assisted learning led by PGY-II residents is potentially more effective in improving the postgraduate education of PGY-I residents than the combination of lecture and peer-assisted learning.

GRK-6 mediates FSH action synergistically enhanced by estrogen and the oocyte in rat granulosa cells.

Estrogen is known to play a pivotal role in granulosa cell responses to follicle-stimulating hormone (FSH) that is critical for the establishment of dominant follicles and subsequent ovulation in mammals. Thus, elucidating the cellular and molecular mechanisms that regulate FSH activity is important to understand female fertility. We previously discovered that the oocyte is required for estrogen to exert its positive effects on FSH activity in rat granulosa cells. This finding supports the new concept that estrogen action in granulosa cells is mediated by the oocyte. In the current study, we explored the underlying mechanism. In the presence of oocytes, estrogens enhanced FSH-induced increases in aromatase, steroidogenic acute regulatory protein and FSH receptor mRNA expression as well as cAMP production. However, as forskolin did not mimic FSH activity this indicated that coexistence of estrogen/oocytes increases FSH activity at a site upstream of adenylate cyclase in granulosa cells. We therefore sought a possible involvement of the autoregulatory molecules for FSH receptor, G protein-coupled receptor kinases (GRKs) and ß-arrestins in enhancing FSH activity in response to the estrogen/oocyte co-treatment in granulosa cells. Among the seven known GRK and two ß-arrestin molecules, we found that estrogens with oocytes suppressed FSH-induced GRK-6 mRNA expression. Consistent with this finding, transfecting granulosa cells with small interfering RNA of GRK-6 significantly increased FSH induction of aromatase mRNA, suggesting that endogenous GRK-6 plays an inhibitory role in FSH-induced aromatase mRNA expression. Consequently, these findings strongly suggest that GRK-6 is involved in the mechanism by which estrogen and oocytes synergistically augment FSH activity in granulosa cells.

Content analysis of medical students' seminars: a unique method of analyzing clinical thinking.

BACKGROUND: The study of communication skills of Asian medical students during structured Problem-based Learning (PBL) seminars represented a unique opportunity to assess their critical thinking development. This study reports the first application of the health education technology, content analysis (CA), to a Japanese web-based seminar (webinar). METHODS: The authors assigned twelve randomly selected medical students from two universities and two clinical instructors to two virtual classrooms for four PBL structured tutoring sessions that were audio-video captured for CA. Both of the instructors were US-trained physicians. This analysis consisted of coding the students' verbal comments into seven types, ranging from trivial to advanced knowledge integration comments that served as a proxy for clinical thinking. RESULTS: The most basic level of verbal simple responses accounted for a majority (85%) of the total students' verbal comments. Only 15% of the students' comments represented more advanced types of critical thinking. The male students responded more than the female students; male students attending University 2 responded more than male students from University 1. The total mean students' verbal response time for the four sessions with the male instructor was 6.9%; total mean students' verbal response time for the four sessions with the female instructor was 19% (p < 0.05). CONCLUSIONS: This report is the first to describe the application of CA to a multi-university real time audio and video PBL medical student clinical training webinar in two Japanese medical schools. These results are preliminary, mostly limited by a small sample size (n = 12) and limited time frame (four sessions). CA technology has the potential to improve clinical thinking for medical students. This report may stimulate improvements for implementation.

Prevalence of psychological distress on public health officials amid COVID-19 pandemic.

OBJECTIVES: While the coronavirus disease 2019 (COVID-19) pandemic has led to increased burnout among frontline healthcare workers (HCWs), little research has been done regarding the potential psychological burden among public health officials who have worked tirelessly to tackle the pandemic from an administrative perspective. This study aimed to determine the prevalence of burnout, depression, and job-related stress in Japanese public health officers amid the COVID-19 pandemic. METHODS: We conducted an anonymous, self-administered web-based cross-sectional survey including basic demographics, work-related questions, the Maslach Burnout Inventory, Patient Health Questionnaire-9, Utrecht Work Engagement Scale-3, and Brief Job Stress Questionnaire. 100 public health officers working in the public health centers (PHCs) in Okayama, Japan, answered the survey in December 2021 when the 5th surge in the number of COVID-19 was over. RESULTS: The prevalence of burnout, depression, and job-related stress was 27%, 43%, and 62%, respectively. The multivariate logistic analysis demonstrated that females, public health nurses, and those who suffered from a lack of support from their workplaces were significantly associated with psychological distress. CONCLUSIONS: While we tend to focus on mitigation plans to help alleviate burnout of frontline HCWs, more focus is needed to help public health officers, and public health nurses, in particular, to alleviate their psychological distress and job-related stress to prevent further staff shortages and secure sustainable health systems.

Effects of Yoga and Mindfulness Programs on Self-Compassion in Medical Professionals during the COVID-19 Pandemic: An Intervention Study.

Stress among healthcare workers (HCWs) increased during the coronavirus disease 2019 pandemic. We aimed to determine whether a yoga and mindfulness program could alleviate burnout and other psychological and physical distress in HCWs, and how this might affect their empathy for patients. A weekly one-hour yoga and mindfulness program was conducted for three months in 2021. Participants were 18 consenting HCWs and, the final analysis included 13 participants. They responded to online questionnaires before and after the program. We measured salivary cortisol levels before and after the program on the first and last days. Self-measured pulse rates (PRs) were taken before and after each session, which decreased significantly in both cases (before, after the first program: 72, 65 bpm, p < 0.05; before, after the last program: 75, 66, p < 0.05), but salivary cortisol levels did not change. No significant changes were observed in Patient Health Questionnaire-9, Maslach Burnout Inventory, Sense of Coherence, Connor-Davidson Resilience Scale, Self-compassion Scale, or Jefferson Scale of Empathy. However, common humanity, a subscale of self-compassion, increased significantly (before the first program: 5.6, after the last program: 6.5, p < 0.05), and over-identification decreased significantly (7.9, 6.7, p < 0.01). Yoga and mindfulness programs may help improve the sense of common humanity and reduce over-identification in HCWs.

Measures for food allergy emergency in nurseries.

Background: As food allergy potentially can induce life-threatening anaphylaxis, measures for food allergy are required at nurseries caring for food allergy children, but a large-scale factual investigation has not been carried out. Objective: We evaluated measures for food allergy emergency in nurseries. Methods: A questionnaire survey regarding emergency measures in all authorized nurseries (411 facilities including 20,586 children) was conducted in Kawasaki city, Japan. Results: The recovery rate of the questionnaire was 46.5%, which include 14,343 children of 191 facilities in total. A total of 637 children (4.4%) in 157 facilities (82.2%) requires elimination diets that were suggested by physicians. Among them, 22 children had been suggested to undergo the use of epinephrine auto-injection kit for emergency. 161 facilities (84.3%) had set a specific manual for emergency of food allergy. Emergency cases over the past one year were 4 cases and there was no case that had been suggested to use epinephrine auto-injection kit. All were anaphylaxis and the causes of these included 2 accidental digestion of culprit foods and the causes of other 2 cases were unknown. A case who required no elimination diet showed first episode of anaphylaxis. All cases were recovered. Conclusion: High percentage of nurseries in Kawasaki city has cared for food allergy children. While many children with food allergy have been in nurseries, only several cases of anaphylaxis have been reported for a 1 year. Among 4 cases of anaphylaxis, no specific cause has been recognized in 2 cases and 1 case has been the first episode of anaphylaxis. While most of nurseries have set specific measures for emergency of food allergy, there is certain possibility that nursery staffs can encounter the first episode of anaphylaxis even if there is no food allergy child. For all nurseries, emergency measures for food allergy are vital.

Burnout of Healthcare Workers amid the COVID-19 Pandemic: A Japanese Cross-Sectional Survey.

The coronavirus disease 2019 (COVID-19) global pandemic has drastically changed how we live and work. Amid the prolonged pandemic, burnout of the frontline healthcare professionals has become a significant concern. We conducted a cross-sectional survey study to provide data about the relationship between the COVID-19 pandemic and the prevalence of burnout in healthcare professionals in Japan. Healthcare workers in a single Japanese national university hospital participated in the survey, including basic demographics, whether a participant engaged in care of COVID-19 patients in the past 2 weeks and the Maslach Burnout Inventory. Of those, 25.4% fully answered the survey; 33.3% were doctors and 63.6% were nurses, and 36.3% engaged in care of COVID-19 patients in the past 2 weeks. Compared to those belonging to General Medicine, those in Emergency Intensive Care Unit were at higher risk of burnout (odds ratio (OR), 6.7; 95% CI, 1.1-42.1; p = 0.031). Of those who engaged in care of COVID-19 patients, 50% reported burnout while 6.1% did not (OR 8.5, 95% CI; 1.3-54.1; p = 0.014). The burnout of healthcare workers is a significant concern amid the pandemic, which needs to be addressed for sustainable healthcare delivery.

Burnout of Healthcare Workers Amid the COVID-19 Pandemic: A Follow-Up Study.

The coronavirus disease 2019 (COVID-19) pandemic has posed a significant challenge to the modern healthcare system and led to increased burnout among healthcare workers (HCWs). We previously reported that HCWs who engaged in COVID-19 patient care had a significantly higher prevalence of burnout (50.0%) than those who did not in November 2020 (period 1). We performed follow-up surveys in HCWs in a Japanese national university hospital, including basic demographics, whether a participant engaged in care of COVID-19 patients in the past 2 weeks, and the Maslach Burnout Inventory in February 2021 (period 2) and May 2021 (period 3). Periods 1 and 3 were amid the surges of COVID-19 cases, and period 2 was a post-surge period with a comparatively small number of COVID-19 patients requiring hospitalization. Response rates to the surveys were 33/130 (25.4%) in period 1, 36/130 (27.7%) in period 2, and 56/162 (34.6%) in period 3, respectively. While no consistent tendency in the prevalence of burnout based on variables was observed throughout the periods, the prevalence of burnout tends to be higher in periods 1 and 3 in those who engaged in COVID-19 patient care in the last 2 weeks (50.0%, 30.8%, 43.1% in period 1, 2, and 3, respectively). Given the prolonged pandemic causing stigmatization and hatred against HCWs leading to increased prevalence of burnout, high-level interventions and supports are warranted.

Effects of growth hormone reduction in a patient with polycystic ovary syndrome complicated with acromegaly.

We report a rare case of polycystic ovary syndrome (PCOS) complicated with acromegaly due to a growth hormone (GH)-producing pituitary adenoma. Complete removal of the pituitary adenoma successfully reduced circulating levels of GH and insulin-like growth factor (IGF)-1, which, in turn, resulted in the amelioration of gonadal dysfunction, hyperandrogenism, lutenizing hormone hypersecretion, and severe insulin resistance. This clinical complication suggests that activation of systemic GH-IGF-1 axis is potentially involved in the development of PCOS.

Factors related to burnout in resident physicians in Japan.

OBJECTIVES: We explore the prevalence and characteristics of burnout among Japanese resident physicians and identifies factors associated with burnout. METHODS: A cross-sectional study was conducted three times between April 2017 and March 2018 at a Japanese teaching hospital. Resident physicians were invited to answer an online survey that included existing valid instruments related to burnout, depression, and empathy. Demographic, background, occupational, and socioeconomic data were also collected. Participants were prompted to report the average daily work hours and the specialty they wish to pursue. RESULTS: Overall, 39/76 (51%), 27/76 (36%), and 21/76 (28%) resident physicians responded to surveys in April 2017, October 2017, and March 2018, respectively. The percentages of participants with burnout for surveys in April 2017, October 2017, and March 2018 were 7/39 (18%), 6/27 (22%), and 7/21 (33.3%). Emotional exhaustion (EE) was the only burnout component strongly correlated with the severity of depression (r = .615, p < .001; r = .706, p < .001; r = .601, p < .01). EE and depersonalization (DP) had no significant correlation with average daily working hours (ß = .156, p = .343 for EE; ß = .061, p = .711 for DP). CONCLUSIONS: The results suggest that capping working hours alone may not be effective in reducing burnout in Japanese resident physicians. Medical educators might need to consider not only working hours but also individual job quality and satisfaction to address burnout. Future studies may need to incorporate qualitative methods to explore the characteristics of burnout.

Aldosterone breakthrough caused by chronic blockage of angiotensin II type 1 receptors in human adrenocortical cells: possible involvement of bone morphogenetic protein-6 actions.

Circulating aldosterone concentrations occasionally increase after initial suppression with angiotensin II (Ang II) converting enzyme inhibitors or Ang II type 1 receptor blockers (ARBs), a phenomenon referred to as aldosterone breakthrough. However, the underlying mechanism causing the aldosterone breakthrough remains unknown. Here we investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6, which is expressed in adrenocortical cells, enhances Ang II- but not potassium-induced aldosterone production in human adrenocortical cells. Accordingly, we examined the roles of BMP-6 in aldosterone breakthrough induced by long-term treatment with ARB. Ang II stimulated aldosterone production by adrenocortical cells. This Ang II stimulation was blocked by an ARB, candesartan. Interestingly, the candesartan effects on Ang II-induced aldosterone synthesis and CYP11B2 expression were attenuated in a course of candesartan treatment for 15 d. The impairment of candesartan effects on Ang II-induced aldosterone production was also observed in Ang II- or candesartan-pretreated cells. Levels of Ang II type 1 receptor mRNA were not changed by chronic candesartan treatment. However, BMP-6 enhancement of Ang II-induced ERK1/2 signaling was resistant to candesartan. The BMP-6-induced Smad1, -5, and -8 phosphorylation, and BRE-Luc activity was augmented in the presence of Ang II and candesartan in the chronic phase. Chronic Ang II exposure decreased cellular expression levels of BMP-6 and its receptors activin receptor-like kinase-2 and activin type II receptor mRNAs. Cotreatment with candesartan reversed the inhibitory effects of Ang II on the expression levels of these mRNAs. The breakthrough phenomenon was attenuated by neutralization of endogenous BMP-6 and activin receptor-like kinase-2. Collectively, these data suggest that changes in BMP-6 availability and response may be involved in the occurrence of cellular escape from aldosterone suppression under chronic treatment with ARB.

Generation and suppression of 3-/4-functionalized benzynes using zinc ate base (TMP-Zn-ate): new approaches to multisubstituted benzenes.

We present full details of our new methods for preparing functionalized benzynes with lithium di-alkyl(2,2,6,6-tetramethylpiperidino)zincate (R2Zn(TMP)Li) through deprotonative zincation as a key reaction. In this system, by choosing appropriate ligands for the zincate, either regioselective zincation of functionalized haloaromatics or the generation of substituted benzynes can be controlled in good yields with excellent chemoselectivity, using the same substrate. Zincation with (t)Bu2Zn(TMP)Li followed by electrophilic trapping or zincation with Me2Zn(TMP)Li followed by nucleophilic or diene trapping is shown to be a powerful tool for the chemoselective preparation of 1,2,3-/1,2,4-trisubstituted benzene derivatives. These methods offer far greater generality than previous methods for the synthesis of multifunctionalized benzenes. Computational/theoretical studies of the reaction mechanism of this unique benzyne formation indicated that preferential coordination of the dialkylzinc moiety of zincate to halogen is the reason for the reduced activation energy of the elimination, that is, for the formation of the benzyne. The role of the ligands on Zn in accelerating/decelerating the elimination is also discussed.

A rare tumor in the adrenal region: neuron-specific enolase (NSE)-producing leiomyosarcoma in an elderly hypertensive patient.

A 73-year-old Japanese woman was referred for examination of right flank pain and progressive hypertension. Abdominal CT incidentally detected a right adrenal mass 8 cm in size. The tumor exhibited isodensity by CT and contained high-intense lesion by T2-weighted MRI. Scintigraphy with (131) I-metaiodobenzylguanidine and (131) I-adosterol showed no abnormal uptake by whole body scan. Positron emission tomography scan with (18) F-2-fluoro-D-deoxyglucose demonstrated an exclusive uptake in the right adrenal mass. Adrenocortical hormone levels and catecholamine secretion were within normal range; however, the level of serum neuron-specific enolase (NSE) was found to be markedly high. After controlling systemic blood pressure with an alpha1-blocker, the right adrenal tumor was surgically removed, along with the right kidney and inferior vena cava which adhered to it. The tumor was pathologically proven to be leiomyosarcoma, which was immunohistochemically positive with alpha-smooth muscle actin and negative with CD57, S-100 and c-kit proteins. Notably, NSE protein was massively expressed in the resected tumor. After surgery blood pressure was controlled with regular medication and serum NSE levels have since normalized. The possibility of leiomyosarcoma should be kept in mind in adrenal incidentalomas with rapid growth and atypical radiological images. Our findings suggest that circulating NSE levels may be clinically useful for early detection of recurrence.