Creation and Validation of Patient-Derived Cancer Model Using Peritoneal and Pleural Effusion in Patients with Advanced Ovarian Cancer: An Early Experience.

Background: The application of personalized cancer treatment based on genetic information and surgical samples has begun in the field of cancer medicine. However, a biopsy may be painful for patients with advanced diseases that do not qualify for surgical resection. Patient-derived xenografts (PDXs) are cancer models in which patient samples are transplanted into immunodeficient mice. PDXs are expected to be useful for personalized medicine. The aim of this study was to establish a PDX from body fluid (PDX-BF), such as peritoneal and pleural effusion samples, to provide personalized medicine without surgery. Methods: PDXs-BF were created from patients with ovarian cancer who had positive cytology findings based on peritoneal and pleural effusion samples. PDXs were also prepared from each primary tumor. The pathological findings based on immunohistochemistry were compared between the primary tumor, PDX, and PDX-BF. Further, genomic profiles and gene expression were evaluated using DNA and RNA sequencing to compare primary tumors, PDXs, and PDX-BF. Results: Among the 15 patients, PDX-BF was established for 8 patients (5 high-grade serous carcinoma, 1 carcinosarcoma, 1 low-grade serous carcinoma, and 1 clear cell carcinoma); the success rate was 53%. Histologically, PDXs-BF have features similar to those of primary tumors and PDXs. In particular, PDXs-BF had similar gene mutations and expression patterns to primary tumors and PDXs. Conclusions: PDX-BF reproduced primary tumors in terms of pathological features and genomic profiles, including gene mutation and expression. Thus, PDX-BF may be a potential alternative to surgical resection for patients with advanced disease.

Consistency between Primary Uterine Corpus Malignancies and Their Corresponding Patient-Derived Xenograft Models.

Patient-derived xenograft (PDX) models retain the characteristics of tumors and are useful tools for personalized therapy and translational research. In this study, we aimed to establish PDX models for uterine corpus malignancies (UC-PDX) and analyze their similarities. Tissue fragments obtained from 92 patients with uterine corpus malignancies were transplanted subcutaneously into immunodeficient mice. Histological and immunohistochemical analyses were performed to compare tumors of patients with PDX tumors. DNA and RNA sequencing were performed to validate the genetic profile. Furthermore, the RNA in extracellular vesicles (EVs) extracted from primary and PDX tumors was analyzed. Among the 92 cases, 52 UC-PDX models were established, with a success rate of 56.5%. The success rate depended on tumor histology and staging. The pathological and immunohistochemical features of primary and PDX tumors were similar. DNA sequencing revealed similarities in gene mutations between the primary and PDX tumors. RNA sequencing showed similarities in gene expressions between primary and PDX tumors. Furthermore, the RNA profiles of the EVs obtained from primary and PDX tumors were similar. As UC-PDX retained the pathological and immunohistochemical features and gene profiles of primary tumors, they may provide a platform for developing personalized medicine and translational research.

A mixed-methods study on the pharmacological management of pain in Australian and Japanese nursing homes.

BACKGROUND: Understanding how analgesics are used in different countries can inform initiatives to improve the pharmacological management of pain in nursing homes. AIMS: To compare patterns of analgesic use among Australian and Japanese nursing home residents; and explore Australian and Japanese healthcare professionals' perspectives on analgesic use. METHODS: Part one involved a cross-sectional comparison among residents from 12 nursing homes in South Australia (N = 550) in 2019 and four nursing homes in Tokyo (N = 333) in 2020. Part two involved three focus groups with Australian and Japanese healthcare professionals (N = 16) in 2023. Qualitative data were deductively content analysed using the World Health Organization six-step Guide to Good Prescribing. RESULTS: Australian and Japanese residents were similar in age (median: 89 vs 87) and sex (female: 73% vs 73%). Overall, 74% of Australian and 11% of Japanese residents used regular oral acetaminophen, non-steroidal anti-inflammatory drugs or opioids. Australian and Japanese healthcare professionals described individualising pain management and the first-line use of acetaminophen. Australian participants described their therapeutic goal was to alleviate pain and reported analgesics were often prescribed on a regular basis. Japanese participants described their therapeutic goal was to minimise impacts of pain on daily activities and reported analgesics were often prescribed for short-term durations, corresponding to episodes of pain. Japanese participants described regulations that limit opioid use for non-cancer pain in nursing homes. CONCLUSION: Analgesic use is more prevalent in Australian than Japanese nursing homes. Differences in therapeutic goals, culture, analgesic regulations and treatment durations may contribute to this apparent difference.

Triple repeated fetal congenital heart disease linked to PLD1 mutation: a case report.

BACKGROUND: Congenital heart disease occurs in approximately 1 in 100 cases. Although sibling occurrence is high (3-9%), the causative genes for this disease are still being elucidated. PLD1 (Phospholipase D1) is a recently discovered gene; however, few case reports have been published on it. In this report, we describe a case of triplicate fetal congenital heart disease that was diagnosed as a PDL1 mutation. Our objective is to explore the clinical manifestations of PLD1 mutations in this particular case. CASE PRESENTATION: A 32-year-old Japanese woman (gravida, para 0) was introduced since fetus four chamber view was not clear and was diagnosed with ductus arteriosus-dependent left ventricular single ventricle and pulmonary atresia at 21 weeks and 1 day of gestation during her first pregnancy. Artificial abortion using Gemeprost was performed at 21 weeks and 5 days of gestation. The second pregnancy was diagnosed as pulmonary atresia with intact ventricular septum with cardiomegaly, a cardiothoracic area ratio of more than 35%, and a circulatory shunt at 13 weeks and 3 days of gestation. Subsequently, intrauterine fetal death was confirmed at 14 weeks and 3 days of gestation. Regarding the third pregnancy, fetal ultrasonography at 11 weeks and 5 days of gestation showed mild fetal hydrops and moderate tricuspid valve regurgitation. At 16 weeks and 5 days of gestation, the fetus was suspected to have a left ventricular-type single ventricle, trace right ventricle, pulmonary atresia with intact ventricular septum, or cardiomyopathy. Cardiac function gradually declined at 26 weeks of gestation, and intrauterine fetal death was confirmed at 27 weeks and 5 days of gestation. The fourth pregnancy resulted in a normal heart with good progression and no abnormal baby. We submitted the first and second fetuses' umbilical cord, third fetus' placenta, and the fourth fetus' blood to genetic testing using whole exome analysis with next generation sequencing. Genetic analysis identified hemizygous PLD1 mutations in the first, second, and third fetuses. The fourth fetus was heterozygous. In addition, the parents were heterozygous for PLD1. This case is based on three consecutive cases of homozygosity for the PLD1 gene in the sibling cases and the fetuses with recurrent right ventricular valve dysplasia. This will elucidate the cause of recurrent congenital heart disease and intrauterine fetal death and may serve as an indicator for screening the next fetus. To date, homozygous mutations in PLD1 that repeat three times in a row are not reported, only up to two times. The novelty of this report is that it was repeated three times, followed by a heterozygous live birth. CONCLUSIONS: This report is consistent with previous reports that mutations in PLD1 cause right ventricular valve dysplasia. However, there have been few case reports of PLD1 mutations, and we hope that this report will contribute to elucidate the causes of congenital heart disease, especially right ventricular valve dysplasia, and that the accumulation of such information will provide more detailed information on PLD1 mutations in heart disease.

Lymphatic Complications Following Sentinel Node Biopsy or Pelvic Lymphadenectomy for Endometrial Cancer.

Sentinel node biopsy (SNB) is performed worldwide in patients with endometrial cancer (EC). The aim of this study was to evaluate and compare the occurrence rate of lymphatic complications between SNB and pelvic lymphadenectomy (LND) for EC. The medical records of women who underwent SNB or pelvic LND for EC between September 2012 and April 2022 were assessed. A total of 388 patients were enrolled in the current study. Among them, 201 patients underwent SNB and 187 patients underwent pelvic LND. The occurrence rates of lower-extremity lymphedema (LEL) and pelvic lymphocele (PL) were compared between the patients who underwent SNB and those who underwent pelvic LND. The SNB group had a significantly lower occurrence rate of lower-extremity LEL than the pelvic LND group (2.0% vs. 21.3%, p < 0.01). There were no patients who had PL in the SNB group; however, 4 (2.1%) patients in the pelvic LND group had PL. The occurrence rates of lower-extremity LEL and PL were significantly lower in patients who underwent SNB than those who underwent pelvic LND. SNB for EC has a lower risk of lymphatic complications compared to systemic LND.

Changes in chronic disease medications after admission to a Geriatric Health Services Facility: A multi-center prospective cohort study.

Older adults often receive polypharmacy, including some medications for chronic diseases. Nutritional management after admission to a nursing home may enable to deprescribe some chronic disease medications. This study aimed to investigate the status of deprescribing of chronic disease medications among nursing home residents, and to assess the appropriateness based on changes of laboratory test values and nutritional status. A multi-center prospective cohort study was conducted in 6 Geriatric Health Services Facilities, a major type of nursing homes in Japan. Newly admitted residents aged ≥ 65 years who took ≥1 medication for hypertension, diabetes, or dyslipidemia at admission were recruited. Participants who stayed for 3 months were included in the analysis. Medications at admission and 3 months after admission and situations for deprescribing were investigated. Changes in body mass index, blood pressure, laboratory tests (e.g., cholesterol and hemoglobin A1c levels), energy intake, and International Classification of Functioning, Disability and Health staging were evaluated. Sixty-nine participants (68% female, 62% aged ≥ 85 years) were included. At admission, 60 participants had medications for hypertension, 29 for dyslipidemia, and 13 for diabetes. Those receiving lipid-modifying drugs (mainly statins) decreased from 29 to 21 (72%; P = .008), since their cholesterol levels was within the normal range or was low at admission, and they had no history of cardiovascular events. However, there were no statistically significant changes in the frequencies of antihypertensive drugs (60 to 55; 92%; P = .063) or antidiabetic drugs (13 to 12; 92%; P = 1.000). During the 3-month observation, body mass index and diastolic blood pressure decreased, while energy intake and serum albumin level increased. Nutritional management after admission to a ROKEN may facilitate appropriate deprescribing of lipid-modifying drugs, by offseting the effects of discontinuation of these drugs.

Cancer-Specific miRNAs Extracted from Tissue-Exudative Extracellular Vesicles in Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinomas (OCCs) arise from endometriotic cysts that many women develop. Biomarkers for early OCC detection need to be identified. Extracellular vesicles have attracted attention as biomarker carriers. This study aims to identify cancer-specific miRNAs as novel OCC biomarkers using tissue-exudative extracellular vesicles (Te-EVs). Te-EVs were collected from four patients with OCC on one side and a normal ovary on the other side. Microarray analysis was performed to identify cancer-specific miRNAs in Te-EVs. Serum samples obtained before and after surgery from patients with OCC and atypical endometrial hyperplasia (AEH) (controls) were compared using real-time PCR to examine changes in the detected EV miRNA levels. Thirty-seven miRNAs were >2-fold upregulated on the OCC side compared with the normal ovarian side. We selected 17 miRNAs and created specific primers for 12 of these miRNAs. The levels of six EV miRNAs were significantly decreased in postoperative OCC serum compared to those in preoperative OCC serum. In contrast, no significant change was observed between the pre and postoperative values in the control group. We identified OCC tissue-specific miRNAs in the EVs secreted by OCC tissues. These EV miRNAs have potential for use as biomarkers for the early diagnosis and detection of OCC.

Use of psychotropic drugs and drugs with anticholinergic properties among residents with dementia in intermediate care facilities for older adults in Japan: a cohort study.

OBJECTIVES: To evaluate the prescription and discontinuation of psychotropic drugs (PD) and drugs with anticholinergic properties (DAP) in residents with dementia admitted to Roken, a major type of long-term care facility in Japan. DESIGN: Cohort study. SETTING: A nationwide questionnaire survey across 3598 Roken in Japan in 2015 (up to five randomly selected residents per facility). PARTICIPANTS: This study included 1201 residents from 343 Roken (response rate: 10%). We determined the presence and severity of dementia using a nationally standardised measure. PRIMARY AND SECONDARY OUTCOME MEASURES: Prescriptions of PD and DAP at admission and 2 months after admission were evaluated. Multivariable logistic regression was used to evaluate the associations of residents' baseline characteristics with prescriptions or discontinuation. RESULTS: Prescription rates decreased for antidementia drugs (19.4% to 13.0%), hypnotics (25.1% to 22.6%) and anxiolytics (12.3% to 10.7%), whereas those for other PD, such as antipsychotics (13.2% to 13.6%), antidepressants (7.4% to 6.7%), antiepileptic drugs (7.1% to 7.8%) and DAP (35.2% to 36.6%) did not statistically significantly decrease. Some factors were associated with the prescriptions, for example, for antipsychotics, older age (≥85 years) (adjusted OR (aOR), 0.60; 95% CI 0.43 to 0.85) and being bedridden (aOR 0.67; 95% CI 0.47 to 0.97) were associated with a lower use of antipsychotics, whereas severe dementia was associated with a higher use of antipsychotics (aOR 3.26; 95% CI 2.26 to 4.70). At an individual level, a quarter of residents prescribed PD or DAP at admission had discontinued at least one PD or DAP, respectively, 2 months after admission. Antidementia drug use in severe dementia (aOR 1.86; 95% CI 1.04 to 3.31) and PD use in older age (aOR 1.61; 95% CI 1.00 to 2.60; in residents with disabling dementia) were associated with discontinuation. CONCLUSIONS: There is possible scope for deprescribing PD and DAP in Roken residents with dementia to mitigate the risks of adverse events.

Pelvic Abscess after Cesarean Section Treated with Laparoscopic Drainage.

Cesarean section (CS), the rate of which is increasing worldwide, may be associated with complications. Although pelvic abscess after CS is rare, it is difficult to treat. We herein report two cases of pelvic abscess treated laparoscopically after CS. The abscesses of the patients were located in the pouch of Douglas and the uterine scar after CS, respectively. Several days after CS, the patients presented with lower abdominal pain and fever. Laparoscopic drainage was performed because imaging revealed a pelvic abscess that was not amenable to drainage through interventional radiology. The patients recovered from infection and were discharged four days after drainage.

Effects of neuromuscular electrical stimulation on pulmonary alveola and cytokines in chronic obstructive pulmonary disease (COPD) and skeletal muscle atrophy model mice.

[Purpose] It has been reported that exercise affects skeletal muscle in the chronic obstructive pulmonary disease (COPD) disease model. In this study, we examined the effects of neuromuscular electrical stimulation (NMES) in skeletal muscle on alveoli and cytokines. [Materials and Methods] We used twenty wild-type mice, randomly divided into three groups: Group A: Control (non-COPD, non-amyotrophia, non-NMES), Group B: COPD, amyotrophia with NMES and Group C: COPD, amyotrophia without NMES. Among those, a group of mice with ages from 12 to 14 weeks were used to create a chronic obstructive pulmonary disease (COPD) model, a group of mice with ages from 15 to 16 weeks was used to create a disuse syndrome by hind limb suspension, and a group of mice with ages from 17 to 28 weeks (12 weeks) were used to implement NMES. In this study, we used the real-time PCR method to assess the mRNA expression levels. We also conducted morphological analysis, assessed macrophage expression level by staining (general staining and immunostaining), and employed spirometry. [Results] Our study results showed significant decreases in Interleukin-6 (IL-6) levels in the lungs and muscle RING-finger protein-1 (MuRF1) in the muscles. Moreover, the pulmonary stromal macrophage marker (F4/80) and the protease marker (MMP12) showed significantly decreased expression, while no change was observed in the morphological of the alveolar spaces (mean linear intercept). [Conclusion] On the basis of these findings, our study reveals that NMES affects cytokines and macrophages in COPD skeletal muscle atrophy.

Physical Function and Cardio-Ankle Vascular Index in Elderly Heart Failure Patients.

The number of heart failure patients is increasing rapidly in Japan because of its large elderly population. As age increases, arterial stiffness and physical dysfunction progress. This study aimed to evaluate the association between the physical function and arterial stiffness in elderly heart failure patients.This retrospective, observational study includes data from 100 heart failure patients aged ≥ 65 years who were admitted to our hospital and underwent cardiac rehabilitation. The Cardio-Ankle Vascular Index (CAVI) was measured as an indicator of arterial stiffness. Body composition was assessed by bioelectrical impedance analysis. To determine the degree of physical function, we assessed handgrip strength, five-meter walk speed (5MWS), five-repetition sit-to-stand time (5RSST) and six-minute walk distance (6MWD). Sarcopenia was defined using Asian guidelines based on physical function and body composition.Among 100 patients, 47.0% of patients had sarcopenia. After adjustments for age, sex, atrial fibrillation, and ischemic cardiomyopathy, CAVI was significantly higher in with sarcopenia patients than those without sarcopenia. Age, handgrip strength, 5MWS, 5RSST, and 6MWD were associated with CAVI, and 6MWD was as an independent determinant factor of CAVI.6MWD was recognized as an accurate physical function indicator. These findings suggested that physical function and arterial stiffness complement each other. To restore cardiac dysfunction, improving both arterial stiffness and physical function might be useful.

Utilization of drugs for the management of cardiovascular diseases at intermediate care facilities for older adults in Japan.

OBJECTIVES: No established approaches exist for the pharmacological management of cardiovascular diseases (CVDs) in residents of long-term care facilities (LTCFs). This study aimed to evaluate the use of drugs for CVD prevention and treatment (CVD-related drugs) in a major type of LTCF in Japan. METHODS: This study included 1318 randomly selected residents at 349 intermediate care facilities for older adults (called Roken). Prescriptions were investigated at admission and two months after admission according to therapeutic categories. Logistic regression was used to identify residents' characteristics that were associated with prescriptions of CVD-related drugs. RESULTS: Prescriptions of all types of drugs and CVD-related drugs decreased in 36 % and 16 % of residents, respectively. Half of the residents received antihypertensives, a quarter received antiplatelets and diuretics, whereas one-tenth received antidiabetics, oral anticoagulants, and lipid-modifying drugs. The prevalence of most of individual drug categories were similar among residents with different physical or cognitive function, except for fewer antihypertensive and lipid-modifying drugs in those with severe cognitive disability. Adjusted analyses for prescriptions at two months after admission revealed that bedridden residents were more likely to be prescribed diuretics but less likely to be prescribed antihypertensives, antiplatelets, or lipid-modifying drugs. Residents with severe cognitive disability were less likely to be prescribed antihypertensives or lipid-modifying drugs. A known history of cardiovascular events was associated with greater use of CVD-related drugs. CONCLUSION: CVD-related drugs were commonly prescribed for Roken residents, including those with low physical and cognitive functions. Deprescribing may contribute to the optimization of pharmacotherapy in LTCF residents.

A case of ovarian clear cell carcinoma arising from ovarian mature cystic teratoma.

BACKGROUND: It is well known that ovarian mature cystic teratomas (MCTs) occasionally go through malignant transformations. Among these, approximately 75% of histological types are squamous cell carcinoma, with the other types being exceptionally rare. We report an extremely rare case of ovarian clear cell carcinoma arising from ovarian mature cystic teratoma. CASE PRESENTATION: The case was a 71-year-old woman with abdominal distention. Ultrasonography and magnetic resonance imaging showed a huge mass in her abdominal cavity. Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed FDG uptake not only in the pelvic tumor but also in the hepatic nodule, thus suggesting metastases. We performed a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and an omentectomy. The pathological diagnosis showed clear cell carcinoma of the right ovary which arose from the MCT with malignant transformation pT2aNXM1. Although the patient underwent chemotherapy, she died after 17 months. CONCLUSION: This case is histologically characteristic of the proof of transition from simple squamous epithelium via simple glandular epithelium to papillary change with atypia. This is the first case report of unaccompanied clear cell carcinoma arising from MCT reported in English literatures.

Intraperitoneal cytology after laparoscopic hysterectomy in patients with endometrial cancer: A retrospective observational study.

The aim of this study was to evaluate the dissemination of cancer cells at laparoscopic hysterectomy according to the intraperitoneal cytology.Patients with endometrial cancer underwent total laparoscopic modified radical hysterectomy. Peritoneal wash cytology was performed on entering the peritoneal cavity before surgical preparation and just after hysterectomy.Seventy-eight patients underwent laparoscopic hysterectomy for endometrial cancer. Among the 15 patients who had positive intraperitoneal cytology on entering the peritoneal cavity, 10 converted to negative intraperitoneal cytology after hysterectomy. In contrast, among the 63 patients who had negative intraperitoneal cytology on entering the peritoneal cavity, 2 converted to positive intraperitoneal cytology after hysterectomy.While surgery can reduce the number of cancer cells in the peritoneal cavity, leakage can occur, as seen in some cases of hysterectomy. Careful washing must be performed after hysterectomy.

Effects of simplified lymph drainage on the body: in females with menopausal disorder.

[Purpose] Hormone replacement therapy has been reported to be effective for alleviating menopausal symptoms, its side effects have been a concern. Therefore, it is necessary to investigate methods that could alleviate menopausal symptoms but with fewer side effects. Few previous reports have investigated the effects of simplified, viable manual lymph drainage, particularly the effects of one-time therapy on physiologically active substances and other variables. Effects of one-time simplified lymph drainage performed at salon A were investigated in females with any type of menopausal symptoms, such as edema or a sense of fatigue. [Subjects and Methods] Before and after lymph drainage, saliva was collected to detect substances that would reveal immune function. Questionnaire surveys were also conducted before and after therapy. [Results] Cortisol and dehydroepiandrosterone levels were significantly reduced after therapy compared with those before therapy. The questionnaire survey showed a significant decrease in the visual analog scale. Also apparent were positive opinions, such as "I feel better" and "My legs feel lighter." [Conclusion] These results demonstrated the stress reduction effect of one-time simplified lymph drainage, which decreased cortisol and dehydroepiandrosterone levels. This therapy was also shown to produce positive mental and physical effects.

Amino Acid Metabolomics Using LC-MS/MS: Assessment of Cancer-Cell Resistance in a Simulated Tumor Microenvironment.

We performed a comprehensive quantification of 20 amino acids in RPMI 1640 medium-cultured human colorectal adenocarcinoma cells to evaluate the efficacy of 5-fluorouracil treatment under hypoxic and hypoglycemic conditions, which mimic the tumor microenvironment. In this study, we developed a simple and comprehensive analytical method by using LC-MS/MS connected to the Intrada amino acid column, which eluted amino acids within 9 min. The present method covered a linearity range of 3.6 - 1818 µM, except for Gly (227 - 1818 µM), Ala, Asp, His (7.1 - 1818 µM each), and Trp (3.6 - 909 µM). The limits of detection were in the range of 0.02 - 38.0 pmol per injection in a standard solution. Amino acid concentration data were analyzed using principal-component analysis to represent samples on two-dimensional graphs. Linear discriminant analysis was used to classify samples on the score plots. Using this approach, the effect of 5-fluorouracil treatment could be successfully discriminated at high discrimination rates. Moreover, several amino acids were extracted from corresponding loading plots as candidate markers for distinguishing the effects of the 5-fluorouracil treatment or tumor microenvironmental conditions. These results suggest that our proposed method might be a useful tool for evaluating the efficacy of anticancer drugs in the tumor microenvironment.

Structural Optimization of Ghrelin Receptor Inverse Agonists to Improve Lipophilicity and Avoid Mechanism-Based CYP3A4 Inactivation.

Structural optimization of 2-aminonicotinamide derivatives as ghrelin receptor inverse agonists is reported. So as to avoid mechanism-based inactivation (MBI) of CYP3A4, 1,3-benzodioxol ring of the lead compound was modified. Improvement of the main activity and lipophilicity was achieved simultaneously, leading to compound 18a, which showed high lipophilic ligand efficiency (LLE) and low MBI activity.

Orally active ghrelin receptor inverse agonists and their actions on a rat obesity model.

A series of 2-alkylamino nicotinamide analogs was prepared as orally active ghrelin receptor (ghrelinR) inverse agonists. Starting from compound 1, oral bioavailability was improved by modifying metabolically unstable sites and reducing molecular weight. Brain-permeable compound 33 and compound 24 with low brain permeability were tested in rat models of obesity; 30 mg/kg of compound 33 suppressed weight gain. PK/PD analysis revealed that the anti-obesity effect of ghrelinR inverse agonists depends on their brain concentrations.

2-Aminoalkyl nicotinamide derivatives as pure inverse agonists of the ghrelin receptor.

New inverse agonists of the ghrelin receptor (ghrelinR) were obtained through high-throughput screening and subsequent structural modification of 2-aminoalkyl nicotinamide derivatives. The key structural feature to improve in vitro activity was the introduction of a diazabicyclo ring at the 5-position of the pyridine ring. The final product showed potent inverse agonist activity and, despite its low brain permeability, reduced food intake in both normal and obese mice. These results implied that peripheral ghrelinR activity is important for appetite control and that a peripheral ghrelinR inverse agonist could be an anti-obesity drug with reduced risk of central nervous system (CNS)-related side effects.