Quality indicators for integrating oncology and home palliative care in Japan: modified Delphi study.

CONTEXT: Home palliative care service increases the chance of dying at home, particularly for patients with advanced cancer, but late referrals to home palliative care services still exist. Indicators for evaluating programs that can facilitate the integration of oncology and home palliative care have not been defined. OBJECTIVES: This study developed quality indicators for the integration of oncology and home palliative care in Japan. METHODS: We conducted a systematic literature review (Databases included CENTRAL, MEDLINE, EMBASE, and Emcare) and a modified Delphi study to develop the quality indicators. Panelists rated a potential list of indicators using a 9-point scale over three rounds according to two criteria: appropriateness and feasibility. The criterion for the adoption of candidate indicators was set at a total mean score of 7 or more. Final quality indicators with no disagreement were included. RESULTS: Of the 973 publications in our initial search, 12 studies were included. The preliminary list of quality indicators by systematic literature review comprised 50 items. In total, 37 panelists participated in the modified Delphi study. Ultimately, 18 indicators were identified from the following domains: structure in cancer hospitals, structure in home palliative care services, the process of home palliative care service delivery, less aggressive end-of-life care, patient's psychological comfort, caregiver's psychological comfort, and patient's satisfaction with home palliative care service. CONCLUSION: Comprehensive quality indicators for the integration of oncology and home palliative care were identified. These indicators may facilitate interdisciplinary collaboration between professional healthcare providers in both cancer hospitals and home palliative care services.

Glucocorticoid treatment is associated with ICU-acquired hypernatremia: a nested case-control study.

BACKGROUND: Hypernatremia is a major electrolyte disorder associated with death among critically ill patients. Glucocorticoid therapy may cause hypernatremia in refractory septic shock patients, but the association between glucocorticoid and intensive care unit (ICU)-acquired hypernatremia (IAH) remains unclear. The aim of this study was to clarify whether glucocorticoid administration was associated with IAH. METHODS: This was a nested case-control study using data from an established cohort including 121 IAH cases identified from 1756 patients who were admitted to ICU in a tertiary care facility in Japan. We included patients who were admitted with a normal range of serum sodium concentrations (130-149 mEq/L) from January 1, 2013 to December 31, 2015 and remained in ICU for ≥ 2 days. Hypernatremia was defined as serum sodium concentration ≥ 150 mEq/L. Each case was matched to one control. RESULTS: Multivariable conditional logistic regression revealed high-dose glucocorticoid {odds ratio (OR), 4.15 [95% confidence interval (CI) 1.29-13.4]}, acute kidney injury (AKI) [OR, 2.72 (95% CI 1.31-5.62)], and osmotic diuretics [OR, 3.44 (95% CI 1.41-8.39)] to be significantly associated with IAH. The contents and amounts of fluid infusion were not significantly associated with IAH. There were also significant duration-response effects between duration of glucocorticoid use and IAH; however, pulse glucocorticoid administration was not associated with IAH. CONCLUSION: In this nested case-control study, we demonstrated a significant association between IAH and high-dose glucocorticoid with significant duration-response effects. Serum sodium concentrations should be monitored carefully in critically ill patients administered prolonged high-dose glucocorticoid.

[A Case of Extranodal NK/T-Cell Lymphoma with Perforation of the Small Intestine].

A rare case of extranodal NK/T-cell lymphoma(ENKL)with small intestinal perforation is reported. A 92-year-old man was admitted for a loss of consciousness. Computed tomography(CT)scan revealed the presence of an intraperitoneal abscess that was drained. Two days later, the drained fluid changed to intestinal juice, and intestinal perforation was suspected. The patient underwent surgery which revealed a 1 cm perforation site in the ileum. A high fever continued after surgery, and malignant lymphoma was diagnosed from pathological findings; however, further treatment could not be performed. He died 24 days after the operation. Pathological dissection revealed metastasis of ENKL at the systemic lymph nodes.

Comparison of antibody molecules produced from two cell lines with contrasting productivities and aggregate contents.

Cell culture processes that produce therapeutic antibodies with high productivity (titer) and low aggregate content reduce the risk of adverse effects and expense to patients. To elucidate the mechanism of aggregate formation, we compared trastuzumab samples produced from two contrasting cell lines: cell line A, which exhibits high titer and low aggregate content, and cell line B, which exhibits low titer and high aggregate content. Cell line B produced significantly fewer (approximately 1/3) antibodies compared with cell line A and contained higher (approximately 3-fold) percentages of aggregates. The aggregates of antibodies found in the protein A-purified samples of cell line B were associated mostly with noncovalent interactions. Cell line B exhibited a low content of monomers/dimers of light chains in the medium and within cells. Because light chains are essential for the correct folding of heavy chains and secretion of mature antibodies, the characteristics of cell line B may be attributed to low levels of light chain production. In addition, protein A-purified antibodies from cell line B (but not those from cell line A) contained fragments that are expected to expose the hydrophobic CH3 domain, which may serve as nuclei for aggregation.

Effects of medetomidine and xylazine on intraocular pressure and pupil size in healthy Beagle dogs.

OBJECTIVE: To determine the effects of intramuscular (IM) administration of medetomidine and xylazine on intraocular pressure (IOP) and pupil size in normal dogs. STUDY DESIGN: Prospective, randomized, experimental, crossover trial. ANIMALS: Five healthy, purpose-bred Beagle dogs. METHODS: Each dog was administered 11 IM injections of, respectively: physiological saline; medetomidine at doses of 5, 10, 20, 40 and 80 µg kg(-1), and xylazine at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg kg(-1). Injections were administered at least 1 week apart. IOP and pupil size were measured at baseline (before treatment) and at 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours post-injection. RESULTS: A significant decrease in IOP was observed at 6 hours after 80 µg kg(-1) medetomidine compared with values at 0.25 and 0.50 hours, although there were no significant changes in IOP from baseline. In dogs treated with 8.0 mg kg(-1) xylazine, significant reductions in IOP were observed at 4 and 5 hours compared with that at 0.25 hours after administration. In dogs treated with 5, 10, 20 and 40 µg kg(-1) medetomidine and 0.5, 1.0 and 2.0 mg kg(-1) xylazine, there were no significant changes in IOP. Pupil size did not change significantly after any of the medetomidine or xylazine treatments compared with the baseline value. CONCLUSIONS AND CLINICAL RELEVANCE: Low or moderate doses of medetomidine or xylazine did not induce significant changes in IOP or pupil size. In contrast, high doses of medetomidine or xylazine induced significant changes up to 8 hours after treatment, but values remained within the normal canine physiological range. The results of this study suggest a lack of significant change in IOP and pupil size in healthy dogs administered low or moderate doses of xylazine or medetomidine.

Identification and quantification of amyloid beta-related peptides in human plasma using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Proteolytic processing of the amyloid precursor protein (APP) by ß-secretase and γ-secretase leads to the generation and deposition of amyloid ß (Aß) in Alzheimer's disease (AD). N-terminally or C-terminally truncated Aß variants have been found in human cerebrospinal fluid and cultured cell media using immunoprecipitation and mass spectrometry. Unfortunately, the profile of plasma Aß variants has not been revealed due to the difficulty of isolating Aß from plasma. We present here for the first time studies of Aß and related peptides in human plasma. Twenty-two Aß-related peptides including novel peptides truncated before the ß-secretase site were detected in human plasma and 20 of the peptides were identified by tandem mass spectrometry. Using an internal standard, we developed a quantitative assay for the Aß-related peptides and demonstrated plasma dilution linearity and the precision required for their quantitation. The present method should enhance the understanding of APP processing and clearance in AD progression.

Safety of cannabidiol products as a social issue: A case series.

Background: Cannabidiol (CBD) products have increased in popularity in Japan in recent years, particularly among young people. Some CBD products contain tetrahydrocannabinol (THC), the main ingredient of cannabis, and its analogs, which are illegal in Japan and have become a social issue. This report discusses the safety of CBD products. Case Presentation: Five patients with symptoms of CBD ingestion, including nausea, presented to our hospital. Three of the products these patients ingested contained THC. Metabolites of THC were detected in the blood and urine of all three patients, although there were some discrepancies in the urine drug screening test (DS10®). These examination results differed even when the same product was consumed. Conclusion: CBD products are unsafe and may unintentionally contain THC. It is also important to understand that CBD can turn into THC, and the effective time needed to conduct urine drug screening.

A rare case of synchronous double primary hepatocellular carcinoma and intrahepatic cholangiocarcinoma: A case report.

INTRODUCTION: Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are two primary liver cancers. Synchronous occurrence of both types is rare. Here, we present a case of synchronous, double primary liver cancer in a patient who underwent successful surgical resection. PRESENTATION OF A CASE: A 77-year-old woman presented with two suspected liver tumors. Dynamic computed tomography (CT) and ethoxybenzyl-magnetic resonance imaging revealed two lesions, one in hepatic segments S8/4 and another in S5. Positron emission tomography (PET)/CT scans revealed an elevated maximum standardized uptake value (SUVmax) of 5.7 in the S8/4 tumor, and no elevation in the S5 tumor. The S8/4 tumor was diagnosed as either ICC or mixed-type liver cancer, while the S5 tumor was confirmed HCC. Surgical resection confirmed the diagnosis, while pathology identified the S8/4 tumor as ICC and the S5 tumor as HCC. Two months post-operation, the patient received adjuvant chemotherapy and completed eight courses with no recurrence one year later. DISCUSSION: Synchronous double-primary HCC and ICC is uncommon and exhibits diagnostic and therapeutic challenges. Notably, PET-CT scans can differentiate between the two cancers, with HCC typically showing similar uptake to the background liver tissue, whereas ICC is often found with higher accumulation. This highlights the potential utility of PET/CT in preoperative diagnoses and the potential benefit of postoperative adjuvant chemotherapy in patients with double primary HCC and ICC. CONCLUSION: We report a successful case of synchronous double primary liver cancer, emphasizing the potential role of PET/CT in preoperative differentiation, and the efficacy of postoperative adjuvant chemotherapy.

Surgical resection of double advanced pancreatic neuroendocrine tumors with multiple renal cell carcinoma associated with von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease, an autosomal dominant genetic disorder caused by a germline mutation, is associated with non-functional and slow-growing pancreatic neuroendocrine tumor (PNET) and kidney cancer. We describe the case of a 46 year-old man with a 35 mm mass in the pancreatic head causing stricture of the bile duct and main pancreatic duct, a 55 mm mass in the pancreatic tail causing obstruction of the splenic vein (SV), and multiple masses of > 36 mm on both kidneys. We performed a two-stage resection. First, a total pancreatectomy with superior mesenteric vein (SMV) resection and reconstruction and retroperitoneoscopic right partial nephrectomy (NP) for five lesions was performed, followed by retroperitoneoscopic left partial NP of the five lesions 6 months later. Postoperative histopathological examination revealed NET G2 in the pancreatic head with SMV invasion and somatostatin receptor type 2A (SSTR2A) positivity, NET G2 in the pancreatic tail showed SV invasion and negative SSTR2A, and multiple clear cell renal cell carcinomas (RCC) were also noted. Multiple liver recurrences occurred 22 months after primary surgery. The patient remains alive 41 months after primary surgery. Kidney cancer generally determines VHL prognosis; however, we experienced dual-advanced PNETs with a more defined prognosis than multiple RCC associated with VHL.

Sphingosine-1-phosphate receptor 1/5 selective agonist alleviates ocular vascular pathologies.

Ocular abnormal angiogenesis and edema are featured in several ocular diseases. S1P signaling via S1P1 likely is part of the negative feedback mechanism necessary to maintain vascular health. In this study, we conducted pharmacological experiments to determine whether ASP4058, a sphingosine 1-phosphate receptor 1/5 (S1P1/5) agonist, is useful in abnormal vascular pathology in the eye. First, human retinal microvascular endothelial cells (HRMECs) were examined using vascular endothelial growth factor (VEGF)-induced cell proliferation and hyperpermeability. ASP4058 showed high affinity and inhibited VEGF-induced proliferation and hyperpermeability of HRMECs. Furthermore, S1P1 expression and localization changes were examined in the murine laser-induced choroidal neovascularization (CNV) model, a mouse model of exudative age-related macular degeneration, and the efficacy of ASP4058 was verified. In the CNV model mice, S1P1 tended to decrease in expression immediately after laser irradiation and colocalized with endothelial cells and Müller glial cells. Oral administration of ASP4058 also suppressed vascular hyperpermeability and CNV, and the effect was comparable to that of the intravitreal administration of aflibercept, an anti-VEGF drug. Next, efficacy was also examined in a retinal vein occlusion (RVO) model in which retinal vascular permeability was increased. ASP4058 dose-dependently suppressed the intraretinal edema. In addition, it suppressed the expansion of the perfusion area observed in the RVO model. ASP4058 also suppressed the production of VEGF in the eye. Collectively, ASP4058 can be a potential therapeutic agent that normalizes abnormal vascular pathology, such as age-related macular degeneration and RVO, through its direct action on endothelial cells.

Multi epitope-targeting immunoprecipitation using F(ab') fragments with high affinity and specificity for the enhanced detection of a peptide with matrix-assisted laser desorption ionization-time-of-flight mass spectrometry.

Human plasma has been frequently studied using mass spectrometry for new biomarker discovery, although detection of low-abundance biological molecules can be challenging due to sample complexity and dynamic protein concentration ranges of plasma proteins. While immunoprecipitation coupled with mass spectrometric analysis is an essential method for overcoming this difficulty, its sensitivity can be insufficient to detect clinically relevant circulating biomarkers because of limited antibody affinity or specificity. To increase antibody affinity, we developed a strategy using a F(ab') fragment coupled to polyethylene glycol. We produced hetero-F(ab')-(PEG)24 beads composed of two monoclonal antiamyloid ß antibodies (6E10 and 4G8) that are specific for different epitopes of amyloid ß and assessed the detection limit of amyloid ß(1-28)-spiked human plasma. In human plasma, the detection limit of amyloid ß(1-28) was 6.14 pM, which was 25- to 50-fold more sensitive than single IgG-protein G beads. In addition, an introduction of polyethylene glycol as a linker reduced nonspecific binding, leading to highly specific MS detection. Finally, the present IP method enabled the detection of endogenous amyloid ß(1-40) in 250 µL of human plasma with matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). This technique provides a powerful approach for enhancing the sensitivity and specificity of immunoprecipitation (IP)-MS for detection of low-abundance peptides in plasma and has the potential to accelerate MS-based clinical applications.

Improvement of mass spectrometry analysis of glycoproteins by MALDI-MS using 3-aminoquinoline/α-cyano-4-hydroxycinnamic acid.

Protein glycosylation analysis is important for elucidating protein function and molecular mechanisms in various biological processes. We previously developed a glycan analysis method using a 3-aminoquinoline/α-cyano-4-hydroxycinnamic acid liquid matrix (3-AQ/CHCA LM) and applied it to the quantitative glycan profiling of glycoproteins. However, information concerning glycosylation sites is lost; glycopeptide analysis is therefore required to identify the glycosylation sites in glycoproteins. Human epidermal growth factor receptor 2 (HER2) is a glycoprotein that plays a role in the regulation of cell proliferation, differentiation, and migration. Several reports have described the structure of HER2, but the structures of N-glycans attached to this protein remain to be fully elucidated. In this study, 3-AQ/CHCA LM was applied to tryptic digests of HER2 to reveal its N-glycosylation state and to evaluate the utility of this LM in characterizing glycopeptides. Peptide sequence coverage was considerably improved compared to analysis of HER2 using α-cyano-4-hydroxycinnamic acid or 2,5-dihydroxybenzoic acid. Most of the peaks observed using only this LM were localized at the inner or outer regions of sample spots. Furthermore, five of the peptide peaks that were enriched within the inner region were confirmed to be glycosylated by MS/MS analysis. Three glycosylation sites were identified and their glycan structures were elucidated. The reduction in sample complexity by on-target separation allowed for higher sequence coverage, resulting in effective detection and characterization of glycopeptides. In conclusion, these results demonstrate that MS-based glycoprotein analysis using 3-AQ/CHCA is an effective method to identify glycosylation sites in proteins and to elucidate the glycan structures of glycoproteins in complex samples.

Adiponectin attenuates human eosinophil adhesion and chemotaxis: implications in allergic inflammation.

OBJECTIVE: Growing evidence has shown an association between obesity and asthma. Adiponectin, an adipocyte-derived cytokine, is known to have anti-inflammatory effects with reduced concentrations in obese subjects. Recent findings raised the intriguing possibility that adiponectin might play a role in allergic inflammation, although the mechanistic basis for their relationship remains unclear. The purpose of this study was to examine whether adiponectin might affect functions of eosinophils, which play an important role in the pathogenesis of asthma. METHODS: Human peripheral blood eosinophils were purified to study expression of adiponectin receptors AdipoR1 and AdipoR2 using RT-PCR and flow cytometry. The effect of adiponectin on eosinophil survival was investigated using annexin V and propidium iodide staining. Eotaxin-induced cell adhesion was investigated using ICAM-1-coated plates. A Boyden chamber and real-time horizontal migration system were used for eotaxin-directed chemotaxis assay. Expression of eotaxin receptor CCR3 and intracellular calcium influx were assessed by flow cytometry. RESULTS: AdipoR1 and AdipoR2 were expressed in human eosinophils. Adiponectin did not affect eosinophil survival or CCR3 expression; however, eotaxin-enhanced adhesion was inhibited by pretreatment with adiponectin. Adiponectin also diminished eotaxin-directed chemotactic responses by disturbing both velocity and directionality. Calcium influx in response to eotaxin was attenuated by adiponectin. CONCLUSIONS: These results indicate that adiponectin attenuates the eosinophil functions induced by eotaxin without affecting cell viability. The inhibitory effect was associated with diminished calcium signaling rather than altering of surface receptor expression. Increasing circulating adiponectin might be a novel therapeutic modality for treatment of asthma, especially in obese asthmatics.

Self-organizing map analysis using multivariate data from theophylline tablets predicted by a thin-plate spline interpolation.

The "quality by design" concept in pharmaceutical formulation development requires the establishment of a science-based rationale and a design space. We integrated thin-plate spline (TPS) interpolation and Kohonen's self-organizing map (SOM) to visualize the latent structure underlying causal factors and pharmaceutical responses. As a model pharmaceutical product, theophylline tablets were prepared based on a standard formulation. The tensile strength, disintegration time, and stability of these variables were measured as response variables. These responses were predicted quantitatively based on nonlinear TPS. A large amount of data on these tablets was generated and classified into several clusters using an SOM. The experimental values of the responses were predicted with high accuracy, and the data generated for the tablets were classified into several distinct clusters. The SOM feature map allowed us to analyze the global and local correlations between causal factors and tablet characteristics. The results of this study suggest that increasing the proportion of microcrystalline cellulose (MCC) improved the tensile strength and the stability of tensile strength of these theophylline tablets. In addition, the proportion of MCC has an optimum value for disintegration time and stability of disintegration. Increasing the proportion of magnesium stearate extended disintegration time. Increasing the compression force improved tensile strength, but degraded the stability of disintegration. This technique provides a better understanding of the relationships between causal factors and pharmaceutical responses in theophylline tablet formulations.

Iontophoretic transdermal delivery of glycyrrhizin: effects of pH, drug concentration, co-ions, current intensity, and chemical enhancers.

The aim of the present study was to evaluate the feasibility of transdermal delivery of glycyrrhizin, an agent used in the treatment of chronic hepatitis C, by cathodal iontophoresis using Ag/AgCl electrodes in vitro. The effects of donor pH (pH 4-7), concentration of drug (0.025-0.2% (w/v)), concentration of external chloride ions (Cl(-)) (0-133 mM), current strength (0-0.5 mA/cm(2)), and permeation enhancers (urea and Tween 80) on the skin permeability of glycyrrhizin were examined in in vitro skin permeation studies using porcine ear skin as the membrane. The cumulative amount of permeated glycyrrhizin and the steady-state skin permeation flux of glycyrrhizin across porcine skin increased in a pH-dependent manner. The skin permeability of glycyrrhizin was independent of the concentration of drug and competed only with a high external Cl(-) concentration. The skin permeation flux of glycyrrhizin increased with the current (R(2)=0.8955). The combination of iontophoresis and enhancers provided an additive or synergistic effect, and a skin permeation flux of about 60 µg/h/cm(2) was achieved. The plasma concentration of glycyrrhizin in humans, extrapolated from the in vitro steady-state permeation flux across porcine skin, was within the therapeutic level. These results suggest that cathodal iontophoresis can be used as a transdermal drug delivery system for glycyrrhizin using reasonable patch sizes and acceptable levels of current intensity.

A Case of Mesangial Proliferative Nephritis Caused by Slow Cryoglobulin.

The patient was a woman in her 60s. She was found to have proteinuria on a health checkup. She did not have any particular subjective symptoms, and no definitive diagnosis was made, despite serological findings indicative of immune abnormalities. A renal biopsy was performed. Light microscopy of renal tissue section revealed mesangial proliferative nephritis. Electron microscopic findings included electron-dense deposits and fibrillar/tubular structures with a diameter of 20-30 nm. These findings suggested the presence of cryoglobulin (CG), but CG was not detected in qualitative or quantitative hematologic tests. Thus, the serum samples were stored at 37°C for a long period of time and then cooled to 4°C. When the obtained precipitates were examined, CG was successfully detected. CG that precipitates only after a long period of time is referred to as slow cryoglobulin (sCG), and sCG is extremely rare. The present case is the first documented case, to our knowledge, of renal disorders caused by sCG. It should be noted that there are some cases in which it takes much time for CG to precipitate. Thus, when CG cannot be detected, it is necessary to spend much time to determine whether CG precipitates.

Acute acrylamide poisoning with severe symptoms in a short time: a case report.

BACKGROUND: Acrylamide poisoning is often reported as chronic poisoning presenting with peripheral neuropathy or carcinogenic action due to long-term exposure to low concentrations. However, there have been few reports of acute poisoning due to oral ingestion of acrylamide, where the symptoms appear a few hours after ingestion. Here, we report a case of acute acrylamide poisoning where a high concentration was ingested in a short time, resulting in a fatal outcome due to the rapid course of events. CASE PRESENTATION: The patient was an adolescent female who ingested 150 ml (148 g) of acrylamide with suicidal intent. A disorder of consciousness was observed when the emergency medical team arrived 36 min later. An hour later, tracheal intubation and intravenous access were performed at a hospital, and 2 h after that, she was transported to our hospital. After she arrived at the hospital, circulatory dynamics could not be maintained despite vasopressor and colloid osmotic infusion, and hemodialysis could not be introduced. Subsequently, cardiopulmonary arrest occurred, and the patient passed away 7 h after ingestion. In the present case, severe symptoms appeared shortly after acrylamide ingestion, unlike other reported cases. In previous report summarizing animal studies, there was a relationship among the symptoms of acute poisoning, the dose, and onset time. The data from this case were compared to those from previous reports, and we were able to predict the early appearance of severe symptoms based on this comparison. CONCLUSION: The severity of acute acrylamide poisoning by oral ingestion was primarily dependent on the amount and rate of ingestion.

Successful Preoperative QUAD SHOT for Bulky Parotid Carcinoma: Potential Preoperative Ultra-Hypofractionated Radiotherapy for Conversion Surgery.

QUAD SHOT is an ultra-hypofractionated radiotherapy (RT) technique that prescribes 14.0-14.8 Gy over 2 days. Although this technique has already gained some status as an effective palliative treatment for inoperable head and neck cancer (HNC), its application in other situations has not been given much consideration. Herein, we report a case of a 62-year-old woman who received preoperative QUAD SHOT therapy for poorly differentiated parotid carcinoma. In this case, after two courses of QUAD SHOT plus a standard chemotherapy regimen with pembrolizumab, the patient's inoperable, bulky tumor shrank dramatically and became operable. Best of all, while adequate therapeutic effects were achieved, the patient's time commitment and physical exertion were limited. RT during this period consisted of only eight fractions over 4 days. According to previous reports, the response rate for QUAD SHOT is sufficiently high, and the rate of serious adverse events is quite low. This case asks the question of whether the indications for QUAD SHOT irradiation can be expanded as one of the preoperative interventions undertaken by HNC surgeons to achieve conversion surgery.

Angiotensin II type 1 receptor signaling regulates feeding behavior through anorexigenic corticotropin-releasing hormone in hypothalamus.

The activation of renin-angiotensin system contributes to the development of metabolic syndrome and diabetes as well as hypertension. However, it remains undetermined how renin-angiotensin system is implicated in feeding behavior. Here, we show that angiotensin II type 1 (AT(1)) receptor signaling regulates the hypothalamic neurocircuit that is involved in the control of food intake. Compared with wild-type Agtr1a(+/+) mice, AT(1) receptor knock-out (Agtr1a(-/-)) mice were hyperphagic and obese with increased adiposity on an ad libitum diet, whereas Agtr1a(-/-) mice were lean with decreased adiposity on a pair-fed diet. In the hypothalamus, mRNA levels of anorexigenic neuropeptide corticotropin-releasing hormone (Crh) were lower in Agtr1a(-/-) mice than in Agtr1a(+/+) mice both on an ad libitum and pair-fed diet. Furthermore, intracerebroventricular administration of CRH suppressed food intake both in Agtr1a(+/+) and Agtr1a(-/-) mice. In addition, the Crh gene promoter was significantly transactivated via the cAMP-responsive element by angiotensin II stimulation. These results thus demonstrate that central AT(1) receptor signaling plays a homeostatic role in the regulation of food intake by maintaining gene expression of Crh in hypothalamus and suggest a therapeutic potential of central AT(1) receptor blockade in feeding disorders.