Cytochrome P450 and UDP-glucuronosyltransferase expressions, activities, and induction abilities in 3D-cultured human renal proximal tubule epithelial cells.

The role of the kidney as an excretory organ for exogenous and endogenous compounds is well recognized, but there is a wealth of data demonstrating that the kidney has significant metabolizing capacity for a variety of exogenous and endogenous compounds that in some cases surpass the liver. The induction of drug-metabolizing enzymes by some chemicals can cause drug-drug interactions and intraindividual variability in drug clearance. In this study, we evaluated the expression and induction of cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) isoforms in 3D-cultured primary human renal proximal tubule epithelial cells (RPTEC) to elucidate their utility as models of renal drug metabolism. CYP2B6, CYP2E1, CYP3A4, CYP3A5, and all detected UGTs (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7) mRNA levels in 3D-RPTEC were significantly higher than those in 2D-RPTEC and HK-2 cells and were close to the levels in the human kidney cortex. CYP1B1 and CYP2J2 mRNA levels in 3D-RPTEC were comparable to those in 2D-RPTEC, HK-2 cells, and the human kidney cortex. Midazolam 1'-hydroxylation, trifluoperazine N-glucuronidation, serotonin O-glucuronidation, propofol O-glucuronidation, and morphine 3-glucuronidation in the 3D-RPTEC were significantly higher than the 2D-RPTEC and comparable to those in the HepaRG cells, although bupropion, ebastine, and calcitriol hydroxylations were not different between the 2D- and 3D-RPTEC. Treatment with ligands of the aryl hydrocarbon receptor and farnesoid X receptor induced CYP1A1 and UGT2B4 expression, respectively, in 3D-RPTEC compared to 2D-RPTEC. We provided information on the expression, activity, and induction abilities of P450s and UGTs in 3D-RPTEC as an in vitro human renal metabolism model. Significance Statement This study demonstrated that the expression of P450s and UGTs in 3D-RPTEC was higher than those in 2D-RPTEC and HK-2 cells. The results were comparable to that in the human kidney cortex. 3D-RPTEC are useful for evaluating the induction of kidney P450s, UGTs, and human renal drug metabolism in cellulo.

Risk Factors for Developing Metachronous Superficial Gastric Epithelial Neoplasms after Endoscopic Submucosal Dissection.

Background: Although endoscopic submucosal dissection (ESD) provides a high rate of curative resection, the remaining gastric mucosa after ESD is at risk for metachronous superficial gastric epithelial neoplasms (MSGENs). It leaves room for risk factors for developing MSGENs after ESD. This study aimed to identify clinicopathological risk factors for the occurrence of MSGENs, and to evaluate the association of Helicobacter pylori (H. pylori) with the MSGENs. Methods: We conducted a retrospective cohort study including 369 patients with 382 lesions that underwent ESD for adenoma/early gastric cancer. Results: Twenty-seven MSGENs occurred. The subjects were divided into MSGEN and not-MSGEN groups. There was a significantly higher frequency of histological intestinal metaplasia (HIM) and initial neoplasm location in the upper or middle parts (INUM) in the MSGEN group. The HIM and INUM groups had a significantly higher cumulative incidence of MSGENs. We compared 27 patients from the MSGEN group and 27 patients from the not-MSGEN group that were matched to the MSGEN group for variables including HIM and INUM. There was a significantly higher frequency of the spontaneous disappearance of H. pylori in the MSGEN group. Conclusions: HIM, INUM, and the spontaneous disappearance of H. pylori may be clinicopathological risk factors for developing MSGENs after ESD.

Superficial esophageal squamous cell carcinoma with melanocytosis that was endoscopically difficult to differentiate from malignant melanoma.

Esophageal squamous cell carcinoma (SCC) with dark spots caused by melanocytosis is very rare. A reddish and flat lesion, 4 cm in length and covering over two-thirds of the circumference, was found in the midthoracic esophagus of a 66-year-old male. Multiple brown and black spots are observed in the lesion. Superficial SCC with melanocytosis or malignant melanoma was also suspected. Endoscopic submucosal dissection was performed without biopsies of the spots. Histologically, a few melanocytes were observed in the black spots, and the lesion was diagnosed as SCC (T1a-lamina propria mucosae) with melanocytosis. We report a case of esophageal SCC with dark black spots that were difficult to differentiate endoscopically from malignant melanoma.

Hereditary Diffuse Gastric Cancer Treated by Prophylactic Total Gastrectomy.

We herein report a rare case of hereditary diffuse gastric cancer in a Japanese man. A 41-year-old man underwent esophagogastroduodenoscopy which revealed a small gastric erosion. Biopsy specimens showed signet ring cell carcinoma, and endoscopic submucosal dissection was performed. The patient's elder sister had died of gastric cancer at 38 years old. Considering the family history, a genetic test was conducted and revealed a CDH1 germline mutation. Although no carcinomatous lesion was detected endoscopically, prophylactic total gastrectomy was performed. The resection specimen showed seven microlesions of signet ring cell carcinoma confined to the lamina propria mucosae.

Improvement of Protein Expression Profile in Three-Dimensional Renal Proximal Tubular Epithelial Cell Spheroids Selected Based on OAT1 Gene Expression: A Potential In Vitro Tool for Evaluating Human Renal Proximal Tubular Toxicity and Drug Disposition.

The proximal tubule plays an important role in the kidney and is a major site of drug interaction and toxicity. Analysis of kidney toxicity via in vitro assays is challenging, because only a few assays that reflect functions of drug transporters in renal proximal tubular epithelial cells (RPTECs) are available. In this study, we aimed to develop a simple and reproducible method for culturing RPTECs by monitoring organic anion transporter 1 (OAT1) as a selection marker. Culturing RPTECs in spherical cellular aggregates increased OAT1 protein expression, which was low in the conventional two-dimensional (2D) culture, to a level similar to that in human renal cortices. By proteome analysis, it was revealed that the expression of representative two proximal tubule markers was maintained and 3D spheroid culture improved the protein expression of approximately 7% of the 139 transporter proteins detected, and the expression of 2.3% of the 4,800 proteins detected increased by approximately fivefold that in human renal cortices. Furthermore, the expression levels of approximately 4,800 proteins in three-dimensional (3D) RPTEC spheroids (for 12 days) were maintained for over 20 days. Cisplatin and adefovir exhibited transporter-dependent ATP decreases in 3D RPTEC spheroids. These results indicate that the 3D RPTEC spheroids developed by monitoring OAT1 gene expression are a simple and reproducible in vitro experimental system with improved gene and protein expressions compared with 2D RPTECs and were more similar to that in human kidney cortices. Therefore, it can potentially be used for evaluating human renal proximal tubular toxicity and drug disposition. SIGNIFICANCE STATEMENT: This study developed a simple and reproducible spheroidal culture method with acceptable throughput using commercially available RPTECs by monitoring OAT1 gene expression. RPTECs cultured using this new method showed improved mRNA/protein expression profiles to those in 2D RPTECs and were more similar to those of human kidney cortices. This study provides a potential in vitro proximal tubule system for pharmacokinetic and toxicological evaluations during drug development.

Natural History of Small Gastric Subepithelial Lesions Less than 20 mm: A Multicenter Retrospective Observational Study (NUTSHELL20 Study).

BACKGROUND AND AIM: Small gastric subepithelial lesions (SELs) are sometimes encountered in daily esophagogastroduodenoscopy (EGD) practice, but whether once-annual or twice-annual endoscopy can provide sufficient follow-up remains unclear. Because follow-up based on small-SEL characteristics is important, this study clarified the natural history of gastric SELs less than 20 mm. METHODS: This retrospective multicenter observation study conducted at 24 Japanese hospitals during April 2000 to March 2020 examined small gastric SELs of ≤20 mm diameter. The primary outcome was the rate of size increase of those SELs detected using EGD, with growth times assessed irrespective of SEL pathological diagnoses. RESULTS: We examined 824 cases with tumors of 1-5 mm diameter in 298 (36.2%) cases, 6-10 mm in 344 (41.7%) cases, 11-15 mm in 112 (13.6%) cases, and 16-20 mm in 70 (8.50%) cases. An increase of small gastric SELs was observed in 70/824 patients (8.5%). The SELs larger than 6 mm increased, even after 10 years. No-change and increasing groups had no significantly different malignant findings at diagnosis. In cases of gastrointestinal stromal tumors (GISTs), internal cystic change in endoscopic ultrasound (EUS) is a risk factor for an increased tumor size. The predictive tumor growth cutoff size at initial diagnosis was 13.5 mm. CONCLUSIONS: Small gastric SELs less than 20 mm have an approximately 8.5% chance of increase. Predictive markers for GIST growth are tumor size ≥13.5 mm and internal cystic change in EUS.

Size reduction of gastric fundic gland polyposis by de-escalation of acid-suppressive therapy.

The patient, a 73-year-old woman, had been taking acid-suppressive therapy for refractory reflux esophagitis for 10 years. A potassium-competitive acid blocker was administered to strengthen acid-suppressive therapy for worsening symptoms of gastroesophageal reflux disease. Esophagogastroduodenoscopy showed an increase in the number and size of fundic gland polyposis (FGPs). When acid-suppressive therapy was changed from potassium-competitive acid blocker to proton pump inhibitor, the FGPs showed reduced size 1 year later. Furthermore, when acid-suppressive therapy was changed from proton pump inhibitor to histamine-2 receptor antagonist, FGPs were even smaller after 1 and 2 years. The patient, who had no flare-up of gastroesophageal reflux disease symptoms, continues to be treated medically with histamine-2 receptor antagonist. This case report describes changes in endoscopic findings of a patient with FGPs caused by acid-suppressive therapy for refractory gastroesophageal reflux disease.

Advanced Endoscopy for Benign Esophageal Disease: A Review Focused on Non-Erosive Reflux Disease and Eosinophilic Esophagitis.

Advanced endoscopy (AVE) techniques include image-enhanced endoscopy methods, such as narrow-band imaging (NBI), and types of microscopic endoscopy, such as endocytoscopy. In the esophagus, AVE first showed diagnostic utility in the diagnosis of superficial esophageal cancer and was then applied to inflammatory disease. This review focuses on non-erosive reflux disease (NERD) and eosinophilic esophagitis (EoE), which sometimes show no abnormal findings on standard white light endoscopy alone. Studies have demonstrated that advanced endoscopy, including NBI magnification endoscopy and endocytoscopy, improved the diagnostic performance of white-light endoscopy alone for NERD and EoE. In this review, we explain why advanced endoscopy is needed for the diagnosis of these esophageal inflammatory diseases, summarize the study results, and discuss future perspectives.

Making Hematochezia of Unknown Origin Known: A Retrospective Analysis.

INTRODUCTION: Hematochezia is observed frequently in daily practice. However, natural hemostasis often prevents identification of the bleeding source during observations. This study was conducted to clarify risk factors related to rebleeding in hematochezia patients without an identified cause of bleeding. METHODS: We analyzed patients who were admitted to Dokkyo Medical University Hospital during April 1, 2009, through March 31, 2015, with the chief complaint of hematochezia. Main outcome measures included the rebleeding rate and the period until rebleeding in hematochezia patients without an identified bleeding source. RESULTS: We selected 159 patients for analyses. Rebleeding was observed in 46 (28.9%) of 159 patients. The median period until first rebleeding was 166 days (2-3,046 days). Univariate analysis indicated that risk factors for rebleeding were male gender (p = 0.029), higher age (p = 0.023), antithrombotic medicines (p = 0.047), lower hemoglobin on admission (p = 0.024), and the presence of diverticula (p = 0.002). Multivariate analysis indicated the presence of diverticula (p = 0.023) and male gender (p = 0.043) as rebleeding risk factors. DISCUSSION/CONCLUSION: In patients with hematochezia of unknown origin, risk factors for rebleeding indicated in this study, especially the presence of diverticula and male gender, should be given particular attention by physicians.

Curative resection with endoscopic submucosal dissection of early gastric cancer in Helicobacter pylori-negative Ménétrier's disease: A case report.

BACKGROUND: Adult-onset Ménétrier's disease is strongly associated with Helicobacter pylori (H. pylori) infection and an elevated risk of carcinogenesis. Cases of early-stage gastric cancer developed in H. pylori-negative Ménétrier's disease are extremely rare. We report a case of early gastric cancer in H. pylori-negative Ménétrier's disease that was curatively resected with endoscopic submucosal dissection (ESD). CASE SUMMARY: A 60-year-old woman was referred to our hospital after her medical examination detected anemia. Contrast-enhanced upper gastrointestinal (UGI) radiography revealed translucency of the nodule-aggregating surface with giant rugae. Blood tests showed hypoproteinemia and were negative for serum H. pylori immunoglobulin G antibodies. The 99mTc-DTPA-human serum albumin scintigraphy showed protein loss from the stomach. UGI endoscopy showed a 40-mm protruding erythematous lesion on giant rugae of the greater curvature of lower gastric body, suggesting early-stage gastric cancer due to Ménétrier's disease. En bloc resection with ESD was performed for diagnosis and treatment. Histology of ESD showed well-differentiated tubular adenocarcinoma. The cancer was confined to the mucosa, and complete curative resection was achieved. Foveolar hyperplasia and atrophy of the gastric glands were observed in non-tumor areas, histologically corresponding to Ménétrier's disease. Three years after ESD, gastric cancer had not recurred, and Ménétrier's disease remained in remission with spontaneous regression of giant gastric rugae. CONCLUSION: Complete curative resection was achieved through ESD in a patient with early-stage gastric cancer and H. pylori-negative Ménétrier's disease.

Salvage Endoscopic Submucosal Dissection for Local Recurrence of Superficial Esophageal Squamous Cell Cancer after Photodynamic Therapy.

Photodynamic therapy is useful as organ-preservation salvage therapy for residual recurrence of esophageal squamous cell carcinoma after chemoradiation therapy. However, the high residual recurrence rate of photodynamic therapy poses a problem. We herein report a patient who underwent photodynamic therapy for recurrence of superficial esophageal squamous cell carcinoma after chemoradiation therapy. The patient later exhibited another episode of recurrence of superficial esophageal squamous cell carcinoma, and R0 curative resection was obtained with endoscopic submucosal dissection. This suggests that endoscopic submucosal dissection may be an effective treatment option that can achieve R0 resection even for residual superficial cancer after salvage photodynamic therapy.

Decadal variability in land carbon sink efficiency.

BACKGROUND: The climate mitigation target of limiting the temperature increase below 2 °C above the pre-industrial levels requires the efforts from all countries. Tracking the trajectory of the land carbon sink efficiency is thus crucial to evaluate the nationally determined contributions (NDCs). Here, we define the instantaneous land sink efficiency as the ratio of natural land carbon sinks to emissions from fossil fuel and land-use and land-cover change with a value of 1 indicating carbon neutrality to track its temporal dynamics in the past decades. RESULTS: Land sink efficiency has been decreasing during 1957-1990 because of the increased emissions from fossil fuel. After the effect of the Mt. Pinatubo eruption diminished (after 1994), the land sink efficiency firstly increased before 2009 and then began to decrease again after 2009. This reversal around 2009 is mostly attributed to changes in land sinks in tropical regions in response to climate variations. CONCLUSIONS: The decreasing trend of land sink efficiency in recent years reveals greater challenges in climate change mitigation, and that climate impacts on land carbon sinks must be accurately quantified to assess the effectiveness of regional scale climate mitigation policies.

Refractory Immune Checkpoint Inhibitor-Induced Colitis Improved by Tacrolimus: A Case Report.

Immune checkpoint inhibitors (ICIs) increase T-cell activity and antitumor immune response. However, they also have immune-related adverse effects that can affect the gastrointestinal (GI) tract. A 62-year-old male patient who had undergone right lung upper lobectomy for adenocarcinoma of the lung received chemotherapy with pemetrexed sodium hydrate, carboplatin, and pembrolizumab to prevent postoperative recurrence of liver metastasis. However, the patient experienced severe diarrhea four months after the start of chemotherapy. Although a corticosteroid and two biological preparations were administered to alleviate the diarrhea, no improvement was observed. Eventually, remission was achieved when tacrolimus was administered. Treatment with corticosteroids is recommended for patients with GI adverse effects of ICIs. Rapid introduction of infliximab is necessary for refractory patients. Nevertheless, for refractory cases such as that of our patient, for whom even this regimen is inefficacious, tacrolimus might be recommended to induce remission as with cases of ulcerative colitis.

State of the science in reconciling top-down and bottom-up approaches for terrestrial CO2 budget.

Robust estimates of CO2 budget, CO2 exchanged between the atmosphere and terrestrial biosphere, are necessary to better understand the role of the terrestrial biosphere in mitigating anthropogenic CO2 emissions. Over the past decade, this field of research has advanced through understanding of the differences and similarities of two fundamentally different approaches: "top-down" atmospheric inversions and "bottom-up" biosphere models. Since the first studies were undertaken, these approaches have shown an increasing level of agreement, but disagreements in some regions still persist, in part because they do not estimate the same quantity of atmosphere-biosphere CO2 exchange. Here, we conducted a thorough comparison of CO2 budgets at multiple scales and from multiple methods to assess the current state of the science in estimating CO2 budgets. Our set of atmospheric inversions and biosphere models, which were adjusted for a consistent flux definition, showed a high level of agreement for global and hemispheric CO2 budgets in the 2000s. Regionally, improved agreement in CO2 budgets was notable for North America and Southeast Asia. However, large gaps between the two methods remained in East Asia and South America. In other regions, Europe, boreal Asia, Africa, South Asia, and Oceania, it was difficult to determine whether those regions act as a net sink or source because of the large spread in estimates from atmospheric inversions. These results highlight two research directions to improve the robustness of CO2 budgets: (a) to increase representation of processes in biosphere models that could contribute to fill the budget gaps, such as forest regrowth and forest degradation; and (b) to reduce sink-source compensation between regions (dipoles) in atmospheric inversion so that their estimates become more comparable. Advancements on both research areas will increase the level of agreement between the top-down and bottom-up approaches and yield more robust knowledge of regional CO2 budgets.

Land use change and El Niño-Southern Oscillation drive decadal carbon balance shifts in Southeast Asia.

An integrated understanding of the biogeochemical consequences of climate extremes and land use changes is needed to constrain land-surface feedbacks to atmospheric CO2 from associated climate change. Past assessments of the global carbon balance have shown particularly high uncertainty in Southeast Asia. Here, we use a combination of model ensembles to show that intensified land use change made Southeast Asia a strong source of CO2 from the 1980s to 1990s, whereas the region was close to carbon neutral in the 2000s due to an enhanced CO2 fertilization effect and absence of moderate-to-strong El Niño events. Our findings suggest that despite ongoing deforestation, CO2 emissions were substantially decreased during the 2000s, largely owing to milder climate that restores photosynthetic capacity and suppresses peat and deforestation fire emissions. The occurrence of strong El Niño events after 2009 suggests that the region has returned to conditions of increased vulnerability of carbon stocks.

Clinical effectiveness of the pocket-creation method for colorectal endoscopic submucosal dissection.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is a technically advanced procedure for colorectal tumors. Hayashi et al. invented the "pocket-creation method (PCM)," and reported that Is-type lesions with fibrosis could be efficaciously and safely resected. However, only case studies have been published, and there are no previous reports on the usefulness of PCM in colorectal ESD for all lesions, as compared with the conventional method. This study aimed to evaluate the effectiveness and safety of PCM in colorectal ESD. PATIENTS AND METHODS: Ninety-six colorectal tumors were treated: 47 using the PCM and the other 49, considered the control group, using the conventional method. Therapeutic effectiveness and safety were retrospectively assessed. RESULTS: The comparison between the PCM and control groups revealed higher rates of en bloc resection (100 % vs. 88 %, P  = 0.015) and curative endoscopic resection (100 % vs. 84 %, P  = 0.0030) with PCM. There was no significant difference in perforation as an adverse event (AE) between the two groups, though perforation was observed in only 6 % of the control group and none of the PCM group. Compared with the control group, the PCM group had lower incidences of perforation and post-ESD coagulation syndrome, and both AEs were associated with excessive thermal denaturation of the muscle layer (2 % vs. 16 %, P  = 0.018). CONCLUSIONS: This study demonstrated the effectiveness and safety of ESD with PCM for colorectal tumors. Although there is a possible learning curve, PCM enables the endoscopist to safely perform ESD in most cases without encountering the difficulties associated with conventional ESD.

Can tryptophan supplement intake at breakfast enhance melatonin secretion at night?

BACKGROUND: Tryptophan (TRP) is an essential amino acid, and it has been suggested that TRP intake at breakfast combined with daytime bright light exposure can increase nocturnal melatonin secretion. However, the mechanisms involved are not yet clear. The aim of this study was to examine the effect of TRP supplement intake at breakfast on nocturnal melatonin secretion under different daytime light intensities in humans. METHOD: Twelve subjects (aged 21.3 ± 3.0 years, mean ± standard deviation) participated in a random order in experimental sessions lasting 3 days under four conditions in a laboratory setting. The four conditions were TRP*Bright, Placebo*Bright, TRP*Dim, and Placebo*Dim. A TRP capsule (1000 mg) or a placebo starch capsule (1000 mg) were taken at breakfast. In addition, during the daytime (07:00-18:00), the subjects were asked to stay under different light intensities: >5000 lx (bright) or <50 lx (dim). Saliva samples were collected for measuring the concentration of melatonin. The time courses of melatonin concentration and dim light melatonin onset (DLMO) were compared among the four conditions using repeated measurements analysis of variance (ANOVA). RESULT: Nocturnal melatonin concentrations in the bright light condition tended to be higher than in the dim light condition (main effect of light: p = .099). Moreover, in the bright light condition, the change in DLMO between baseline and after the intervention was significantly higher than that in the dim light condition (main effect of light: p <.001). However, the ANOVA results indicated no significant effect of TRP intake on melatonin secretion. CONCLUSION: Our findings indicated that intake of 1000 mg of TRP at breakfast on 1 day did not change nocturnal melatonin secretion, even though TRP is the precursor of melatonin. In contrast, daytime bright light exposure increased nocturnal melatonin secretion and advanced the phase of melatonin onset. Therefore, TRP supplementation, unlike exposure to daytime bright light, does not acutely affect biological rhythm and sleep in humans. TRIAL REGISTRATION: UMIN Clinical Trial Registry: UMIN000024121.

Dynamics and plasticity of the epithelial to mesenchymal transition induced by miR-200 family inhibition.

Whereas miR-200 family is known to be involved in the epithelial-to-mesenchymal transition (EMT), a crucial biological process observed in normal and pathological contexts, it has been largely unclear how far the functional levels of these tiny RNAs alone can propagate the molecular events to accomplish this process within several days. By developing a potent inhibitor of miR-200 family members (TuD-141/200c), the expression of which is strictly regulatable by the Tet (tetracycline)-On system, we found using a human colorectal cell line, HCT116, that several direct gene target mRNAs (Zeb1/Zeb2, ESRP1, FN1and FHOD1) of miR-200 family were elevated with distinct kinetics. Prompt induction of the transcriptional suppressors, Zeb1/Zeb2 in turn reduced the expression levels of miR-200c/-141 locus, EpCAM, ESRP1 and E-Cad. The loss of ESRP1 subsequently switched the splicing isoforms of CD44 and p120 catenin mRNAs to mesenchymal type. Importantly, within 9 days after the release from the inhibition of miR-200 family, all of the expression changes in the 14 genes observed in this study returned to their original levels in the epithelial cells. This suggests that the inherent epithelial plasticity is supported by a weak retention of key regulatory gene expression in either the epithelial or mesenchymal states through epigenetic regulation.

Effects of tryptophan-rich breakfast and light exposure during the daytime on melatonin secretion at night.

BACKGROUND: The purpose of the present study is to investigate effects of tryptophan intake and light exposure on melatonin secretion and sleep by modifying tryptophan ingestion at breakfast and light exposure during the daytime, and measuring sleep quality (by using actigraphy and the OSA sleep inventory) and melatonin secretion at night. METHODS: Thirty three male University students (mean ± SD age: 22 ± 3.1 years) completed the experiments lasting 5 days and 4 nights. The subjects were randomly divided into four groups: Poor*Dim (n = 10), meaning a tryptophan-poor breakfast (55 mg/meal) in the morning and dim light environment (<50 lx) during the daytime; Rich*Dim (n = 7), tryptophan-rich breakfast (476 mg/meal) and dim light environment; Poor*Bright (n = 9), tryptophan-poor breakfast and bright light environment (>5,000 lx); and Rich*Bright (n = 7), tryptophan-rich breakfast and bright light. RESULTS: Saliva melatonin concentrations on the fourth day were significantly lower than on the first day in the Poor*Dim group, whereas they were higher on the fourth day in the Rich*Bright group. Creatinine-adjusted melatonin in urine showed the same direction as saliva melatonin concentrations. These results indicate that the combination of a tryptophan-rich breakfast and bright light exposure during the daytime could promote melatonin secretion at night; further, the observations that the Rich*Bright group had higher melatonin concentrations than the Rich*Dim group, despite no significant differences being observed between the Poor*Dim and Rich*Dim groups nor the Poor*Bright and Rich*Bright groups, suggest that bright light exposure in the daytime is an important contributor to raised melatonin levels in the evening. CONCLUSIONS: This study is the first to report the quantitative effects of changed tryptophan intake at breakfast combined with daytime light exposure on melatonin secretion and sleep quality. Evening saliva melatonin secretion changed significantly and indicated that a tryptophan-rich breakfast and bright light exposure during the daytime promoted melatonin secretion at this time.

Dorsolateral prefrontal cortical oxygenation during REM sleep in humans.

Previous neuroimaging studies that examined cerebral blood flow during rapid eye movement (REM) sleep have reported inconsistent findings regarding the activity of the dorsolateral prefrontal cortex (DLPFC). Although most previous positron emission tomography (PET) studies failed to detect DLPFC activation during REM sleep, several studies have observed DLPFC activation, possibly reflecting transient prefrontal activities related to REM. More recently, an event-related functional magnetic resonance imaging (fMRI) study observed REM-locked activation of the DLPFC during REM sleep. The present study investigated hemodynamic changes of the DLPFC throughout the REM sleep period in 25 subjects using near-infrared spectroscopy. Continuous monitoring of changes in the hemoglobin (Hb) concentration and tissue oxygenation index (TOI, proportion of oxygenated-Hb to total-Hb) in the bilateral DLPFC was conducted every 0.5s, simultaneously with polysomnographic recordings. Eight of the 25 subjects showed REM sleep, and all indicated a clear increase in both the oxygenated-Hb concentration and TOI from baseline at the occurrence of first REM, relative to prior stage 2 sleep. The results indicate that the appearance of the first REM that occurred just after onset of the REM sleep closely coincides with the activation of the DLPFC, which could play a role in cognitive activities during REM sleep in humans.