The phase angle as a predictor of postoperative complications in patients undergoing lung cancer surgery.

PURPOSE: The phase angle (PhA), calculated by bioelectrical impedance analysis, is used as a nutritional risk indicator. A low preoperative PhA has been reported as a marker of postoperative complications in patients with cancer; however, the relationship between the PhA and postoperative complications in patients with lung cancer remains unknown. We conducted this study to assess the predictive ability of the preoperative PhA for postoperative complications in patients undergoing surgery for primary lung cancer. METHODS: We reviewed the data on 240 patients who underwent surgery for primary lung cancer at our institution between August, 2019 and August, 2021. RESULTS: The PhA value in this study was 4.7 ± 0.7°. According to the Clavien-Dindo classification, grade ≥ II postoperative complications occurred in 53 patients (22.0%). Based on the multivariate logistic analysis, only the PhA (odds ratio, 0.51, 95% confidence interval, 0.29-0.90, p = 0.018) was an independent predictor of Clavien-Dindo grade ≥ II postoperative complications. CONCLUSIONS: The PhA may be a valuable marker for predicting the risk of postoperative complications following lung cancer surgery.

[Paclitaxel plus Bevacizumab Combination Therapy for Esophageal Metastasis of Breast Cancer-A Case Report].

An 80-year-old woman with a history of left breast cancer complained of dysphagia. At the age of 67 years, she had undergone a left modified radical mastectomy, chemotherapy, and endocrine therapy for left breast cancer. Six years after adjuvant therapy completion, she developed dysphagia. Chest CT showed only midesophageal stenosis. Endoscopic examination revealed whole circumferential stenosis without mucosal abnormality located 25 cm from the incisors, and a biopsy showed histologically normal mucosa. Endoscopic balloon dilatation was performed 5 times in 1 year and 3 months. Subsequently, a biopsy specimen revealed adenocarcinoma, which suggested metastasis from the previous breast cancer. One month after the initiation of tamoxifen administration, dyspnea due to pleural effusion was encountered. We treated this via pleural adhesion therapy and changed the treatment to paclitaxel plus bevacizumab combination therapy. She continued paclitaxel plus bevacizumab therapy for 1 year and 4 months without any signs of recurrence.

Whole genome population structure of North Atlantic kelp confirms high-latitude glacial refugia.

Coastal refugia during the Last Glacial Maximum (~21,000 years ago) have been hypothesized at high latitudes in the North Atlantic, suggesting marine populations persisted through cycles of glaciation and are potentially adapted to local environments. Here, whole-genome sequencing was used to test whether North Atlantic marine coastal populations of the kelp Alaria esculenta survived in the area of southwestern Greenland during the Last Glacial Maximum. We present the first annotated genome for A. esculenta and call variant positions in 54 individuals from populations in Atlantic Canada, Greenland, Faroe Islands, Norway and Ireland. Differentiation across populations was reflected in ~1.9 million single nucleotide polymorphisms, which further revealed mixed ancestry in the Faroe Islands individuals between putative Greenlandic and European lineages. Time-calibrated organellar phylogenies suggested Greenlandic populations were established during the last interglacial period more than 100,000 years ago, and that the Faroe Islands population was probably established following the Last Glacial Maximum. Patterns in population statistics, including nucleotide diversity, minor allele frequencies, heterozygosity and linkage disequilibrium decay, nonetheless suggested glaciation reduced Canadian Atlantic and Greenlandic populations to small effective sizes during the most recent glaciation. Functional differentiation was further reflected in exon read coverage, which revealed expansions unique to Greenland in 337 exons representing 162 genes, and a modest degree of exon loss (103 exons from 56 genes). Altogether, our genomic results provide strong evidence that A. esculenta populations were resilient to past climatic fluctuations related to glaciations and that high-latitude populations are potentially already adapted to local conditions as a result.

Providing a phylogenetic framework for trait-based analyses in brown algae: Phylogenomic tree inferred from 32 nuclear protein-coding sequences.

In the study of the evolution of biological complexity, a reliable phylogenetic framework is needed. Many attempts have been made to resolve phylogenetic relationships between higher groups (i.e., interordinal) of brown algae (Phaeophyceae) based on molecular evidence, but most of these relationships remain unclear. Analyses based on small multi-gene data (including chloroplast, mitochondrial and nuclear sequences) have yielded inconclusive and sometimes contradictory results. To address this problem, we have analyzed 32 nuclear protein-coding sequences in 39 Phaeophycean species belonging to eight orders. The resulting nuclear-based phylogenomic trees provide virtually full support for the phylogenetic relationships within the studied taxa, with few exceptions. The relationships largely confirm phylogenetic trees based on nuclear, chloroplast and mitochondrial sequences, except for the placement of the Sphacelariales with weak bootstrap support. Our study indicates that nuclear protein-coding sequences provide significant support to conclusively resolve phylogenetic relationships among Phaeophyceae, and may be a powerful approach to fully resolve interordinal relationships with increased taxon sampling.

[Case of Unresectable Gastric Mixed Neuroendocrine Neoplasm(MiNEN)Treated with Chemotherapy].

A 68-year-old man diagnosed with gastric mixed neuroendocrine-non-neuroendocrine neoplasia(MiNEN)concomitant with liver metastasis received chemotherapy using ramucirumab and paclitaxel. A decrease in tumor marker levels and size of the metastatic liver lesions was observed after 3 courses of treatment. However, the patient developed progressive disease after 9 courses of chemotherapy; hence, nivolumab chemotherapy was initiated. Although liver metastases were reduced after 2 courses of nivolumab, the patient developed new liver lesions after 18 courses of treatment; irinotecan, S-1 and oxaliplatin, and trifluridine/tipiracil were then administered. Liver metastases progressed despite changing the regimen, and the patient died 25 months after the initiation of chemotherapy. Gastric MiNEN usually shows poor prognosis, and there is lack of consensus regarding optimal treatment. Ramucirumab and nivolumab are relatively well-tolerated and may be effective for chemotherapy.

Global Diversity and Geographic Distributions of Padina Species (Dictyotales, Phaeophyceae): New Insights Based on Molecular and Morphological Analyses.

The taxonomic status and species diversity of the brown algal genus Padina (Dictyotales, Phaeophyceae) was assessed based on DNA sequences and the morpho-anatomy of specimens collected worldwide, especially from tropical and subtropical western Pacific regions. Phylogenetic analyses using chloroplast rbcL and mitochondrial cox3 gene sequences demonstrated four distinct clades for newly collected samples with high bootstrap support. Each species clade possesses a suite of morphological features that are not shared by any known species of Padina. These are P. imbricata sp. nov., Padina lutea sp. nov., P. moffittianoides sp. nov., and P. nitida sp. nov. The occurrence of these and other species of Padina clearly points to an elevated diversity of the genus in tropical/subtropical waters of the western Pacific. Phylogenetic analyses provided new insights into biogeographic characteristics of the genus, with many species in the Pacific Ocean showing shared/overlapping distributions, whereas species from the Mediterranean/Atlantic and/or the Indian Ocean tend to be confined to particular regions. Consideration has also been given to the evolutionary time frame of the genus Padina based on molecular time trees: a time tree of the concatenated data set (rbcL + cox3) revealed the estimated divergence time in the mid-Cretaceous, whereas those of cox3 and rbcL showed older estimates pointing to the periods of mid-Jurassic and Early Cretaceous, respectively.

Whole-genome sequencing reveals forgotten lineages and recurrent hybridizations within the kelp genus Alaria (Phaeophyceae).

The genomic era continues to revolutionize our understanding of the evolution of biodiversity. In phycology, emphasis remains on assembling nuclear and organellar genomes, leaving the full potential of genomic datasets to answer long-standing questions about the evolution of biodiversity largely unexplored. Here, we used whole-genome sequencing (WGS) datasets to survey species diversity in the kelp genus Alaria, compare phylogenetic signals across organellar and nuclear genomes, and specifically test whether phylogenies behave like trees or networks. Genomes were sequenced from across the global distribution of Alaria (including Alaria crassifolia, A. praelonga, A. crispa, A. marginata, and A. esculenta), representing over 550 GB of data and over 2.2 billion paired reads. Genomic datasets retrieved 3,814 and 4,536 single-nucleotide polymorphisms (SNPs) for mitochondrial and chloroplast genomes, respectively, and upwards of 148,542 high-quality nuclear SNPs. WGS revealed an Arctic lineage of Alaria, which we hypothesize represents the synonymized taxon A. grandifolia. The SNP datasets also revealed inconsistent topologies across genomic compartments, and hybridization (i.e., phylogenetic networks) between Pacific A. praelonga, A. crispa, and putative A. grandifolia, and between some lineages of the A. marginata complex. Our analysis demonstrates the potential for WGS data to advance our understanding of evolution and biodiversity beyond amplicon sequencing, and that hybridization is potentially an important mechanism contributing to novel lineages within Alaria. We also emphasize the importance of surveying phylogenetic signals across organellar and nuclear genomes, such that models of mixed ancestry become integrated into our evolutionary and taxonomic understanding.

[Change in Therapy for Malignant Pleural Mesothelioma at Our Hospital].

When molecular target drug began to be used for chemotherapy to treat malignant pleural mesothelioma in 2014, we introduced this treatment strategy for 61 patients who were diagnosed and were being treated in our hospital. Chemotherapy was performed on 37 patients, while 12 patients underwent surgical remedy and best supportive care was provided to another 12 patients. Molecular target drug was used as the primary chemotherapy treatment in 14 cases, while it was the secondary treatment in 22 others. Pleural decortication was performed as the operative method for all the 12 cases requiring surgical remedy, and 2 of these cases were shifted to extrapleural pneumonectomy. By the chemotherapy, there were many cases of PS≥2, non‒epithelial type, advanced stage, LMR<2.74 of the biomarker. When we compared surgical remedy with the chemotherapy clinicopathologically. In the prognostic examination, in median survival time of all cases, as for 23 months, the chemotherapy, 31 months, the surgical remedy was not reached. Prognostic improvement of stage ⅢA was determined according to the stage of the chemotherapy. A multivariate variable analysis revealed that only a non‒sarcomatous type was a good prognostic factor, and surgery remedy was not.

[A Case of Metastatic Pancreatic Ductal Adenocarcinoma Successfully Treated with Modified FOLFIRINOX and Concurrent Radiotherapy].

A 70-year-old man with metastatic pancreatic ductal adenocarcinoma(cT4N1bM1, cStage Ⅳ)underwent chemotherapy with modified FOLFIRINOX without any severe adverse event to 20 cycles. In the middle of that, concurrent irradiation toward primary lesion(total dose, 43.2 Gy)was administered. Grade 1 adverse events include anemia, thrombocytopenia, hypoalbuminemia, hypokalemia, alkaline phosphatase increased, hypertension, peripheral sensory neuropathy, fatigue, anorexia and nausea. The relative dose intensities of oxaliplatin, irinotecan and fluorouracil at 6 months after beginning of treatment were 77.6, 84.0 and 88.3 percent, respectively. The total dose of administered oxaliplatin was 825 mg to the square meter. The primary lesion had been stable for the 20 cycles, although peritoneal dissemination had progressively increased in size. For 17 months, opioid was not necessary for the control of abdominal or back pain to the end of third-line treatment. Though safety or clinical benefits of modified FOLFIRINOX plus concurrent radiotherapy for metastatic pancreatic ductal adenocarcinoma have not been reported, in this case, such treatment might contribute to prolong prognosis or prevent developing abdominal or back pain.

[A Case of Malignant Thyroid Lymphoma That Was Difficult to Differentiate from Methotrexate-Associated Lymphoproliferative Disorders(MTX-LPD)].

A female patient in her 60s was going to get treatment for rheumatoid arthritis(RA). Considering the possibility of using biologics, CT examination was performed for screening of malignant diseases. A mass shadow in the left lobe of the thyroid gland was detected. The patient was followed up, and ultrasonography did not reveal any malignant findings. She was treated with methotrexate(MTX), and 1 year later, the thyroid mass was enlarged on CT. Ultrasonography revealed an enlarged hypoechoic region. Fine needle aspiration cytology revealed malignant lymphoma. Excisional biopsy was performed to determine the treatment plan. The pathological diagnosis was follicular lymphoma, and the possibility of methotrexate- associated lymphoproliferative disorders(MTX-LPD)persisted. It was difficult to discontinue MTX because of the high activity of RA. She was treated with rituximab for malignant lymphoma and concurrently with MTX for RA. The thyroid tumor disappeared for 3 months. Four years later, there is no sign of tumor recurrence.

[A Case of Intraductal Apocrine Carcinoma of the Breast].

A female in her 60s who complained of nipple discharge in her left breast for 1 year. A soft mass ill-defined margin in the border of AB area was observed. Mammography showed a focal asymmetric density. Ultrasonography disclosed an irregular heterogenous low echoic lesion in the AB area of her left breast. MRI image showed an enhanced lesion in the inner area. The pathological diagnosis by core needle biopsy was non-invasive ductal carcinoma with apocrine metaplasia. Mastectomy with sentinel lymph node biopsy of the left breast was performed. Post operative histopathological examination revealed intraductal apocrine carcinoma without lymph node metastasis. Estrogen and progesterone receptors were negative. Three years after operation without any adjuvant treatment, she has no recurrence of lesion.

[A Case of Unresectable Intrahepatic Cholangiocarcinoma Successfully Treated with Chemoradiotherapy].

A 69-year-old woman with unresectable intrahepatic cholangiocarcinoma(T3N1M1, Stage Ⅳ)underwent chemoradiotherapy with gemcitabine, cisplatin and irradiation toward primary lesion(total dose, 36 Gy). Grade 3 or 4 adverse events include leukopenia, neutropenia, and anemia. The relative dose intensities at 6 months after beginning of treatment were 58.9%(gemcitabine)and 80.2%(cisplatin), respectively. The total dose of administered cisplatin was 525 mg to the square meter. Partial response was obtained, and after that, the representative lesions have been stable with continuous administration of gemcitabine. As some studies have reported clinical benefits of chemoradiotherapy for unresectable intrahepatic cholangiocarcinoma, further clinical investigations are expected.

[Two Cases of Stage â £ Occult Breast Cancer].

The first case is a 62-year-old female who complained of painful left axillary lymph node swelling. Six months later, a CT scan revealed multiple lung nodules. Biopsies of the axillary lymph node and lung showed metastatic carcinoma from breast cancer. However, no breast tumor was found. She was diagnosed with occult breast cancer with metastasis to the axillary lymph node and lung. ER(+), PgR(±), HER2(1+). Letrozole was administered, and effective control was achieved for 20 months. The second case is a 62-year-old female who presented with back pain. A CT scan revealed left axillary lymph node swelling and multiple osteolytic changes in the thoracolumbar spine and rib. Biopsies of the axillary lymph node and thoracic spine showed metastatic carcinoma from breast cancer. However, no breast tumor was found. She was diagnosed with occult breast cancer with metastasis to the axillary lymph nodule and bone. ER(+), PgR(+), HER2(1+). Fulvestrant and denosumab were administered. However, after 6 months, she discontinued the treatment. Our results suggested that effective control could be achieved through systemic therapy and local therapy was not necessary for Stage Ⅳ occult breast cancer.

A comprehensive kelp phylogeny sheds light on the evolution of an ecosystem.

Reconstructing phylogenetic topologies and divergence times is essential for inferring the timing of radiations, the appearance of adaptations, and the historical biogeography of key lineages. In temperate marine ecosystems, kelps (Laminariales) drive productivity and form essential habitat but an incomplete understanding of their phylogeny has limited our ability to infer their evolutionary origins and the spatial and temporal patterns of their diversification. Here, we reconstruct the diversification of habitat-forming kelps using a global genus-level phylogeny inferred primarily from organellar genome datasets, and investigate the timing of kelp radiation. We resolve several important phylogenetic features, including relationships among the morphologically simple kelp families and the broader radiation of complex kelps, demonstrating that the initial radiation of the latter resulted from an increase in speciation rate around the Eocene-Oligocene boundary. This burst in speciation rate is consistent with a possible role of recent climatic cooling in triggering the kelp radiation and pre-dates the origin of benthic-foraging carnivores. Historical biogeographical reconstructions point to a northeast Pacific origin of complex kelps, with subsequent colonization of new habitats likely playing an important role in driving their ecological diversification. We infer that complex morphologies associated with modern kelp forests (e.g. branching, pneumatocysts) evolved several times over the past 15-20 MY, highlighting the importance of morphological convergence in establishing modern upright kelp forests. Our phylogenomic findings provide new insights into the geographical and ecological proliferation of kelps and provide a timeline along which feedbacks between kelps and their food-webs could have shaped the structure of temperate ecosystems.

High potassium seawater inhibits ascidian sperm chemotaxis, but does not affect the male gamete chemotaxis of a brown alga.

Male gamete chemotaxis towards the female gamete is a general strategy to facilitate the sexual reproduction in many marine eukaryotes. Biochemical studies of chemoattractants for male gametes of brown algae have advanced in the 1970s and 1980s, but the molecular mechanism of male gamete responses to the attractants remains elusive. In sea urchin, a K+ channel called the tetraKCNG channel plays a fundamental role in sperm chemotaxis and inhibition of K+ efflux through this channel by high K+ seawater blocks almost all cell responses to the chemoattractant. This signalling mechanism could be conserved in marine invertebrates as tetraKCNG channels are conserved in the marine invertebrates that exhibit sperm chemotaxis. We confirmed that high K+ seawater also inhibited sperm chemotaxis in ascidian, Ciona intestinalis (robusta), in this study. Conversely, the male gamete chemotaxis towards the female gamete of a brown alga, Mutimo cylindricus, was preserved even in high K+ seawater. This result indicates that none of the K+ channels is essential for male gamete chemotaxis in the brown alga, suggesting that the signalling mechanism for chemotaxis in this brown alga is quite different from that of marine invertebrates. Correlated to this result, we revealed that the channels previously proposed as homologues of tetraKCNG in brown algae have a distinct domain composition from that of the tetraKCNG. Namely, one of them possesses two repeats of the six transmembrane segments (diKCNG) instead of four. The structural analysis suggests that diKCNG is a cyclic nucleotide-modulated and/or voltage-gated K+ channel.

[A Case of Long-Term Survival after Para-Aortic Lymph Node Recurrence Following the Curative Resection of Gastric Cancer Treated Using Multimodality Therapy Including Salvage Surgery].

This case was observed in a man in his 70s. Although symptomatic treatment was performed for epigastralgia, endoscopic examination revealed a type 3 tumor on the fornix of the stomach to the lesser curvature of the body just above the esophagogastric junction, and the patient was diagnosed with moderately differentiated tubular adenocarcinoma(cT4bN3aM0, cStage ⅣA). As esophageal and diaphragmatic invasion was suspected based on CT findings, S-1 plus CDDP was started as preoperative chemotherapy. Although the primary lesion and lymph node metastasis decreased in size, chemotherapy was discontinued after one course due to stenosis symptoms, and total gastrectomy and D2 dissection were performed. Postoperative adjuvant chemotherapy with S-1 was started. However, 6 months after starting the treatment, para-aortic lymph node recurrence was observed, and the treatment strategy was changed to weekly PTX. After 5 courses of weekly PTX, the lymph nodes continued to increase in size, and chemotherapy was discontinued per the patient's request. The patient was followed up with CT and PET-CT; however, no new recurrent lesions were found in other sites for approximately 1 year. Therefore, para-aortic lymph node dissection was performed as the salvage surgery. Pathological findings showed that gastric cancer metastasis was present in 1 swollen lymph node only, as confirmed by PET. At present, 6 years have passed since the first operation, and there has been no recurrence. In general, para-aortic lymph node metastasis is considered to result in poor prognosis in gastric cancer. However, in the absence of other noncurative factors, a good prognosis may be obtained with combined therapeutic modalities.

[A Case of Breast Metastasis of Gastric Cancer after an Eight Year Latency Period].

A 66-year-old woman underwent distal gastrectomy because of gastric cancer(stage ⅠB)and received no adjuvant chemotherapy. Eight years after the operation, computed tomography showed a small nodule in the right breast. Mammography did not reveal any abnormalities. Ultrasound sonography showed a diffuse and gradual non-mass-like low echoic lesion. Core needle biopsy indicated a malignancy. Partial resection of the right breast was performed to obtain a diagnosis. On postoperative histopathological examination, signet-ring cells were found in the tumor, and immunohistochemical analysis showed that both the breast tumor and the gastric carcinoma were MUC5AC-positive and MUC1-negative. We diagnosed this breast tumor as metastasis from gastric cancer. The patient has received chemotherapy with no subsequent metastatic tumors, and good control has been achieved for 21 months after the detection of the breast metastasis.

Reduction in Secretion of Very Low Density Lipoprotein-Triacylglycerol by a Matrix Metalloproteinase Inhibitor in a Rat Model of Diet-Induced Hypertriglyceridemia.

Matrix metalloproteinase inhibitors (MMPIs) reduced serum triacylglycerol (TAG) levels in streptozotocin-induced diabetic rats and Zucker fa/fa rats in our previous study. However, the mechanisms underlying TAG reduction by MMPIs remain unclear. The present study aimed to elucidate the mechanism by which F81-1144b, an MMPI, lowers serum TAG levels in an animal model of high-sucrose diet (HSD)-induced hypertriglyceridemia. F81-1144b was repeatedly administered to rats fed HSD, and its effects were evaluated on TAG levels in serum and the liver, very low density lipoprotein (VLDL) secretion, de novo fatty acid (FA) synthesis in the liver, and the expression of genes regulating the metabolism of FA, TAG, and VLDL in the liver and serum. F81-1144b lowered TAG levels in serum and the liver, VLDL-TAG secretion, de novo FA synthesis in the liver, and serum levels of insulin and glucose. F81-1144b suppressed the expression of genes related to the de novo synthesis of FA and TAG, key proteins (lipin 1 and apolipoprotein CIII) responsible for VLDL metabolism, and sterol regulatory element-binding protein-1c and carbohydrate response element-binding protein. F81-1144b little affected the expression of genes related directly to the degradation of TAG or FA, but it upregulated that of gene for uncoupling protein 2 in the liver. These results suggest that MMPIs are a novel type of therapeutic agent for the treatment of hypertriglyceridemia, because the metabolic effects of F81-1144b expected from changes in the expression of genes regulating lipid metabolism would alter metabolism differently from those induced by fibrates, niacin, or n-3 FAs.

Treatment patterns and outcomes of unresectable pancreatic cancer patients in real-life practice: a region-wide analysis.

BACKGROUND: FOLFIRINOX (FFX) and gemcitabine (GEM) plus nab-paclitaxel (GnP) have recently been available for treating pancreatic ductal adenocarcinoma (PDAC). We investigated trends in characteristics, treatment and outcomes of unselected patients with unresectable PDAC in real-life practice in Japan. METHODS: We retrospectively reviewed the medical records of 1085 patients diagnosed as having unresectable or recurrent PDAC in multiple centers in the Hokuriku area between January 2009 and July 2015. RESULTS: The incidence of pathologically proven PDAC had increased from 18.7% in 2009 to 56.2% in 2015. Oncological therapy was administered to 779 patients (71.8%): chemotherapy (n = 675), chemo-radiotherapy (n = 92) or radiotherapy (n = 12); the remaining patients were treated with best supportive care. Of 100 patients diagnosed in 2009, 62.0% received GEM as first-line chemotherapy; whereas 30.7% of the 75 patients diagnosed in 2015 received FFX, 25.3% GnP, 22.7% GEM and 17.3% S-1. The objective response rates of patients treated with FFX, GnP and GEM were 14.9%, 35.0% and 5.5%, respectively and the OS 10.3, 9.9 and 7.5 months after FFX, GnP and GEM, respectively. Grade 3 or greater any hematological toxicity occurred in 70.2%, 70.0% and 18.8% of the patients treated with FFX, GnP and GEM, respectively. The reasons for treatment discontinuation were adverse events in 9.8%, 26.7% and 24.1% of the patients treated with FFX, GnP and GEM, respectively. CONCLUSION: Chemotherapeutic protocols changed dramatically between 2009 and 2015. Continuous collection and analysis for our cohort with longer follow-up provides useful information about treatment selection and prediction of outcome.

Chronopharmacological Analysis of Antidepressant Activity of a Dual-Action Serotonin Noradrenaline Reuptake Inhibitor (SNRI), Milnacipran, in Rats.

Biological rhythms are thought to be related to the pathogenesis and therapy of various diseases including depression. Here we investigated the influence of circadian rhythms on the antidepressant activity of the dual-action serotonin-noradrenaline reuptake inhibitor (SNRI) milnacipran. Rats administered milnacipran in the morning (8:00 a.m.; zeitgeber time [ZT]1) or in the evening (8:00 p.m.; ZT13) were analyzed in a forced swim test (FST). At ZT1, the rats' immobility was reduced and the swimming was increased, whereas at ZT13, their climbing was increased. These results suggest that the serotonergic and noradrenergic systems are preferentially affected at ZT1 and ZT13, respectively by milnacipran. We analyzed the plasma and brain levels of milnacipran after administration, and there were no differences between ZT1 and ZT13. The circadian rhythm of monoamine neurotransmitters was analyzed in several brain regions. The serotonin turnover showed rhythms with a peak during ZT18-ZT22 in hippocampus. The noradrenaline turnover showed rhythms with a peak during ZT22-ZT2. There was a difference of approx. 4 h between the serotonergic and noradrenergic systems. This time difference might be one of the factors that affect the action of milnacipran and contribute to the dosing time-dependent behavioral pattern in the FST.