Improving glycemic control by transitioning from the MiniMedTM 640G to 770G in Japanese adults with type 1 diabetes mellitus: a prospective, single-center, observational study.

The effectiveness of a hybrid closed-loop (HCL) system in improving glycemic control is unclear in Japanese individuals. Therefore, we assessed the effect impact of the MiniMed 770G HCL system on glycemic control in this population. This prospective, single-center, 24-week observational study (registration number: UMIN000047394) enrolled 23 individuals with type 1 diabetes mellitus using the Medtronic MiniMed 640G system. The primary endpoint was the improvement in time in the range of 70-180 mg/dL after transitioning to the MiniMed 770G HCL system. We observed an increase in time in range (from 64.1 [55.8-69.5] to 70.9 [67.1-74.4] %, interquartile range 25-75%, p < 0.001) and a decrease in glycated hemoglobin level (from 7.4 [7.0-7.9] to 7.1 [6.8-7.4] %, p = 0.003). There was a significant reduction in time above the range (181-250 mg/dL: 25.8 [20.9-28.6] to 19.5 [17.1-22.1] %, p < 0.001; >251 mg/dL: 8.7 [4.0-13.0] to 4.7 [3.6-9.1] %, p < 0.001). Time below the range remained unchanged (54-69 mg/dL: 1.8 [0.4-2.4] to 2.1 [0.4-3.9] %, p = 0.24; <54 mg/dL: 0.2 [0.0-1.0] to 0.5 [0.1-1.3] %, p = 0.14). In a subgroup of 12 patients with a high HCL implementation rate, the basal insulin infusion decreased immediately after mealtime insulin administration and increased after approximately 120 minutes. The ratings from questionnaires assessing treatment burden, satisfaction, and quality of life remained unchanged. The MiniMed 770G HCL system improved glycemic control and optimized insulin delivery, particularly in patients with high implementation rates.

Nanosized and metastable molybdenum oxides as negative electrode materials for durable high-energy aqueous Li-ion batteries.

The development of inherently safe energy devices is a key challenge, and aqueous Li-ion batteries draw large attention for this purpose. Due to the narrow electrochemical stable potential window of aqueous electrolytes, the energy density and the selection of negative electrode materials are significantly limited. For achieving durable and high-energy aqueous Li-ion batteries, the development of negative electrode materials exhibiting a large capacity and low potential without triggering decomposition of water is crucial. Herein, a type of a negative electrode material (i.e., Li x Nb2/7Mo3/7O2) is proposed for high-energy aqueous Li-ion batteries. Li x Nb2/7Mo3/7O2 delivers a large capacity of ∼170 mA ⋅ h ⋅ g-1 with a low operating potential range of 1.9 to 2.8 versus Li/Li+ in 21 m lithium bis(trifluoromethanesulfonyl)amide (LiTFSA) aqueous electrolyte. A full cell consisting of Li1.05Mn1.95O4/Li9/7Nb2/7Mo3/7O2 presents high energy density of 107 W ⋅ h ⋅ kg-1 as the maximum value in 21 m LiTFSA aqueous electrolyte, and 73% in capacity retention is achieved after 2,000 cycles. Furthermore, hard X-ray photoelectron spectroscopy study reveals that a protective surface layer is formed at the surface of the negative electrode, by which the high-energy and durable aqueous batteries are realized with Li x Nb2/7Mo3/7O2 This work combines a high capacity with a safe negative electrode material through delivering the Mo-based oxide with unique nanosized and metastable characters.

An integrative epigenomic approach identifies ELF3 as an oncogenic regulator in ASCL1-positive neuroendocrine carcinoma.

Neuroendocrine carcinoma (NEC) is a highly aggressive subtype of the neuroendocrine tumor with an extremely poor prognosis. We have previously conducted a comprehensive genomic analysis of over 100 cases of NEC of the gastrointestinal system (GIS-NEC) and unraveled its unique and organ-specific genomic drivers. However, the epigenomic features of GIS-NEC remain unexplored. In this study, we have described the epigenomic landscape of GIS-NEC and small cell lung carcinoma (SCLC) by integrating motif enrichment analysis from the assay of transposase-accessible chromatin sequencing (ATAC-seq) and enhancer profiling from a novel cleavage under targets and tagmentation (CUT&Tag) assay for H3K27ac and identified ELF3 as one of the super-enhancer-related transcriptional factors in NEC. By combining CUT&Tag and knockdown RNA sequencing for ELF3, we uncovered the transcriptional network regulated by ELF3 and defined its distinctive gene signature, including AURKA, CDC25B, CLDN4, ITGB6, and YWAHB. Furthermore, a loss-of-function assay revealed that ELF3 depletion led to poor cell viability. Finally, using gene expression of clinical samples, we successfully divided GIS-NEC patients into two subgroups according to the ELF3 signature and demonstrated that tumor-promoting pathways were activated in the ELF3 signature-high group. Our findings highlight the transcriptional regulation of ELF3 as an oncogenic transcription factor and its tumor-promoting properties in NEC.

An Incremental Sit-to-Stand Exercise for Evaluating Physical Capacity in Older Patients with Type 2 Diabetes.

Exercise is recommended for older patients with type 2 diabetes mellitus (T2DM), and increased physical activity contributes to better management of their condition. The conventional exercise test with treadmill or cycle ergometer (CE) for assessing physical capacity, such as peak oxygen uptake (VO2) and anaerobic threshold (AT), is not always usable for older patients with T2DM. The incremental sit-to-stand (ISTS) exercise is an incremental exercise test using external signals to control the sit-to-stand rate in a given time frame and can be performed in a small space using only a chair. This study aimed to examine the validity of the physical capacity assessment during the ISTS exercise, based on the relationships between the ISTS performance, peak VO2, AT on ISTS exercise and CE test, in older patients with T2DM. Twenty-two patients with T2DM (10 men, 12 women; mean age, 68.0 years; range, 61-77 years) performed ISTS exercise (according to an existing protocol) and CE test in a randomized manner. Peak VO2, AT, and completion time were determined for the ISTS exercise and CE test. Peak VO2 during ISTS exercise was significantly associated with that during the CE test (r = 0.89, p < 0.01). The completion time on the ISTS exercise was significantly associated with peak VO2 (r = 0.80, p < 0.01) and AT on the ISTS exercise (r = 0.78, p < 0.01). The ISTS exercise is a useful tool to determine the physical capacity and estimate peak VO2 and AT in older people with T2DM.

Does blended problem-based learning make Asian medical students active learners?: a prospective comparative study.

BACKGROUND: Asian educators have struggled to implement problem-based learning (PBL) because students rarely discuss their work actively and are not sufficiently engaged in self-directed learning. Supplementing PBL with additional e-learning, i.e. 'blended' PBL (bPBL), could stimulate students' learning process. METHODS: We investigated the effects of bPBL on tutorial group functioning (discussion, self-efficacy, self-directed learning, active participation, and tutor's perceived authority) and students' level of acceptance of the e-learning elements. We compared PBL and bPBL in a medical university in Japan. In the bPBL condition, the tutor's instructions were replaced with online materials and short quizzes. After the course, a 13-item questionnaire using a 5-point Likert scale was distributed regarding the tutorial group functioning of the tutorial group (influence of discussion, self-efficacy, self-directed learning, active participation, and tutors' authority). The mean scores of subscales were compared with analysis of covariance. Knowledge levels were measured using a pre-test post-test design. A multiple regression analysis was performed to explore the association between e-learning acceptance and the subscales related to PBL. RESULTS: Ninety-six students participated in the study (PBL: n = 24, bPBL: n = 72). Self-efficacy and motivation for learning triggered by group discussions was significantly higher for students in bPBL (p = 0.032 and 0.007, respectively). Knowledge gain in test scores was also significantly better in the bPBL condition (p = 0.026), and self-directed learning related positively to the acceptance of blended learning (p = 0.044). CONCLUSIONS: bPBL seemed more effective in promoting active learning and improving knowledge, without affecting tutors' authority. Implementing e-learning into PBL is suggested to be an effective strategy in the Asian context.

Mesenteric inflammatory veno-occlusive disease occurring during the course of ulcerative colitis: a case report.

BACKGROUND: Mesenteric inflammatory veno-occlusive disease (MIVOD) is difficult to diagnose because of its rarity, nonspecific clinical findings, and frequent confusion with other diseases including inflammatory bowel disease. This report presents a very rare case of MIVOD that occurred during the course of ulcerative colitis (UC). CASE PRESENTATION: A 32-year-old man, who had been diagnosed with UC at the age of 29 and was in remission maintained by oral administration of 5-aminosalicylic acid (5-ASA), showed exacerbation of diarrhea and was admitted to the hospital. Since it was deemed an exacerbation of UC, intravenous steroid therapy and oral administration of tacrolimus were initiated, but his condition continued to worsen. Abdominal computed tomography (CT) was performed and showed intraperitoneal free air, leading to a diagnosis of gastrointestinal perforation and the performance of emergency surgery (subtotal colectomy and ileostomy). Histopathological examination of the resected colon of the patient showed mucosal inflammatory findings that were not typical of UC, including multiple organized thrombi with recanalization in the veins existing in the submucosal layer to the subserosal layer and an increased infiltration of inflammatory cells. These findings led to the pathological diagnosis of MIVOD. CONCLUSION: We report a very rare case in which MIVOD occurred during the course of UC.

Careful readings for a flash glucose monitoring system in nondiabetic Japanese subjects: individual differences and discrepancy in glucose concentrarion after glucose loading [Rapid Communication].

The FreeStyle Libre Flash Glucose Monitoring System (FGM), which can continuously measure glucose concentration in the interstitial fluid glucose (FGM-ISFG), has been in clinical use worldwide. However, it is not clear how accurately FGM-ISFG reflects plasma glucose concentration (PG). In the present study, we examined the clinical utility of FGM by oral glucose tolerance test (OGTT). In eight healthy volunteers (3 males; mean age, 41.8 y) wearing FGM sensors for 14 days, OGTT was performed during days 1-7 and days 8-14, and then both FGM-ISFG and PG were compared. Parkes error grid analysis indicated that all of 65 FGM-ISFG values were within Zone A (no effect on clinical action) and Zone B (little or no effect on clinical outcome). However, in OGTT, the mean FGM-ISFG was higher than the mean actual PG at 30, 60, and 90 minutes after loading (155.5 vs. 139.2 mg/dL, 166.2 vs. 139.2 mg/dL, 149.5 vs. 138.2 mg/dL, respectively; p<0.05). Moreover, the area under the curve of FGM-ISFG was also significantly larger than that of PG (17,626.2 vs. 15,195.0 min·mg/dL; p<0.05). In four of eight subjects, FGM-ISFG tended to be higher than PG in both OGTTs, and the greatest difference between the two values was 58 mg/dL. FGM is useful for glycemic control, whereas it is not appropriate to change therapeutic regimens based on the judgment of nocturnal hypoglycemia and postprandial hyperglycemia by FGM-ISFG. Careful attention is required for proper application of FGM.

Factors associated with healing of artificial ulcer after endoscopic submucosal dissection with reference to Helicobacter pylori infection, CYP2C19 genotype, and tumor location: Multicenter randomized trial.

BACKGROUND AND AIM: Healing speed of peptic ulcer is affected by a number of factors, including Helicobacter pylori (H. pylori) infection and intragastric pH. Acid inhibition exerted by proton pump inhibitors differs by CYP2C19 genotype. Herein, we investigated whether healing speed of artificial ulcers formed after endoscopic submucosal dissection (ESD) was influenced by H. pylori infection, CYP2C19 genotype, or other factors. METHODS: A total of 96 H. pylori-positive patients with gastric tumors scheduled for ESD were randomly assigned to receive eradication therapy for H. pylori before ESD (pre-ESD eradication) (n = 44) or after (post-ESD eradication) (n = 52). Patients received eradication therapy consisting of lansoprazole 30 mg, amoxicillin 750 mg, and clarithromycin 200 mg twice daily for 1 week. After ESD, lansoprazole 30 mg was given once daily for 8 weeks. Ulcer size was endoscopically measured on the next day and at 4 and 8 weeks after ESD. RESULTS: Mean reduction rate of artificial ulcer area in the pre-ESD eradication group was 94.7% ± 5.5% at 4 weeks, which was similar to that in the post-ESD eradication group (94.7% ± 6.7%, P = 0.987), irrespective of CYP2C19 genotype. In multivariate analyses, location of gastric tumor (middle and upper, odds ratio: 4.05, 95% CI: 1.620-10.230, P = 0.003) was a factor for 97% reduction of artificial ulcer area at 4 weeks post-ESD, but CYP2C19 genotype and H. pylori infection were not. CONCLUSION: Healing speed of ESD-induced artificial ulcer was affected by tumor location, but not by time of H. pylori eradication, resected size, or CYP2C19 genotype.

Hearing loss caused by a P2RX2 mutation identified in a MELAS family with a coexisting mitochondrial 3243AG mutation.

OBJECTIVES: We present a family with a mitochondrial DNA 3243A>G mutation resulting in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), of which some members have hearing loss in which a novel mutation in the P2RX2 gene was identified. METHODS: One hundred ninety-four (194) Japanese subjects from unrelated families were enrolled in the study. Targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes were performed to identify the genetic causes of hearing loss. RESULTS: A novel mutation in the P2RX2 gene that corresponded to c.601G>A (p.Asp201Tyr) was identified. Two patients carried the mutation and had severe sensorineural hearing loss, while other members with MELAS (who did not carry the P2RX2 mutation) had normal hearing. CONCLUSION: This is the first case report of a diagnosis of hearing loss caused by P2RX2 mutation in patients with MELAS. A potential explanation is that a decrease in adenosine triphosphate (ATP) production due to MELAS with a mitochondrial 3243A>G mutation might suppress activation of P2X2 receptors. We also suggest that hearing loss caused by the P2RX2 mutation might be influenced by the decrease in ATP production due to MELAS.

Trifluridine and Tipiracil Hydrochloride Combination-Induced Interstitial Pneumonia: A Case Report.

We report a case of a 62-year-old male who was diagnosed with advanced rectal cancer. The attending gastro-enterologist initiated chemotherapy using capecitabine plus oxaliplatin and bevacizumab; however, this treatment regimen was discontinued, as the patient developed a skin rash. Once the skin rash improved, chemotherapy was re-initiated using a combination of trifluridine and tipiracil hydrochloride (TAS-102). The patient developed high fever and dyspnea 2 months after initiation of TAS-102. Chest high-resolution computed tomography showed bilateral diffuse ground glass opacities in all lung lobes with traction bronchiectasis. At this time, the gastro-enterologist consulted our department. The patient was put on non-invasive positive pressure ventilation due to worsening respiratory symptoms. The patient was suspected to develop TAS-102-induced interstitial pneumonia based on positive TAS-102 drug-induced lymphocyte stimulation test. The patient's respiratory symptoms and radiological findings improved after corticosteroid treatment. The corticosteroid dose was gradually decreased by 5 mg. Thereafter, chemotherapy was re-initiated using different anti-cancer agents.

A case of middle-aged central sleep apnea due to Joubert syndrome with different treatment effects of oxygen and acetazolamide.

We report a case of severe central sleep apnea incidentally diagnosed during polysomnography for suspected obstructive sleep apnea. Characteristic clinical features included episodic hyperventilation followed by apnea from hypocapnia, which did not follow a Cheyne-Stokes pattern. Combined with the identification of cerebellar and brainstem malformations known as the "molar tooth sign" on a brain MRI, developmental delay, and motor coordination problems, Joubert syndrome (a congenital disease) was first diagnosed at the age of 50 years. Central apneas were also observed during wakefulness, although not continuously. During sleep, continuous positive airway pressure and adaptive servo-ventilation were ineffective at the referring clinic and at our hospital. Supplemental oxygen decreased the frequency of central apneas and significantly shortened the duration of each central sleep apnea compared with room air. In contrast, the opposite response was observed with acetazolamide administration.

Hyperprogressive disease under anti-PD-1 rechallenge after initial response to anti-PD-1 treatment for non-small cell lung cancer: a case report.

Background: Hyperprogressive disease is an unexpected response pattern observed in immune checkpoint therapy and associated with poor prognosis. The rechallenge of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors can be a treatment option in non-small cell lung cancer (NSCLC) patients who once responded to them. Here, we reported the hyperprogressive phenomenon after PD-1/PD-L1 rechallenge in a patient with NSCLC. Case Description: This case report described a patient with recurrent large cell lung cancer undergoing hyperprogressive disease with pleural and pericardial dissemination shortly after the pembrolizumab rechallenge, although he had a favorable response to the initial pembrolizumab treatment. A lower ratio of CD8+ T cells to Foxp3+ regulatory T cells was distributed in the cell blocks of pleural and pericardial effusion which were taken after hyperprogressive disease, compared to the resected tumor microenvironment. Neutrophil-to-lymphocyte ratio (NLR) was lower in peripheral blood when the disease was controlled and it rose when the disease progressed. Notably, NLR increased dramatically when hyperprogression occurred. Conclusions: For the first time, we reported that a patient who showed a favorable response to initial anti-PD-1 treatment underwent hyperprogressive disease when rechallenging the same immunotherapy. The increased Foxp3+ regulatory T cells in the tumor microenvironment and the longitudinal change of NLRs in peripheral blood were suggested to be associated with hyperprogressive disease.

A new experimental model of ATP-sensitive K⁺ channel-independent insulinotropic action of glucose: a permissive role of cAMP for triggering of insulin release from rat pancreatic ß-cells.

In pancreatic ß-cells, glucose metabolism leads to closure of ATP sensitive K⁺ channels (K(ATP) channel) and Ca²âº influx, which is regarded as a required step for triggering of insulin release. Here, we demonstrate that glucose triggers rapid insulin release independent from its action on K(ATP) channels given the cellular cAMP is elevated. We measured insulin release from rat pancreatic islets by static and perifusion experiments. Changes in cytosolic free Ca²âº concentration ([Ca²âº]i) were monitored using fura-2 loaded rat pancreatic ß-cells. Glucose-induced insulin release was abolished when Ca²âº influx was inhibited by a combination of 250 µM diazoxide, an opener of K(ATP) channel, and 10 µM nifedipine, a blocker of L-type voltage-dependent Ca²âº channels. However, with both nifedipine and diazoxide, glucose induced a 5-fold increase in insulin release in the presence of 10 µM forskolin, an activator of adenylyl cyclase. In the presence of diazoxide, nifedipine, and forskolin, 22 mM glucose sharply increased the rate of insulin release within 2 min which peaked at 6 min: this was followed by a further gradual increase in insulin release. In contrast, it lowered [Ca(2+)]i with a nadir at 2-3 min followed by a gradual increase in [Ca²âº]i. The glucose effect was mimicked by 20 mM α-ketoisocaproic acid, a mitochondrial fuel, and it was nullified by 2 mM sodium azide, an inhibitor of mitochondrial electron transport. Cerulenin, an inhibitor of protein acylation, decreased the glucose effect. In conclusion, a rise in [Ca²âº]i through voltage-dependent Ca²âº channels is not mandatory for glucose-induced triggering of insulin release.

Agrobacterium-mediated genetic transformation using cotyledons in Japanese pear (Pyrus pyrifolia).

Genetic transformation was successfully established producing both transformed adventitious shoots and calli in Japanese pear (Pyrus pyrifolia Nakai) by using cotyledons as explants. Cotyledons of five cultivars were co-cultivated with Agrobacterium tumefaciens strain LBA4404 carrying the pBIN19-sgfp, which contained a green fluorescent protein gene and the neomycin phosphotransferase gene. In order to increase transformation efficiency, sonication and ethylenedioxybis (ethylamine)-N,N,N',N'-tetraacetic acid (EGTA) treatments were applied, which could produce physical wounds across the tissue and prevent plant defense reaction, respectively. Green fluorescent protein (GFP) fluorescence was evaluated two weeks and five months after Agrobacterium inoculation as measures of transient and stable transformations, respectively. As a result, sonication significantly increased both transient and stable expression of GFP fluorescence, whereas EGTA treatment did not show a positive effect on either. Out of 18 regenerated plantlets obtained, one plant regenerated from 'Agenosho Shinanashi' showed stable GFP fluorescence. This plant was confirmed as a transformant by PCR and genomic Southern blotting. Three other transformed regenerated shoots by myb gene showed red color, which were derived from 'Imamuraaki' by the same transformation method. Transformation system in this study was shown to be reproducible since plural transformants were obtained.

A case of severe and recurrent painless thyroiditis requiring thyroidectomy.

OBJECTIVE: To report a case of severe and recurrent painless thyroiditis requiring thyroidectomy. CLINICAL PRESENTATION AND INTERVENTION: A 47-year-old man who presented with severe thyrotoxicosis was found to have extremely low radioactive iodine uptake, negative TSH receptor antibodies, and normal C-reactive protein; these findings suggested a diagnosis of painless thyroiditis. Due to the severity and recurrence of thyrotoxicosis, surgical resection of the thyroid gland was performed to prevent a thyrotoxic storm. Histological examination revealed typical lymphoid infiltration of the thyroid gland. CONCLUSION: This case illustrates that a patient with painless thyroiditis was successfully treated with surgery.

Lipoaspirate stored at a constant low temperature by electric control suppresses intracellular metabolism and maintains high cell viability.

Background: Cell therapy is a useful treatment method for wide spectrum of diseases which utilizes the immunosuppressive and regenerative abilities of administered cells. It is essential to build a transport system of tissues from which cells are harvested, because various external factors, such as temperature, time, air pressure, and vibration affect the cell functions isolated from body tissues. In particular, temperature is a critical factor which determines the viability of the cells and organs. In this study, we investigated the optimal temperature during the transportation of lipoaspirates from which adipose -derived stem cells (ASCs) were isolated. Method: Lipoaspirates obtained by liposuctions (lipomatic or vaser method) were transported in four different temperature zones (4, 20, 32, and 37 °C) in a transport container which is electrically controlled to maintain a constant temperature during transport. Stromal vascular fractions (SVFs) were harvested from the lipoaspirate, and the cell number, viability and proliferation rate and the yield of ASCs were examined. In addition, the metabolic state of the cells was examined. Results: ASCs from lipoaspirates transported at high temperature significantly decreased cell viability, while those at low temperature maintained high cell viability and showed good cell proliferation. In addition, transportation of lipoaspirates at low temperature resulted in a high level of NAD+/NADH, coenzymes involved in intracellular metabolism, and a low level of lactate in lipoaspirate suppressed the glycolytic system of intracellular metabolism, in ASCs. Conclusion: The lipoaspirate transported at 4 °C exhibited best results regarding live cell number, viability and cell proliferation in our experiments. This study offers a direction to build a transport system that connects laboratories and hospitals and achieve a beneficial therapy for patients.

Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: modification of the core skeleton for improved solubility.

We recently reported the discovery of the novel pyrrolo[3,2-c]quinoline-4-one derivative 1 as a potent inhibitor of Hedgehog (Hh) pathway signaling. However, the PK evaluation of 1 at high dosage (100 mg/kg) revealed the C(max) value 3.63 µg/mL, likely due to poor solubility of this compound. Efforts to improve solubility by reducing the aromatic ring count of the core system led to N-methylpyrrolo[3,2-c]pyridine derivative 11. Further optimization of the 3-alkoxy group led to compound 11d with acceptable solubility and potent Hh inhibitory activity. Compound 11d suppressed transcription factor Gli1 mRNA expression in tumor-associated stromal tissue and inhibited tumor growth (treatment/control ratio, 3%) in a mouse medulloblastoma allograft model owing to the improved PK profile based on increased solubility. Compound 11d (TAK-441) is currently in clinical trials for the treatment of advanced solid tumors.

Discovery of pyrrolo[3,2-c]quinoline-4-one derivatives as novel hedgehog signaling inhibitors.

The Hedgehog (Hh) signaling pathway plays a significant role in the regulation of cell growth and differentiation during embryonic development. Since activation of the Hh signaling pathway is implicated in several types of human cancers, inhibitors of this pathway could be promising anticancer agents. Using high throughput screening, thieno[3,2-c]quinoline-4-one derivative 9a was identified as a compound of interest with potent in vitro activity but poor metabolic stability. Our efforts focused on enhancement of in vitro inhibitory activity and metabolic stability, including core ring conversion and side chain optimization. This led to the discovery of pyrrolo[3,2-c]quinoline-4-one derivative 12b, which has a structure distinct from previously reported Hh signaling inhibitors. Compound 12b suppressed stromal Gli1 mRNA expression in a murine model and demonstrated antitumor activity in a murine medulloblastoma allograft model.

Glucose-incretin interaction revisited.

Pancreatic beta cell dysfunction is pivotal to the development of diabetes, and restoration of insulin action is of primary importance. Here, we present a review of the mechanism of insulin secretion by pancreatic beta cells and discuss the mutual interaction of signaling pathways in stimulus-secretion coupling to better understand the scientific basis of pharmacological treatment for insulin secretion deficiency. Glucose stimulates insulin secretion via membrane depolarization by closure of ATP-sensitive K(+) channels (K(ATP) channels) and opening of L-type voltage-dependent Ca(2+) channels. The resultant elevation of cytosolic free Ca(2+) triggers insulin exocytosis. This is termed the "K(ATP)-dependent pathway" and is shared by sulfonylurea, which closes K(ATP) channels. Glucose also stimulates insulin release independent of its action on K(ATP) channels. This is referred to as the "K(ATP)-independent pathway," the molecular basis of which remains elusive. In the pancreatic beta cell, incretin hormones increase cAMP level, which enhances glucose-stimulated insulin release by protein kinase A-dependent and -independent mechanisms. Importantly, cAMP does not directly augment Ca(2+)-stimulated insulin release per se. The stimulatory level of ambient glucose is an absolute requirement for incretin to enhance insulin release. Therefore, incretin/cAMP enhances K(ATP)-independent insulinotropic action of glucose. The robust glucose-lowering effect of DPP4 inhibitor add-on in diabetic patients with sulfonylurea secondary failure is intriguing. With the clinical availability of DPP4 inhibitor and GLP-1 mimetics, the importance of the interactions between cAMP signaling and K(ATP) channel-independent actions of glucose is reappraised.

Fungal airsacculitis associated with multiple helminth infestations in a black-eared kite (Milvus migrans).

A young, female black-eared kite was rescued from a small reservoir adjacent to a rice paddy in Nagano Prefecture, Japan. The bird was given a fluid diet through the esophagus and started to eat by herself from the fifth day. Her fecal samples were examined for parasites on the seventh day and fluke eggs were detected. Capillaria and Ascarididae eggs were also detected from day 19 and day 32, respectively. The bird started to show loss of appetite from day 22 and finally showed no appetite on day 35. On day 38, the bird was treated with Profender Spot (Bayer Health Care, Tokyo, Japan) but died on day 41. A necropsy revealed a thickened air sac associated with considerable fungal growth. Histopathologic examination showed that the mucous membrane of the saccobronchus was thickened with hyphal proliferation, and the fungus was identified as Aspergillus fumigatus. A number of trematodes, thin nematodes, and four roundworms were obtained from the alimentary tract. Parasitologically, they were identified as Neodiplotomum pseudattenuatum, a Capillaria sp., and Porrocaecum phalacrocoracis, respectively. In conclusion, the bird was diagnosed as having fungal airsacculitis associated with multiple helminth infestations.