Inhibitory Effects of Auraptene and Naringin on Astroglial Activation, Tau Hyperphosphorylation, and Suppression of Neurogenesis in the Hippocampus of Streptozotocin-Induced Hyperglycemic Mice.

Auraptene, a citrus-related compound, exerts anti-inflammatory effects in peripheral tissues, and we demonstrated these effects in the brains of a lipopolysaccharide-injected systemic inflammation animal model and a brain ischemic mouse model. Naringin, another citrus-related compound, has been shown to exert antioxidant effects in several animal models. Hyperglycemia induces oxidative stress and inflammation and causes extensive damage in the brain; therefore, we herein evaluated the anti-inflammatory and other effects of auraptene and naringin in streptozotocin-induced hyperglycemic mice. Both compounds inhibited astroglial activation and the hyperphosphorylation of tau at 231 of threonine in neurons, and also recovered the suppression of neurogenesis in the dentate gyrus of the hippocampus in hyperglycemic mice. These results suggested that auraptene and naringin have potential effects as neuroprotective agents in the brain.

Suppressive effects of the peel of Citrus kawachiensis (Kawachi Bankan) on astroglial activation, tau phosphorylation, and inhibition of neurogenesis in the hippocampus of type 2 diabetic db/db mice.

We previously reported that the dried peel powder of Citrus kawachiensis exerted anti-inflammatory effects in the brain in several animal models. Hyperglycemia induces inflammation and oxidative stress and causes massive damage in the brain; therefore, we herein examined the anti-inflammatory and other effects of the dried peel powder of C. kawachiensis in the streptozotocin-induced hyperglycemia mice model and in the type 2 diabetic db/db mice model. The C. kawachiensis administration inhibited microglial activation in the hippocampus in the streptozotocin-injected mice. Moreover, The C. kawachiensis treatment inhibited astroglial activation in the hippocampus and the hyperphosphorylation of tau at 231 of threonine and 396 of serine in hippocampal neurons, and also relieved the suppression of neurogenesis in the dentate gyrus of the hippocampus in the db/db mice. It was suggested that the dried peel powder of C. kawachiensis exerts anti-inflammatory and neuroprotective effects in the brain.

Phase I study of primary treatment with 5-FU, oxaliplatin, irinotecan, levofolinate, and panitumumab combination chemotherapy in patients with advanced/recurrent colorectal cancer involving the wild-type RAS gene: the JACCRO CC-14 study.

BACKGROUND: FOLFOXIRI is now regarded as the chemotherapy regimen that offers the best platform for the treatment of colorectal cancer. However, the safety and efficacy of FOLFOXIRI + panitumumab has not been demonstrated. We conducted a phase I study to determine the recommended dose of FOLFOXIRI + panitumumab as first-line treatment for RAS wild-type metastatic colorectal cancer (mCRC). METHODS: Patients received combination therapy consisting of panitumumab (6 mg/kg on day 1) + FOLFOXIRI [irinotecan (CPT-11), oxaliplatin (L-OHP) 85 mg/m2, and folinate (LV) 200 mg/m2] on day 1, followed by fluorouracil (5-FU) 3200 mg/m2 infused as a 46-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of RAS wild-type mCRC patients. A decrease in CPT-11 dose was planned (started at level 1: CPT-11 165 mg/m2). RESULTS: Seven patients were enrolled, and six were assessed for safety and efficacy. Maximum tolerated dose was not reached at level 1; all patients were treated at these levels. The common Grade 3 or 4 relevant toxicities were diarrhea (50%), hypokalemia (33%) and stomatitis (33%). No treatment-related deaths occurred. Of the six patients assessed four had partial response and the two others had stable disease; hence, the response rate was 66.7% (95% confidence interval 28.9-100%) and the disease control rate was 100%. Time to protocol treatment failure was 7.2 (1.4-7.3) months. CONCLUSION: The FOLFOXIRI + panitumumab chemotherapy regimen was well tolerated by our patients with mCRC and showed promising anti-tumor activity. The recommended phase II dose was determined to be the same as the standard doses of this regimen used worldwide.

Development and evaluation of an "Interdisciplinary Postoperative Support Program" in outpatient clinics after thoracic esophagectomy.

BACKGROUND: To support patients discharged from the hospital after surgery, we launched an "Interdisciplinary Postoperative Support Program" in outpatient clinics for patients who were discharged within 1 month after thoracic esophagectomy and their families. We introduce our program and clarify the patient's physical and psychologic status by analyzing the questionnaire provided from this program. MATERIALS AND METHODS: From August 2014 to January 2015, we conducted the Interdisciplinary Postoperative Support Program every month. Thus, questionnaires regarding physical and psychologic symptoms as well as the meaningfulness of the program were obtained from 59 patients and prospectively analyzed. RESULTS: We obtained valid responses from 48 patients (81.4%). Frequent postoperative difficulties included dysphagia (50%) and decreased physical strength (39.5%). Oral intake decreased to half (55.3%) and one-fourth (25.5%) of that before esophagectomy. Frequent requests made by patients to medical staff included explanations of the postoperative symptoms (97.9%), further information on the treatments of esophageal cancer (93.8%), and the typical postoperative course experienced by other patients (76.6%). A higher percentage of positive comments were obtained regarding the management of symptoms (87.8%) and optimal access to the consultations (78.9%). The incidences of unscheduled outpatient visits were 4.1% and 14.0%, respectively, under conditions with and without this postoperative program (P = 0.03). CONCLUSION: We found that our program could provide appropriate information with higher levels of satisfaction after thoracic esophagectomy. Further investigations regarding longer periods of physical and psychologic symptoms, as well as the needs of patients and their families should be conducted to augment our program.

[Efficacy of Rebamipide Gargle against Chemotherapy-induced Oral Mucositis].

Chemotherapy-induced oral mucositis (CIOM) is a severe adverse event resulting from cancer chemotherapy. Toxic free radicals and pro-inflammatory cytokines produced by anticancer drugs have been reported to be associated with CIOM. Rebamipide has been shown to increase gastric endogenous prostaglandin E2 and I2, to promote gastric epithelial mucin, and to behave as an oxygen free-radical scavenger in addition to other anti-inflammatory actions. We developed a gargle solution of rebamipide, adding ultrahydrogel for mucosal protection and to maintain rebamipide on the oral mucosa. A 300 mL rebamipide gargle solution combines 600 mg rebamipide, 3 g high molecular-weight polyethylene oxide, 1.2 g carrageenan, pineapple flavoring, and water. The efficacy of the rebamipide gargle was evaluated in 175 patients with CIOM from November 2009 to December 2012, each instructed to use the rebamipide gargle 5-6 times daily. The severity of CIOM was assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). Their CTCAE scores (3/2/1/0) changed from n=13/64/98/0 to 0/10/103/62, respectively, after initiation of the rebamipide gargle (p<0.01; paired t-test). The median duration to best response was 14 days (range: 1-49). CTCAE scores decreased in 132 patients (75.4%), including 62 (35.4%) who achieved grade 0. There were no unexpected safety events. Rebamipide gargle was well tolerated and demonstrated to have significant therapeutic efficacy against CIOM.

Altered responses to vasopressors of a patient medicated with carvedilol, pilsicainide and enalapril.

A patient scheduled for laparoscopic rectal surgery was medicated with carvedilol, an antagonist of beta 1-, beta 2- and alpha 1-adrenergic receptors, pilsicainide, a class Ic antiarrhythmic drug and enalapril, an angiotensin-converting enzyme inhibitor. Because the patient experienced attacks of atrial fibrillation with rapid ventricular response almost weekly, carvedilol and pilsicainide were continued up to the day of surgery, while enalapril was discontinued for 24 h prior to surgery. During the operation, he showed prolonged hypotension that did not respond to usual doses of vasopressors such as ephedrine, phenylephrine and dopamine but responded to higher doses of norepinephrine. Postoperatively, he was given dopamine but exhibited tachyarrhythmia until the dopamine infusion was discontinued.

Postoperative neuroleptic malignant syndrome-like symptoms improved with intravenous diazepam: a case report.

A 75-year-old man who had undergone left upper lobectomy of the lung exhibited fever and insomnia on postoperative day (POD) 1 and muscle rigidity, autonomic instability, and somnolence on POD2 after epidural administration of droperidol and withdrawal of oral etizolam. He had not been known to have any neuromuscular diseases or psychiatric diseases, with the exception of anxiety disorder. Brain computed tomography did not show cerebrovascular disorders. Consultation with a neurologist led to a suspicion of neuroleptic malignant syndrome (NMS). Epidural droperidol was stopped and administration of dantrolene was initiated. These measures, in addition to supportive care, only partially ameliorated the symptoms of the patient, and consciousness disturbance developed; the patient finally became comatose on POD3. However, intravenous diazepam (10 mg) improved his symptoms abruptly. Subsequently, oral administration of lorazepam (1 mg/day) was started, and his symptoms disappeared within 2 days (POD5). Although NMS-like symptoms are rarely seen in clinical practice, some factors may induce it during the perioperative period, such as the administration of dopamine antagonists and the cessation of benzodiazepines. Intravenous diazepam is an effective treatment in cases with suspected gamma-aminobutyric acid (GABA) hypoactivity at the GABA(A) receptor induced by the cessation of benzodiazepines.

[Evaluation of usability of an anticancer drug after changing it to liquid formulation].

Although the advantages of a liquid formulation over a lyophilized one have been mentioned, few studies have quantified the differences between the two. For the purpose of clarifying the advantages of a liquid formulation, we carried out a comparison of ELPLAT I. V. INFUSION SOLUTION, which is a liquid formulation of oxaliplatin, and ELPLAT FOR INJECTION, which is a lyophilized formulation of oxaliplatin. Since multiple factors(such as skill in drug preparation and the dosage)as well as the formulation influenced the preparation time, each factor was assessed by a Latin square design. The mean preparation time was 62. 39 seconds for the liquid formulation and 171. 22 seconds for the lyophilized formulation, and a decrease of approximately two minutes(p<0. 0001)was observed with the liquid formulation. Furthermore, after linear regression analysis of multiple factors, shortening of the preparation time was found to be related to the liquid formulation. The preparation time was significantly shortened according to the level of skill in drug preparation with the liquid formulation, but not the lyophilized formulation. This was because the total preparation time was relatively long for the lyophilized formulation. Superior usability of liquid formulation was shown by our quantification of the advantages of liquid oxaliplatin.

[A case-control study of factors associated with intermittent home care among elderly inpatients in home care wards].

We present a case-control study that was conducted to examine the factors associated with intermittent home care on elderly inpatients in home care wards. The results showed that the proportion of intermittent home care was approximately 20%, and the risks for intermittent home care were strongly associated with a lack of intention for continued home care for the elderly, lack of experience of home care, refusal of the family caregiver, and protracted length of stay.

[A comparison of the characteristics on cancer and non-cancer in-patients receiving a registration system based home support].

PURPOSE: To clarify the characteristics of cancer and non-cancer in-patients receiving a registration system based home support. METHODS: A total of 254 patients who were hospitalized from April 2009 to March 2010 were included for this observational study. An analysis was made by classifying the subjects into two groups: cancer group and non-cancer group. RESULTS: A comparison of the two groups showed that the cancer patient group consisted of many men (p<0. 01). The average BI score in the cancer patient group tended to be high upon admission and discharge(p<0. 005). The nursing care level was low(p<0. 01), and both the average length of stay(p<0. 01)as well as the average number of admissions were low(p<0. 05). In case of readmission, both the number of days from the previous discharge until the current admission and the number of days from registration until admission were low(p<0. 01). With regard to the number of drugs administered to the cancer patient group(p<0. 01), the use of narcotics(p=0. 000)was high. Sedative measures(p<0. 01)and the percentage of patients receiving nursing instructions(p<0. 01)were also high. On the other hand, the ratio of patients receiving oral care(p<0. 05), nasolgastric-tube(p<0. 01)and PEG(p<0. 01)was low and few patients needed care in relation to respiration(p<0. 01). Dietary care, physical care, bedsores and falls were not statically significant between two groups. The hospital mortality rate was significantly higher (p<0. 01)in the cancer patient group. CONCLUSIONS: A comparison of cancer and non-cancer in-patients regarding the support of a home-based medical care provided through the ward revealed that both home nursing and home medical care were required. Both physical care and preventive support measures were also needed as well. Cooperation between the hospital and community needs should be addressed for an effective home-care support measure during a hospitalization.

[Awareness during general anesthesia for head and neck surgery--a case report].

We report a second case of awareness during general anesthesia with sevoflurane supplemented with fentanyl. A 58-year-old man, weighing 61 kg, underwent an 8.8-hour operation for a malignant tumor of the right mandible. His right eye was guarded with ointment but kept open for observation of facial movement following muscle stimulation by the surgeon. The intraoperative course and emergence from anesthesia were otherwise uneventful. The patient became agitated in the recovery room and could recall his visual memory during the operation. We speculated contribution of visual input through the open eye and/or the effects of cranial bone oscillation during the surgery to his intraoperative awareness.

Effects of Kurozu concentrated liquid on adipocyte size in rats.

BACKGROUND: Kurozu concentrated liquid (KCL) is used as a health-promoting supplement for the treatment of disorders such as cancer, hyperlipidemia, and hypertension in Japan. We investigated the possible anti-obesity effects of KCL in rats. METHODS: Male Sprague Dawley rats were fed American Institute of Nutrition 76 formula diet and were orally administrated KCL or acetic acid at a dose of 100 mg/kg body weight or deionized water for 4 weeks. Adipocyte size, DNA content in subcutaneous adipose tissue, lipid levels in the serum and liver, and the rate of fatty acid excretion were determined. Effects of KCL on pancreatic lipase activity and 3T3-L1 preadipocyte differentiation were investigated in vitro. RESULTS: In the KCL group, the average adipocyte size in subcutaneous and perirenal adipose tissues was significantly reduced. The KCL-administered rats displayed greater numbers of small adipocytes in the subcutaneous, perirenal and mesenteric adipose tissues than did rats from the other groups. In the KCL group, the DNA content in subcutaneous adipose tissue was significantly increased. The rate of fatty acid excretion was significantly increased in the KCL group. Furthermore, KCL significantly inhibited pancreatic lipase activity in vitro, and also significantly inhibited fat accumulation and mRNA expression of fatty acid binding protein 2 (aP2) and peroxisome proliferator-activated γ (PPARγ) in 3T3-L1 preadipocyte. The levels of serum and liver lipids, the concentration of serum glucose, and the levels of adiponectin were similar among the 3 groups. CONCLUSION: Oral administration of KCL decreases the adipocyte size via inhibition of dietary fat absorption and reductions of PPARγ and aP2 mRNA expression levels in adipocytes.

[Myoclonus following spinal and epidural anesthesia--a case report].

We report a case of spinal myoclonus following cesarean section. The patient was a 34-year-old woman without history of neurologic disorders. In the operating room, after placement of an epidural catheter at T12-L1, bupivacaine 2.4 ml was administered intrathecally via a 25 G needle at L2-3. Epidural administration of ropivacaine (0.13%, 4 ml x hr(-1)) was started 72 min after spinal anesthesia. The intra- and postoperative courses were otherwise uneventful. The patient complained of involuntary jerky movements of her lower legs 195 min after the start of the spinal anesthesia. The sensory level was T12 and she could move her legs on command but could not stop her involuntary movements. The myoclonic movements ceased 150 min later without medication and did not reappear, despite restarting the epidural anesthesia with ropivacaine.

[Role of home medical care support system in aged cancer patients' symptom relief and regional alliances].

The aim of this study was to evaluate the role of home medical care support system to relieve the symptom and regional alliances for elderly cancer patients. We investigated clinical parameters to study the features of this system. The home medical care support system is designed for patients who are B75-year-old with decrease in activities of daily living and severe dementia. The support system plays a significant role in patients with impaired oral ingestion, dyspnea, delirium, and a poor general status.

[Anesthetic management of undiagnosed pheochromocytoma: a case report].

A 55-year-old man was scheduled for resection of an adrenal tumor under the diagnosis of a non-functioning adrenal tumor. He was admitted for unstable angina 58 days preoperatively, and on the second hospital day, he had an episode of ventricular tachycardia for 20 seconds following epigastric pain. Abdominal computed tomography scans revealed a retroperitoneal abscess, which was subsequently drained effectively, and a right adrenal tumor. Because of the almost normal plasma catecholamine concentration, the tumor was considered a nonfunctioning tumor. However, when the surgeon manipulated the tumor during the operation, the patient's blood pressure increased suddenly to 240/120 mmHg. The hypertensive crisis was managed with nicardipine and phentolamine. After resection of the tumor, his blood pressure decreased to 80/40 mmHg, and the patient was treated with ephedrine, phenylephrine, and noradrenaline. After surgery, the tumor was confirmed histopathologically as a pheochromocytoma. The management of patients with a hypertensive crisis under suspicion of pheochromocytoma is discussed.

[Anaphylactic reaction to latex during spinal anesthesia: a case report].

A 46-year-old man, with a history of atopic dermatitis and bronchial asthma, underwent surgery for an inguinal hernia. Forty-three minutes subsequent to spinal anesthesia, the patient complained suddenly of dyspnea with wheezing. Blood pressure decreased and skin eruption was observed on his chest. Postoperative laboratory tests revealed high IgE concentration, and a skin test confirmed an allergy to latex. The patient's allergic reaction was easily overlooked because of his history of bronchial asthma and the possibility that the hypotension was caused by the high spinal anesthesia. Latex allergy should be considered in any suspicious case presenting with these symptoms during surgery. After recovery, a skin test should be used to confirm the allergy to avoid repeated allergic episodes.

Transcriptional regulation of the Drosophila moira and osa genes by the DREF pathway.

The DNA replication-related element binding factor (DREF) plays an important role in regulation of cell proliferation in Drosophila, binding to DRE and activating transcription of genes carrying this element in their promoter regions. Overexpression of DREF in eye imaginal discs induces a rough eye phenotype in adults, which can be suppressed by half dose reduction of the osa or moira (mor) genes encoding subunits of the BRM complex. This ATP-dependent chromatin remodeling complex is known to control gene expression and the cell cycle. In the 5' flanking regions of the osa and mor genes, DRE and DRE-like sequences exist which contribute to their promoter activities. Expression levels and promoter activities of osa and mor are decreased in DREF knockdown cells and our results in vitro and in cultured cells indicate that transcription of osa and mor is regulated by the DRE/DREF regulatory pathway. In addition, mRNA levels of other BRM complex subunits and a target gene, string/cdc25, were found to be decreased by knockdown of DREF. These results indicate that DREF is involved in regulation of the BRM complex and thereby the cell cycle.

Identification of the Drosophila eIF4A gene as a target of the DREF transcription factor.

The DNA replication-related element-binding factor (DREF) regulates cell proliferation-related gene expression in Drosophila. We have carried out a genetic screening, taking advantage of the rough eye phenotype of transgenic flies that express full-length DREF in the eye imaginal discs and identified the eukaryotic initiation factor 4A (eIF4A) gene as a dominant suppressor of the DREF-induced rough eye phenotype. The eIF4A gene was here found to carry three DRE sequences, DRE1 (-40 to -47), DRE2 (-48 to -55), and DRE3 (-267 to -274) in its promoter region, these all being important for the eIF4A gene promoter activity in cultured Drosophila Kc cells and in living flies. Knockdown of DREF in Drosophila S2 cells decreased the eIF4A mRNA level and the eIF4A gene promoter activity. Furthermore, specific binding of DREF to genomic regions containing DRE sequences was demonstrated by chromatin immunoprecipitation assays using anti-DREF antibodies. Band mobility shift assays using Kc cell nuclear extracts revealed that DREF could bind to DRE1 and DRE3 sequences in the eIF4A gene promoter in vitro, but not to the DRE2 sequence. The results suggest that the eIF4A gene is under the control of the DREF pathway and DREF is therefore involved in the regulation of protein synthesis.

[Awareness during anesthesia with sevoflurane: a case report].

We report a case of a patient who experienced awareness during general anesthesia with sevoflurane. A 71-year-old man, weighing 57 kg, was operated on for a malignant tumor of the parotid gland. He was given 2 mg diazepam orally as a premedication. General anesthesia was induced by thiamylal 200 mg, fentanyl 50 microg, and up to 5% of sevoflurane. Muscle relaxation was obtained with vecuronium 6 mg, and the patient was intubated. After induction, fentanyl 150 microg was added, but no other intravenous anesthetics or muscle relaxants were used. The end-expiratory concentration of sevoflurane was maintained at 0.8% to 1.7% before the start of surgery, and 1.5% to 2.9% during surgery. The operation lasted for 10.4 hours. His left eye was guarded by ointment but kept open for observation by the surgeon of facial movement following muscle stimulation. The surgical course, emergence, and the postoperative course were uneventful. On the fifth postoperative day, the patient started to describe his visual memory during the operation, although he did not remember any pain or discomfort. We believe that visual input through his open eyes, the effect of cranial bone oscillation by the surgery, and the idiosyncrasy of the patient contributed to his intraoperative recall.

Distribution of the extrinsic proteins as a potential marker for the evolution of photosynthetic oxygen-evolving photosystem II.

Distribution of photosystem II (PSII) extrinsic proteins was examined using antibodies raised against various extrinsic proteins from different sources. The results showed that a glaucophyte (Cyanophora paradoxa) having the most primitive plastids contained the cyanobacterial-type extrinsic proteins (PsbO, PsbV, PsbU), and the primitive red algae (Cyanidium caldarium) contained the red algal-type extrinsic proteins (PsO, PsbQ', PsbV, PsbU), whereas a prasinophyte (Pyraminonas parkeae), which is one of the most primitive green algae, contained the green algal-type ones (PsbO, PsbP, PsbQ). These suggest that the extrinsic proteins had been diverged into cyanobacterial-, red algal- and green algal-types during early phases of evolution after a primary endosymbiosis. This study also showed that a haptophyte, diatoms and brown algae, which resulted from red algal secondary endosymbiosis, contained the red algal-type, whereas Euglena gracilis resulted from green algal secondary endosymbiosis contained the green algal-type extrinsic proteins, suggesting that the red algal- and green algal-type extrinsic proteins have been retained unchanged in the different lines of organisms following the secondary endosymbiosis. Based on these immunological analyses, together with the current genome data, the evolution of photosynthetic oxygen-evolving PSII was discussed from a view of distribution of the extrinsic proteins, and a new model for the evolution of the PSII extrinsic proteins was proposed.