Fetal heart rate patterns complicated by chorioamnionitis and subsequent cerebral palsy in Japan.

AIM: This retrospective study was performed to investigate whether certain fetal heart rate patterns were associated with subsequent cerebral palsy (CP) in infants with chorioamnionitis at or near term. METHODS: We used cases registered by the Japan Obstetric Compensation System for CP, which is a nationwide population-based database. Among them, 133 infants with chorioamnionitis who were born at ≥34 weeks of gestation were enrolled. All infants underwent magnetic resonance imaging (MRI), and all fetal heart rate charts had been interpreted according to the National Institute of Child Health and Human Development criteria, focusing on antepartum and immediately before delivery. RESULTS: The incidence of CP after chorioamnionitis at ≥34 weeks of gestation was 0.3 per 10 000 in Japan. Between the clinical (24%) and subclinical groups (76%), the incidence of abnormal fetal heart rate patterns did not differ. According to the MRI classification, 88% of the infants with CP showed hypoxic-ischemic encephalopathy. Half of the infants with CP experienced terminal bradycardia, leading to severe acidosis and exclusively to hypoxic-ischemic encephalopathy. In another half, who did not experience bradycardia, 80% had moderate acidosis (pH 7.00-7.20) resulting in hypoxic-ischemic encephalopathy, and the remaining 20% showed non-acidosis resulting in brain damage other than hypoxic-ischemic encephalopathy. The fetal heart rate patterns before the terminal bradycardia showed that the incidence rates of late deceleration or decreased variability were high (>60%). CONCLUSION: Fifty percent of pregnant women with chorioamnionitis-related CP had terminal bradycardia that exclusively resulted in hypoxic-ischemic encephalopathy.

Association between fetal vascular malperfusion and gestational diabetes.

AIM: Diabetes mellitus (DM) is a major complication in pregnancy. Placental lesions with DM remain unclear and controversial. Recently, the terms of placental pathological findings, such as maternal and fetal vascular malperfusions (MVM and FVM, respectively) were introduced by the Amsterdam Placental Workshop Group Consensus Statement (APWGCS). FVM cases were classified as the partial obstruction type (global FVM) and the complete obstruction type (segmental FVM). The aim of this study was to clarify the pathological characteristics of the placenta with pregestational DM/gestational DM; GDM according to APWGCS. METHODS: We studied the placentas of 182 DM women (27 pregestational DM and 155 GDM) and control placentas of 460 women without DM during 2011-2018. We excluded cases of intrauterine fetal death or multiple pregnancies. We reviewed microscopical findings including, MVM, FVM, chorioamnionitis with the slides according to the APWGCS. RESULTS: Microscopically, the incidence of FVM was significantly higher in GDM patients than control (17% vs. 10%, p = 0.0138), but not significant in pregestational DM (11%, p = 0.7410). Segmental FVM (complete obstruction) was significantly more observed in GDM than control group (5% vs. 0.4%, p = 0.0013). Segmental FVM in GDM showed high incidence of light-for-dates infant (three of seven cases, 43%, p = 0.0288). In addition, several segmental FVM findings (villous stromal-vascular karyorrhexis and stem vessel occlusion) were frequently noted in 2 or 3 points positive of 75 g oral glucose tolerance test than 1 point positive GDM. CONCLUSION: Our placental findings suggest disorder of carbohydrate metabolism might affect the fetal vascular damage, especially complete fetal vascular obstruction.

Intrapartum fetal heart rate patterns and perinatal outcome in chorioamnionitis at or beyond 34 weeks of gestation.

AIM: To investigate intrapartum fetal heart rate (FHR) patterns in women with chorioamnionitis at or beyond 34 weeks of gestation in relation to neonatal outcome and to compare clinical and subclinical chorioamnionitis. METHODS: A retrospective questionnaire survey on deliveries during 2015 was conducted by the Perinatology Committee of the Japan Society of Obstetrics and Gynecology from 2016 to 2018. A total of 498 singleton births complicated by chorioamnionitis delivered at ≥34 weeks of gestation without major congenital malformations were included. The subjects were divided into clinical and subclinical chorioamnionitis groups based on Lencki's criteria. Poor perinatal outcome was defined as death or brain damage. We analyzed clinical features, FHR patterns in the last 2 h before delivery, gestational age, birthweight, Apgar score, umbilical arterial blood gas analysis, and infant's outcome. RESULTS: Incidence of chorioamnionitis at ≥34 weeks of gestation was 0.59% (522/87827). Clinical and subclinical chorioamnionitis comprised 240 and 258 cases, respectively. Abnormal FHR patterns (late deceleration or decreased baseline variability) were significantly associated with poor perinatal outcome. Combined late deceleration and decreased variability showed low positive predictive value (12.8%) and high negative predictive value (99.5%), and was significantly associated with long-term poor outcome in clinical chorioamnionitis only (odds ratio: 29.4, p < 0.01). Poor perinatal outcome showed no significant difference between the clinical and subclinical chorioamnionitis groups. CONCLUSIONS: Combined late deceleration and decreased variability could predict poor perinatal outcome in clinical chorioamnionitis. Poor perinatal outcome occurred in infants born to mothers with clinical and subclinical chorioamnionitis.

Improvement of visual function and ocular and systemic symptoms following blepharoptosis surgery.

Purpose: To study the changes of the visual function and ocular and systemic symptoms following blepharoptosis surgery.Methods: Seventy-eight involutional blepharoptosis patients (72.1 ± 6.4 years) underwent levator advancement procedure. Before and at 2 months after the surgery, OPD-Scan III (Nidek) was used to measure corneal astigmatism, total higher order aberrations (HOAs), and area ratio (AR), an index of the objective contrast sensitivity. FVA-100 (Nidek) was used to determine the functional visual acuity (FVA) and visual maintenance ratio (VMR). The ocular and systemic symptoms were also determined by a questionnaire using visual analogue scale (VAS) scores.Results: Before surgery, the corneal astigmatism, HOAs, AR, FVA, and VMR were 1.56 ± 0.52 diopters (D), 0.23 ± 0.24 µm, 14.8 ± 4.2%, 0.68 ± 0.32 logMAR units and 0.76 ± 0.06, respectively. After surgery, these values were 1.29 ± 0.41 D, 0.19 ± 0.21 µm, 18.6 ± 3.4%, 0.31 ± 0.18 logMAR units and 0.88 ± 0.03, respectively. Corneal astigmatism and HOAs were significantly reduced after surgery (P=0.007 and P=0.023, paired t test, respectively), and AR, FVA and VMR were significantly improved after surgery (P=0.033, P=0.012 and P=0.016, respectively). The VAS scores significantly improved after surgery, and this improvement was positively and significantly correlated with the increase of the AR (r=0.421, P=0.003) and the VMR (r=0.497, P =0.005).Conclusions: Blepharoptosis surgery is visual functionally beneficial and can help to reduce the ocular and systemic symptoms.

Evaluation of the risk factors for neurological and neurocognitive impairment after selective cerebral perfusion in thoracic aortic surgery.

PURPOSE: Neurologic complications are seen often after the surgery of the thoracic aorta that uses selective antegrade cerebral perfusion. The objective of this study was to evaluate the impact of atherosclerotic risk factors on neurologic complications in patients who underwent surgery to the thoracic aorta using SCP. METHODS: Data were collected retrospectively on 94 patients who underwent elective ascending aorta/aortic arch replacement. Concomitant procedures were performed as needed. All patients had magnetic resonance imaging (MRI), angiography (MRA) and carotid ultrasound before surgery. Individual cognitive status was measured using four neuropsychological tests before surgery and 7 days after extubation. We compared perioperative factors for risk factors associated with postoperative stroke and postoperative cognitive decline (POCD). RESULTS: 11 patients had strokes after surgery. Operation and extracorporeal circulation times were significantly longer in patients with stroke than those without stroke. Coronary artery disease and SCP time > 150 min were independently associated with postoperative stroke. Of the 83 patients without postoperative stroke, 20 suffered POCD. POCD patients had a significantly higher rate of heterogeneous carotid plaque, and operation time was significant longer in patients with POCD than those without POCD. Independent predictors of POCD were concomitant CABG, heterogeneous carotid plaque, history of cerebrovascular disease and operation time > 450 min. CONCLUSIONS: We found that prolonged SCP time and coronary artery disease increased the risk of postoperative stroke. Heterogeneous carotid plaque, history of cerebrovascular disease, concomitant CABG and prolonged operation time were further significant predictors of POCD.

Geranylgeraniol Suppresses the Expression of IRAK1 and TRAF6 to Inhibit NFκB Activation in Lipopolysaccharide-Induced Inflammatory Responses in Human Macrophage-Like Cells.

Geranylgeraniol (GGOH), a natural isoprenoid found in plants, has anti-inflammatory effects via inhibiting the activation of nuclear factor-kappa B (NFκB). However, its detailed mechanism has not yet been elucidated. Recent studies have revealed that isoprenoids can modulate signaling molecules in innate immune responses. We found that GGOH decreased the expression of lipopolysaccharide (LPS)-induced inflammatory genes in human macrophage-like THP-1 cells. Furthermore, we observed that the suppression of NFκB signaling proteins, in particular interleukin-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6), occurred in GGOH-treated cells prior to LPS stimulation, suggesting an immunomodulatory effect. These results indicate that GGOH may modulate and help prevent excessive NFκB activation that can lead to numerous diseases.

New method to analyze sagittal images of upper eyelid obtained by anterior segment optical coherence tomography.

Purpose: To report a new method to analyze sagittal images of the upper eyelid by anterior segment optical coherence tomography (AS-OCT). Methods: Ninety subjects equally divided into young (20-39 years), middle age (40-59 years), and elderly (60-79 years) group were studied. A sagittal image of the upper eyelid was obtained by AS-OCT (CASIA2, Tomey, Japan) and the following parameters were determined: upper eyelid thickness (UET), the distance between two parallel lines tangential to the apexes of the cornea and the upper eyelid; the upper eyelid angle (UEA) was the angle formed by a line running tangential to the apex of the cornea and a line passing from the apex of the cornea to the apex of the upper eyelid; and the cross-sectional area (CSA), the area from the edge of the eyelid to a point 6 mm above the corneal apex. All parameters were compared among groups and correlation analyses were studied between age and eyelid parameters. Results: The UET was 2.09 ± 0.58 mm, 2.63 ± 1.04 mm and 2.83 ± 0.83 mm in the young, middle age and elderly group, respectively. The difference between the young and the elderly group was significant (P = 0.014). The elderly group had a significantly larger UEA than that of young group (P = 0.022). The elderly group also had significantly larger CSA than the other two groups (all P < 0.01). The age was significantly correlated with all eyelid parameters. Conclusions: AS-OCT can be used as a non-invasive and quantitative method of evaluating sagittal images of the upper eyelid.

Orexigenic action of oral zinc: metabolomic analysis in the rat hypothalamus.

We previously reported an orexigenic action of oral zinc administration in male Sprague-Dawley (SD) rats during an early stage of feeding with a zinc-deficient diet, without decreased zinc concentrations in tissues. The overall conclusion was that orally but not intraperitoneally administered zinc stimulates food intake in short-term zinc-deficient-diet fed rats. We here investigate the mechanism of the orexigenic action of zinc using GC-MS/MS-targeted metabolomic analysis in the rat hypothalamus. Four-week-old, male SD/Slc rats were used, and after 2 days of feeding with a zinc-deficient diet, 3 mg of ZnSO4 in 5 mL saline solution were administered to each rat either orally or intraperitoneally. Three hours after administration, the rats were sacrificed and the hypothalamus were excised and analyzed. We found that the oral administration group showed increased concentrations of 3-aminopropanoic acid (ß-alanine), hypotaurine, dopamine, and biotin. In light of metabolomic analysis of these results, we indicate directions for further research.

Adenosine and adenosine-5'-monophosphate ingestion ameliorates abnormal glucose metabolism in mice fed a high-fat diet.

BACKGROUND: We have previously reported that ingestion of adenosine (ADN) and adenosine-5'-monophosphate (AMP) improves abnormal glucose metabolism in the stroke-prone spontaneously hypertensive rat model of non-obesity-associated insulin resistance. In this study, we investigated the effect of ADN and AMP ingestion on glucose metabolism in mice with high-fat diet-induced obesity. METHODS: Seven-week-old C57BL/6 J mice were administered distilled water (as a control), 10 mg/L ADN, or 13 mg/L AMP via their drinking water for 14 or 25 weeks, during which they were fed a high-fat diet. Oral glucose tolerance test (OGTT) was conducted on 21-week-old mice fasted for 16 h. Insulin tolerance test (ITT) was performed on 22-week-old mice fasted for 3 h. Blood and muscle were collected for further analysis of serum parameters, gene and protein expression levels, respectively. RESULTS: Glucose metabolism in the ADN and AMP groups was significantly improved compared with the control. OGTT and ITT showed that ADN and AMP groups lower than control group. Furthermore, phosphorylation of AMP-activated protein kinase (AMPK) and mRNA levels of genes involved in lipid oxidation were enhanced in the skeletal muscle of ADN- and AMP-treated mice. CONCLUSION: These results indicate that ingestion of ADN or AMP induces activation of AMPK in skeletal muscle and mitigates insulin resistance in mice with high-fat diet-induced diabetes.

Validity of rhinometry in measuring nasal patency for nasotracheal intubtion.

PURPOSE: Numerous techniques have been used to reduce epistaxis during nasotracheal intubation. Rhinometry can assess nasal patency in preoperative conditions. However, the possible role of rhinometry in routine nasotracheal intubation has not been studied. METHODS: One hundred and one patients undergoing dental and maxillofacial surgery that required general anesthesia and nasotracheal intubation were enrolled. We examined whether symmetry or any asymmetry in bilateral airflow patterns by condensation of the expiration, assessed by preoperative rhinometry on seated position, increased the incidence of epistaxis and the need for a nasogastric catheter to guide the endotracheal tube into the oropharynx. We also compared the incidence of changing the site of nasal intubation between the assessment by rhinometry and by cone-beam computed tomography analysis of nasal airspace in the inferior meatus. RESULTS: Patients with any asymmetry in bilateral airflow patterns were 18 % (n = 18), the remaining 82 % (n = 83) had symmetric bilateral nasal cavities. Patients with any asymmetry were more likely to need a guiding nasogastric catheter than patients with symmetry (22 vs. 3.6 %, p = 0.018). The incidence of epistaxis was higher in patients with any asymmetry (39 %) than those with symmetry (16 %), but there was no significant difference between groups (p = 0.055). The site of intubation was changed more frequently based on cone-beam computed tomography analysis than by rhinometry (38 vs. 11 %, p = 0.043). CONCLUSION: Preoperative rhinometry may be a valuable objective tool to assess nasal patency for nasotracheal intubation in patients who undergo dental and maxillofacial surgery.

Properties of Zip4 accumulation during zinc deficiency and its usefulness to evaluate zinc status: a study of the effects of zinc deficiency during lactation.

Systemic and cellular zinc homeostasis is elaborately controlled by ZIP and ZnT zinc transporters. Therefore, detailed characterization of their expression properties is of importance. Of these transporter proteins, Zip4 functions as the primarily important transporter to control systemic zinc homeostasis because of its indispensable function of zinc absorption in the small intestine. In this study, we closely investigated Zip4 protein accumulation in the rat small intestine in response to zinc status using an anti-Zip4 monoclonal antibody that we generated and contrasted this with the zinc-responsive activity of the membrane-bound alkaline phosphatase (ALP). We found that Zip4 accumulation is more rapid in response to zinc deficiency than previously thought. Accumulation increased in the jejunum as early as 1 day following a zinc-deficient diet. In the small intestine, Zip4 protein expression was higher in the jejunum than in the duodenum and was accompanied by reduction of ALP activity, suggesting that the jejunum can become zinc deficient more easily. Furthermore, by monitoring Zip4 accumulation levels and ALP activity in the duodenum and jejunum, we reasserted that zinc deficiency during lactation may transiently alter plasma glucose levels in the offspring in a sex-specific manner, without affecting homeostatic control of zinc metabolism. This confirms that zinc nutrition during lactation is extremely important for the health of the offspring. These results reveal that rapid Zip4 accumulation provides a significant conceptual advance in understanding the molecular basis of systemic zinc homeostatic control, and that properties of Zip4 protein accumulation are useful to evaluate zinc status closely.

Is Modified Radical Hysterectomy Needed for Patients with Clinical Stage I/II Endometrial Cancers? A Historical Control Study.

OBJECTIVE: The aim of the present study was to assess whether hysterectomy with wider resection could improve survival by preventing local recurrence. METHODS: Medical charts of the patients with clinical stage I/II endometrial cancers treated at our hospital between 1990 and 2009 were retrospectively analyzed. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and adverse effects according to the type of hysterectomy. RESULTS: A total of 247 patients were identified: 46 patients treated with total abdominal hysterectomy (TAH group) and 201 patients with modified radical hysterectomy (mRH group). No significant differences were observed in OS (p = 0.52) and PFS (p = 0.67) between the two groups. Also, there was no significant difference in the distribution of recurrent sites between the two groups. The patients treated with mRH had a longer operation time and more frequently developed severe adverse events, such as blood loss and lymphedema. CONCLUSION: In our cohorts, there were no significant differences in both PFS and OS according to surgical procedures, and the mRH group more frequently developed severe adverse events. Overall, clinical benefit was not obtained by mRH in patients with clinical stage I/II endometrial carcinomas.

Geranylgeraniol enhances testosterone production via the cAMP/protein kinase A pathway in testis-derived I-10 tumor cells.

Testosterone levels in men decrease with age; this decline has been linked to various diseases and can shorten life expectancy. Geranylgeraniol (GGOH) is an isoprenoid found in plants that plays an important role in several biological processes; however, its role in steroidogenesis is unknown. Here, we report that GGOH enhances the production of testosterone and its precursor progesterone in testis-derived I-10 tumor cells. GGOH induced protein kinase A (PKA) activity and increased cAMP levels and was found to regulate cAMP/PKA signaling by activating adenylate cyclase without altering phosphodiesterase activity. GGOH also stimulated mRNA and protein levels of steroidogenic acute regulatory protein, a downstream effector in the cAMP/PKA pathway. These results demonstrate that GGOH enhances steroidogenesis in testis-derived cells by modulating cAMP/PKA signaling. Our findings have potential applications for the development of therapeutics that increase testosterone levels in aging men.

Fermented rice bran supplementation mitigates metabolic syndrome in stroke-prone spontaneously hypertensive rats.

BACKGROUND: Previous study shown that enzyme treated-rice bran effectively improved hypertension and glucose intolerance in stroke-prone spontaneously hypertensive rat (SHRSP). However, dual fermentation of rice bran's efficacy against metabolic syndrome in SHRSP is still unknown. METHODS: Fermented rice bran (FRB) was prepared by dual fermentation of rice bran using fungi and lactic acid bacteria. The effect of FRB on metabolic syndrome in stroke-prone spontaneously hypertensive rats (SHRSP) was investigated by single and chronic supplementation. RESULTS: Dual fermentation of rice bran enriches the functional value of rice bran. Single-dose oral administration of FRB (2 g/kg body weight) reduced systolic blood pressure; however, chronic supplementation with 5 % FRB (4 weeks) significantly reduced both systolic and diastolic blood pressure. FRB supplementation improved leptin impairment and increased serum adiponectin levels and angiotensin-converting enzyme inhibitory activity. Furthermore, FRB supplementation improved glucose tolerance and insulin sensitivity as well as serum insulin levels. Lipid profiles were also improved by the regulation of 5' adenosine monophosphate-activated protein kinase activation. Moreover, supplementation with FRB reduced the expressions of hepatic transcription factors such as liver X receptor alpha, sterol regulatory element-binding protein 1c, and carbohydrate-responsive element-binding protein alpha, as well as their target genes. In conclusion, dietary supplementation with FRB may lower hypertension and alleviate metabolic syndrome. CONCLUSION: Metabolic syndrome was better alleviated with FRB supplementation. We therefore suggest FRB as an alternative medicine to reduce the risks of lifestyle-related diseases.

Cerebral dysfunction after coronary artery bypass surgery.

Cerebral dysfunction after cardiac surgery remains a devastating complication and is growing in importance with our aging populations. Neurological complications following cardiac surgery can be classified broadly as stroke, encephalopathy (including delirium), or postoperative cognitive dysfunction (POCD). These etiologies are caused primary by cerebral emboli, hypoperfusion, or inflammation that has largely been attributed to the use of cardiopulmonary bypass. Preventative operative strategies, such as off-pump coronary artery bypass grafting (CABG), can potentially reduce the incidence of postoperative neurological complications by avoiding manipulation of the ascending aorta. Although off-pump CABG is associated with reduced risk of stroke, there are no convincing differences in POCD between off-pump and on-pump CABG. Recently, the focus of postoperative neurological research has shifted from managing cardiopulmonary bypass to patient-related factors. Identifying changes in brains of aged individuals undergoing cardiac surgery may improve strategies for preventing cerebral dysfunction. Advanced age is associated with more undiagnosed cerebrovascular disease and is a major risk factor for stroke and POCD following cardiac surgery. Preoperative cerebrovascular evaluation and adaptation of surgical strategies will provide preventative approaches for cerebral dysfunction after CABG. This review focuses on recent findings of the relationship between perioperative stress and underlying fragility of the brain in cardiac surgical patients.

Incidence and predictors of difficult nasotracheal intubation with airway scope.

PURPOSE: The airway scope (AWS) improves views of the larynx during orotracheal intubation. However, the role of the AWS in routine nasotracheal intubation has not been studied adequately. METHODS: One hundred and three patients undergoing dental and maxillofacial surgery that required general anesthesia and nasotracheal intubation were enrolled. The study was approved by our Institution Review Board, and written informed consent was obtained from all patients. We evaluated the success rate of AWS intubation and the incidence of difficult nasotracheal intubation using a modified intubation difficulty scale (IDS) to examine preoperative characteristics and intubation profiles. Categories were difficult intubation (IDS ≥5), mildly difficult (IDS = 1-4), and intubation without difficulty (IDS = 0). We also assessed the incidence of the use of Magill forceps or cuff inflation (the cuff of endotracheal tube is inflated with 10-15 ml air) to guide the endotracheal tube into the glottis. RESULTS: AWS nasotracheal intubation was 100% successful. The cuff inflation technique was used in 37 patients. Neither Magill forceps nor other devices were needed for any patient during AWS use. The incidence of difficult nasotracheal intubation was 10% (n = 10). Of the patients, 61% (n = 63) had mildly difficult intubation and 29% (n = 30) had no difficulty. Patients with difficult intubation were more likely to be male and to have a larger tongue and a higher Cormack grade than in the other two groups. Complications, involving minor soft tissue injury, were observed in only 1 patient (1%). CONCLUSION: The AWS achieves a high success rate for nasotracheal intubation with cuff inflation in patients undergoing dental and maxillofacial surgery.

Safety and efficacy of ripasudil eye drops in preterm infants with retinopathy of prematurity: phase 1/2, open label, single-arm trial.

PURPOSE: To assess the safety and efficacy of ripasudil for retinopathy of prematurity (ROP). STUDY DESIGN: Phase 1/2, multicenter, open-label, single-arm, 12-week clinical trial. METHODS: Infants born with gestational age (GA) of ≤ 32 weeks or weight of ≤ 1500 g with zone I or II, ≥ stage 1, ROP in both eyes were enrolled. Ripasudil eye drops were administered to patients in both eyes. Phase 1 was a dose-escalation study (once daily for 1 week, then twice daily for 2 weeks); an additional dosing up to 9 weeks was allowed if no safety issues occurred. In phase 2, ripasudil was administered twice daily for up to 12 weeks. Adverse events were assessed. The proportion of patients with type 1 ROP progression, number of days for type 1 ROP progression, and progression to the most advanced ROP stage were estimated. RESULTS: Twenty-four infants were enrolled (phase 1, n = 3; phase 2, n = 21). Nineteen and four patients experienced systemic and ocular adverse events, respectively. Efficacy endpoints were not different between the ripasudil and historical control groups. However, in the GA ≤ 27 weeks subgroup, fewer patients progressed to type 1 ROP in the ripasudil than in the historical control group (P = 0.09). In the GA ≤ 27 weeks subgroups, the 25th percentile for the number of days for type 1 ROP progression was 22 days in the historical control group and 44 days in the ripasudil group. CONCLUSION: Ripasudil was safe and inhibited/delayed type 1 ROP progression, especially in infants with short GA.

Dietary supplementation with geranylgeraniol suppresses lipopolysaccharide-induced inflammation via inhibition of nuclear factor-κB activation in rats.

PURPOSE: The isoprenoid geranylgeraniol (GGOH) inhibits nuclear factor-kappa B (NF-κB) activation in the liver, yet the mechanism remains unclear. We investigated the modulation and inhibition of lipopolysaccharide (LPS)-induced NF-κB signaling in the liver of rats fed a GGOH-supplemented diet. METHODS: Rats were fed a diet supplemented with or without GGOH for 10 days. Rats were then intraperitoneally injected with 0.5 mg/kg LPS or vehicle (sterilized saline) and fasted for 18 h. Plasma levels of the inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6, and the liver damage indicators alanine and aspartate aminotransferases (ALT and AST) were assessed. Liver mRNA and proteins were assayed for changes in NF-κB target genes and signal transduction genes. RESULTS: Rats fed a high-dose, GGOH-supplemented diet showed significantly lower levels of plasma inflammatory cytokines and ALT and AST activities. In the liver, GGOH significantly suppressed NF-κB activation and mRNA expression of its pro-inflammatory target genes. Furthermore, GGOH supplementation substantially suppressed mRNA expression of signal transducer genes upstream of the IκB kinase complex. Western blotting of liver extracts further demonstrated the substantial decrease in total IL-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6), leading to lower signal transduction and inhibition of NF-κB after LPS. CONCLUSION: A 10-day, high-dose, GGOH-supplemented diet was sufficient to inhibit LPS-induced inflammation and activation of NF-κB in rat livers. GGOH significantly modulated NF-κB signaling molecules, inhibiting its signal transduction and activation in the liver, thus protecting against liver damage.

Weekly administration of bevacizumab, gemcitabine, and oxaliplatin in patients with recurrent and refractory ovarian cancer: a preliminary result of 19 cases.

OBJECTIVE: Combination therapy using gemcitabine with oxaliplatin (GEMOX) showed moderate activity in recurrent ovarian cancers. However, severe toxicities have been observed in patients who received full-dose therapy of GEMOX. On the other hand, bevacizumab enhances chemotherapeutic efficacy in various cancers. Here, we evaluated the effect of weekly low-dose administration of GEMOX in combination with bevacizumab (B-GEMOX) for patients with recurrent and refractory ovarian cancers (ROCs). METHODS: A total of 19 patients with ROC were treated with B-GEMOX: 2 mg/kg of bevacizumab, 300 mg/m(2) of gemcitabine, and 30 mg/m(2) of oxaliplatin, 3 weeks on and 1 week off, q4weeks. The treatment was continued until development of severe toxicities or progressive disease. Tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors and Gynecologic Cancer Intergroup criteria. RESULTS: Median number of the B-GEMOX therapy was 5 cycles. Response was observed in 4 (34%) cases by Response Evaluation Criteria in Solid Tumors, and in 2 (29%) cases by Gynecologic Cancer Intergroup criteria, resulting in overall response rate of 32%. Clinical benefit excluding progressive disease was obtained in 79% of the patients. Median progression-free survival was 4.5 months (range, 2-16+ months). Toxicities were mild and mainly consisted of hematologic, gastrointestinal, and neuropathy; however, there were no nonhematologic toxicities more than grade 1. CONCLUSIONS: Weekly administration of B-GEMOX was active for patients with ROC and showed mild toxicities. These results warrant further prospective studies for patients with ROC.

Analysis of Genetic Polymorphism of Bitter Taste Receptor TAS2R38 and TAS2R46, and Its Relationship with Eating and Drinking Habits in Japanese ToMMo Subjects.

Human type 2 taste receptor (TAS2R) genes encode bitter-taste receptors that are activated by various bitter ligands. It has been said that TAS2R38 may detect bitter substances and then suppress their intake by controlling gustatory or digestive responses. The major haplotypes of TAS2R38 involve three non-synonymous, closely-linked single-nucleotide polymorphisms (SNPs), leading to three amino acid substitutions (A49P, V262A and I296V) and resulting in a PAV or AVI allele. The allele frequency of AVI/PAV was 0.42/0.58 in this study. The genotype frequency distributions of TAS2R38 were 18.32%, 46.95% and 33.95% for AVI/AVI, AVI/PAV and PAV/PAV, respectively, and were in Hardy-Weinberg equilibrium. Five haplotype combinations of minor alleles were identified: AVI/AAV, AVI/AVV, AAI/PAV, AVI/PVV, AVI/AAI, with corresponding frequencies of 0.49%, 0.10%, 0.10%, 0.05%, 0.05%, respectively, in 2,047 Japanese Tohoku Medical Megabank Organization (ToMMo) subjects (2KJPN). The 16 subjects with these minor alleles were excluded from the questionnaire analysis, which found no significant differences among the major TAS2R38 genotypes (AVI/AVI, AVI/PAV and PAV/PAV) in the intake frequency of cruciferous vegetables or in the frequency of drinking alcohol. This result differs from previous data using American and European subjects. This is the first study to analyze the relationship between TAS2R38 genotype and the eating and drinking habits of Japanese subjects. It was also shown that there were no relationships at all between the genetic polymorphism of TAS2R46 and the phenotypes such as clinical BMI, eating and drinking habits among the 3 genotypes of TAS2R46 (∗/∗, ∗/W, W/W) at position W250∗ (∗stop codon).