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Introduction Hepatocellular carcinoma (HCC) is a common gastrointestinal cancer that occurs worldwide, and conventional transarterial chemoembolization (cTACE) is one of the first treatment choices for advanced HCC. However, biochemical factors and comorbidity have seldom been reported in the long-term outcomes. Methods This retrospective cohort study included 444 HCC patients who underwent cTACE-based therapy in 2010 to 2012. Survival outcomes were analyzed using a Kaplan–Meier curve and Cox regression analysis. Results The mean age was 62.1 ± 12.5 years, and 74.3% were men. Analysis of the mean biochemical values indicated that the presence of portal vein thrombosis, α-fetoprotein (AFP) >200 ng/mL, AJCC 7th stage III, diabetes, albumin Discussion The presence of venous thrombus and elevation of AFP levels are the most important factors in cTACE treatment. The host factors, including metabolic status and liver damage, should be evaluated in these patients.

Background Therapeutic hypothermia (TH) increases the risk of ventricular arrhythmia (VA) by prolonging action potential duration (APD) and steepening the APD restitution (APDR). The calcium sensitizer levosimendan, a medication for heart failure treatment, has been reported to shorten APD by enhancing ATP-sensitive K current and affect the APDR. Purpose We hypothesized that levosimendan might shorten the already prolonged APD particularly at long pacing cycle length (PCL), thus decreases the maximal slope of APDR, and prevent VA during TH. Methods Langendorff-perfused isolated rabbit hearts were subjected to 15-min TH (30°C) followed by 30-min treatment with levosimendan (0.5 μM, n=9) or vehicle (n=8). Using an optical mapping system, APD was evaluated by S1 pacing and APDR curve was plotted using APD70 versus diastolic interval. Ventricular fibrillation (VF) inducibility was evaluated by burst pacing for 30 s at the shortest PCL that achieved 1:1 ventricular capture. Results The APD was shortened from 259±8 ms at TH to 241±18 ms after levosimendan infusion at long PCL of 400 ms (p=0.024). However, at short PCL of 280 ms, the APD was not changed before (194±19) and after (188±23) levosimendan during TH (p=0.61). Levosimendan decreases the maximal slope of APDR curve from 1.99±0.65 at TH to 1.41±0.32 after adding levosimendan (p=0.034). The VF inducibility was decreased by levosimendan from 39±30% at 30°C to 14±12% with levosimendan (p=0.023). In control hearts, the maximal slope of APDR (p=0.75) and VF inducibility (p=0.12) were not changed by vehicle during TH. Conclusion Levosimendan might protect the hearts against VA during TH by shortening APD at long PCL and flattening the APDR. Enhancing ATP-sensitive K current with levosimendan during TH might be a novel approach to prevent VA during TH. Funding Acknowledgement Type of funding source: None

Background Hypoglycemic episode (HE) increases the risk of cardiovascular mortality. The impact of HE on the risk of sudden death remains unclear. We hypothesized that HE increases the risks of ventricular arrhythmia (VA) and sudden cardiac arrest (SCA), and that anti-diabetic agents (ADAs) causing hypoglycemia also increase the risks of VA and SCA. Methods Patients aged ≥20 years with newly diagnosed diabetes were identified from the Taiwan National Insurance Database. HE was defined as the presentation of hypoglycemic coma or specified/unspecified hypoglycemia. For control group, we included diabetic patients without HE, and they were frequency-matched to the HE group at a 4:1 ratio. The primary outcome was the occurrence of any event of VA (including ventricular tachycardia and fibrillation) and SCA during the defined follow-up periods. Multivariate Cox hazards regression model was used to evaluate the hazard ratio (HR) for VA or SCA. Results A total of 54,303 diabetic patients were screened with 1,037 of them in the HE group, and 4,148 in the control group. During a mean follow-up period of 3.3±2.5 years, 29 VA/SCA events had occurred. Compared to the control group, the HE group had a higher incidence of VA/SCA (adjusted HR: 2.42, p=0.04). Diabetic patients medicated with insulin for glycemic control increased the risk of VA/SCA compared to those without insulin (adjusted HR: 3.05, p=0.01). Kaplan-Meier survival curves Conclusions HEs in patients with diabetes increased the risks of VA and SCA compared to those without. Their use of insulin also independently increased the risk of VA/SCA.

Background Therapeutic hypothermia (TH) increases the susceptibility to ventricular arrhythmias (VA) by prolonging action potential duration (APD) and facilitating arrhythmogenic spatially discordant alternans (SDA). The calcium sensitizer levosimendan has been reported to shorten APD by enhancing ATP-sensitive K current. We hypothesize that levosimendan might shorten the already prolonged APD during TH, decreasing SDA threshold, and prevent the occurrence of VA. Methods Langendorff-perfused isolated rabbit hearts were subjected to 15-min TH (30°C) followed by 30-min treatment with levosimendan (0.5 μM, n=9) or vehicle (n=8). Using an optical mapping system, epicardial APD was evaluated by S1 pacing. SDA threshold was defined as the longest pacing cycle length (PCL) that induced SDA phenomenon. Ventricular fibrillation (VF) inducibility was evaluated by burst pacing for 30 s using the shortest PCL that achieved 1:1 ventricular capture. Results Levosimendan shortened the ventricular APD (at PCL 300 ms, from 229±9 ms to 211±18 ms, p=0.02) and decrease the SDA threshold (from 327±88 ms to 311±68 ms, p=0.001) during TH. The VF inducibility was decreased by levosimendan from 39±30% at 30°C to 14±12% after levosimendan infusion. In control hearts, the APD (p=0.75), SDA threshold (p=ns) and VF inducibility (p=0.12) were not changed by vehicle during TH. Conclusions Levosimendan protects the hearts against VA during TH by shortening APD and decreasing SDA threshold. Enhancing ATP-sensitive K current with levosimendan might be a novel approach to prevent VA during TH.

Background Atherosclerosis is an inflammatory disease characterized by lipid deposits in the subendothelial space leading to severe inflammation. Nonalcoholic fatty liver disease (NAFLD) shares several risk factors with atherosclerosis. Epidemiology studies have indicated that NAFLD may be an independent risk factor for atherosclerosis. Anti-inflammation therapy by inhibiting IL-1β led to a significantly lower cardiovascular event rate in recent clinical trial (CANTOS trial). Ling Zhi 8 (LZ8) is an immunomodulatory protein that possesses a broad range of pharmacological properties, including anti-inflammatory activities. Methods and findings In this study, we developed an oral vaccination of Lactococcus lactis expressing LZ8 protein in a nisin-controlled gene expression system and investigated its anti-inflammation properties. Experimental rabbits received commercial rabbit chow supplemented with 2% cholesterol for 5 weeks and recombinant LZ8 L. lactis vaccine once a day on weekdays. The expression of IL-1β in the aorta (Figure A) was significantly suppressed after LZ8 vaccination. Moreover, in hematoxylin and eosin staining of the aorta, the intima-medial thickness was decreased, and foam cells were significantly reduced in the sub-endothelial space (Figure C). LZ8 also inhibited the expression of IL-1β in the liver (Figure B), decreased fat droplet deposits and infiltration of inflammatory cells (Figure D), and improved liver function by decreasing liver enzymes. Figure 1 Conclusions Our results suggest that LZ8 could be used as a therapeutic tool to improve both atherosclerosis and NAFLD due to its anti-inflammatory effect. Acknowledgement/Funding TCVGH-1067317C, TCVGH-1063108C

Background Hepatocellular carcinoma (HCC) may arise from genomic instability and has dismal outcome. Sorafenib is the first-line treatment for advanced stage HCC, but its therapeutic efficacy is less than 50%. Biomarkers for predicting the therapeutic efficacy of sorafenib administration to patients with advanced HCC are required. Here, we evaluated the role of chromosomal copy number aberrations (CNAs) in patients with advanced HCC who were treated with sorafenib along with their drug response. Methods The response to sorafenib treatment of twenty-three HCC patients who developed advanced recurrence after partial hepatectomy was analyzed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Formalin fixed paraffin embedded (FFPE) tissue specimens obtained after tumor resection were analyzed using the Affymetrix OncoScan® FFPE assay. Results From the 23 patients analyzed in this study, 7 (30.4%) had complete/partial response to sorafenib (CR/PR), 7 (30.4%) had stable disease (SD), and 9 (39.1%) had progressive disease (PD). The mean genome-wide percentage of genome change acquisition via the OncoScan platform was 19.8% for patients with CR/PR/SD and 50.02% in the PD group (P = 0.055). Percentage of genome change above 33% was associated with adverse outcomes for sorafenib treatment in the time-to-progression analysis (P = 0.007) and overall survival (P = 0.096). Among these CNAs, amplification of chromosome 7q, containing the multidrug resistance gene ATP Binding Cassette Subfamily B Member 1 (ACBC1), significantly associated with poor overall survival (P = 0.004) and time-to-progression (P Conclusions Higher percentage genome change and amplification of chromosome 7q in advanced HCC is associated with sorafenib resistance.

The prognosis of patients after liver transplantation (LTx) with high Model of End-Stage Liver Disease (MELD) score (30) is predicted, but patients with lower MELD scores (30) have no conclusive studies of pre- and post-transplant risk factors that influence the long-term outcome.This retrospective study reviewed 268 recipients with MELD score 30, from 2008 to 2013 in our institution, for evaluation of pre-transplant risk factors including patients' clinical background data, pre-transplant lymphocyte subpopulation, and early post-transplant infection complication as predictors for long-term survival after LTx.The post-transplant patients' survival estimates were 90.7%, 85.1%, and 83.6% at 1, 3, and 5 years, respectively. In multivariate analysis, age55years, presence of ascites, cluster of differentiation (CD)3 93.2 (count/μL), CD4/CD8 2.4, fungal infection, and more than one site of fungal colonization significantly influenced survival (P = .0003, P = .002, P = .04, P = .004, P .0001, and P.0001, respectively). We also noticed that these five factors accumulatively influence the long-term survival rate; this means that in the presence of any two risk factors, the 5-year survival can still be 88.4%, whereas in the presence of any three risk factors, the survival rate dropped to only 57.1%.Older patients in the presence of pre-transplant low immune cell number and ascites in association with post-transplant fungal infection are the independent risk factors in MELD scores 30 LTx groups for long-term survival. Patients in these groups with any of the three factors had inferior long-term survival results.

Gallbladder carcinoma (GBC) is the seventh most common cancer across the globe and the most common malignancy of the biliary tract. Epithelial-mesenchymal transition (EMT) is an important pre-requisite for tumor metastasis; however, its mechanism in GBC has not yet been defined. In the present study, we investigated the effects of interleukin-37 (IL-37) on the epithelial-mesenchymal transition (EMT) of gallbladder cancer cells.RT-qPCR and Western blotting were used to determine the expression of IL-37 in GBC cancer cells and non-tumorigenic human intra-hepatic biliary epithelial cell line. Western blotting was also used for detecting the expression of vimentin, Snail, and E-cadherin.Expression level of IL-37 in GBC cells was decreased in GBC cancer cells compared with the non-tumorigenic human intra-hepatic biliary epithelial cell line. Decreased expression of vimentin and Snail and increased expression of E-cadherin were found in the groups which overexpress IL-37 when compared with the control. Mechanism study showed that IL-37 suppressed the expression of HIF1α in cells. However, HIF1α stabilization by CoCl2 could attenuate the function of IL-37.Our results indicate that IL-37 plays an antitumor role during the progression of gallbladder carcinoma. IL-37 could inhibit HIF1α induced EMT. Our data provide a new strategy for the treatment of gallbladder cancer.

Effective coordination of the biological stress response is integral for the behavioural well-being of an organism. Stress reactivity is coordinated by an interplay of the neuroendocrine system and the sympathetic nervous system. The hypothalamic-pituitary-adrenal (HPA) axis plays a key role in orchestrating the bodily responses to stress, and the activity of the axis can be modified by a wide range of experiential events. This review focuses on several factors that influence subsequent HPA axis reactivity. Some of these factors include early-life adversity, exposure to chronic stress, immune activation and traumatic brain injury. The central premise is that each of these experiences serves as a general vulnerability factor that accelerates future HPA axis reactivity in ways that make individuals more sensitive to stress challenges, therefore feeding forward into the exacerbation of ongoing (or greater susceptibility toward) future stress-related disease states, especially as they pertain to negative affect and overall brain health.

Objectives The optimal treatment for serious infections due to Enterococcus spp. is unknown although combination antimicrobial therapy is often recommended for invasive infections to achieve bactericidal activity and improve clinical outcomes. Oritavancin is a novel lipoglycopeptide agent with in vitro activity against enterococci, including vancomycin-resistant VanA-type Enterococcus faecium. Data on its activity in combination with other antibacterials are limited. The objective of this study was to evaluate the activity of oritavancin alone and in combination with ceftriaxone, daptomycin, gentamicin, linezolid and rifampicin against vancomycin-susceptible and -resistant enterococci in in vitro time-kill analyses. Methods Five enterococcal strains were used for all experiments: three vancomycin-resistant VanA-type E. faecium clinical bloodstream isolates, vancomycin-resistant VanA-type E. faecium ATCC 700221 and vancomycin-susceptible Enterococcus faecalis ATCC 29212. Individual drugs were tested at ¼, ½, 1, 2 and 4× MIC. Oritavancin combination experiments were performed with each agent at ¼× MIC. Results Daptomycin was the most active single agent and was bactericidal against all strains at 4× MIC, followed by oritavancin, which was bactericidal against all three clinical VRE strains at ≥2× MIC. In combination experiments at ¼× MIC, oritavancin was synergistic with gentamicin against strains not displaying high-level aminoglycoside resistance. No other synergy against VRE strains was observed in any experiment. Strain- and drug-dependent antagonism was observed for many combinations. Conclusions These in vitro data do not support the routine use of combination therapy with oritavancin in the treatment of infections due to VRE.

Background Currently, pancreas transplantation has been a promising strategy to restore long-term normoglycemia as well as to improve life quality for patients with insulin-dependent diabetes mellitus (DM). However, the discrepancy between the number of organs needed and the number donated for transplantation is always enormous. Under a setting of scarce organ donations, we examined our limited experience of pancreas transplantation. Methods A retrospective review of pancreas transplantations was performed with the use of data from the Taiwan Organ Registry and Sharing Center and the Ministry of Health and Welfare. Pancreas transplantations in the Organ Transplantation Institute of Chang Gung Memorial Hospital also were reviewed. Results At present, there are 5 medical centers approved for pancreas transplantation in Taiwan. Overall, a total of 156 pancreas transplantations were performed from 2005 to the end of 2016; only 9 of them were performed in the Organ Transplantation Institute of Chang Gung Memorial Hospital. Although the number of organ donations is rising, pancreas transplantation numbers remain low. More than 20 pancreas transplantations were performed in 2016, yet there remained a total of 111 patients registered on the wait list for pancreas transplantation at the end of this study. Thus the gap between organ donation and transplantation is still vast. Conclusions With continuing improvements in Taiwanese health policies and public education regarding organ transplantation, organ donation rates have risen steadily in recent years. Moreover, quality control and continuing evolution in organ transplantation is crucial to ameliorate the difficult situation of pancreas transplantation and other solid organ transplantation in the context of low levels of donation.

Given the central role of the decapeptide gonadotropin-releasing hormone (GnRH) in reproductive function, our long-term objective is to delineate the underlying mechanism regulating these reproductive processes. The outcome of GnRH secretion is in part dependent on the proteolytic metabolism of this decapeptide. In contrast to the belief that the metabolism of GnRH serves only as a degradative process that removes excess GnRH, we have shown that a metabolite of the decapeptide, GnRH-(1–5), can directly regulate GnRH gene expression and reproductive behavior. To further characterize the effect of GnRH-(1–5) on GnRH neuronal function, we determined whether GnRH-(1–5) can directly regulate GnRH secretion and pulsatility using an in vitro perifusion system. We compared the effect of GnRH-(1–5) on GnRH secretion in the immortalized GnRH neuron (GT1-7 cell line), whole rat hypothalamic explant, and enzymatically dispersed rat hypothalamic cells. Tissue preparations were perifused continuously for 9 h during which a 3-h challenge with GnRH-(1–5) was administered (4–6 h). The results show that treatment with GnRH-(1–5) increased (p

Reproduction involves the integration of hormonal signals acting across multiple systems to generate a synchronised physiological output. A critical component of reproduction is the luteinising hormone (LH) surge, which is mediated by oestradiol (E2) and neuroprogesterone interacting to stimulate kisspeptin release in the rostral periventricular nucleus of the third ventricle in rats. Recent evidence indicates the involvement of both classical and membrane E2 and progesterone signalling in this pathway. A metabolite of gonadotrophin-releasing hormone (GnRH), GnRH-(1-5), has been shown to stimulate GnRH expression and secretion, and has a role in the regulation of lordosis. Additionally, gonadotrophin release-inhibitory hormone (GnIH) projects to and influences the activity of GnRH neurones in birds. Stress-induced changes in GnIH have been shown to alter breeding behaviour in birds, demonstrating another mechanism for the molecular control of reproduction. Peripherally, paracrine and autocrine actions within the gonad have been suggested as therapeutic targets for infertility in both males and females. Dysfunction of testicular prostaglandin synthesis is a possible cause of idiopathic male infertility. Indeed, local production of melatonin and corticotrophin-releasing hormone could influence spermatogenesis via immune pathways in the gonad. In females, vascular endothelial growth factor A has been implicated in an angiogenic process that mediates development of the corpus luteum and thus fertility via the Notch signalling pathway. Age-induced decreases in fertility involve ovarian kisspeptin and its regulation of ovarian sympathetic innervation. Finally, morphological changes in the arcuate nucleus of the hypothalamus influence female sexual receptivity in rats. The processes mediating these morphological changes have been shown to involve the rapid effects of E2 controlling synaptogenesis in this hypothalamic nucleus. In summary, this review highlights new research in these areas, focusing on recent findings concerning the molecular mechanisms involved in the central and peripheral hormonal control of reproduction. Fil: Rudolph, L. M.. David Geffen School of Medicine at UCLA; Estados Unidos Fil: Bentley, G. E.. University of California at Berkeley; Estados Unidos Fil: Calandra, Ricardo Saul. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Paredes, A. H.. Universidad de Chile; Chile Fil: Tesone, Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Wu, T. J.. Uniformed Services University; Estados Unidos Fil: Micevych, P. E.. David Geffen School of Medicine at UCLA; Estados Unidos

Aim The aim of this trial was to determine whether whole-body vibration (WBV) induced via a noninvasive oscillation platform could improve symptoms and health-related quality of life (HRQOL) in patients with chronic functional constipation. Method A single-blinded, randomized controlled trial was performed in a single hospital in Taiwan. Patients diagnosed with chronic functional constipation, as per the Rome III diagnostic criteria, were included and randomized to either the WBV treatment or no treatment (control) group. The treatment group received six 15-min sessions of WBV therapy over a 2-week period. Patients received vibrations of 2 mm in amplitude at a frequency of 12 Hz. The primary outcome was whether constipation symptoms improved, assessed by the constipation severity instrument (CSI) and the secondary outcome measure was whether there was an improvement in HRQOL. Results Whole-body vibration therapy over a 2-week period in patients with chronic functional constipation (n = 14) significantly reduced the total CSI and obstructive defaecation subscale scores compared with control (n = 13). However, WBV did not improve the pain and chronic inertia subscale scores of the CSI or HRQOL. Conclusion These findings suggest that low-intensity WBV induced via a noninvasive oscillation platform may be an effective therapy for reducing symptom severity in patients with chronic functional constipation.

Left liver grafts have been widely utilized in adult liver transplantation (LT) and yielded acceptable results. However, the conventional orthotopic implantation of a left liver graft imposes the potential risk of perioperative vascular complications. We report herein an alternative modified technique for adult left liver LT and evaluate its feasibility in LT. In this study, 10 recipients had their left liver graft rotated 180°, and heterotopically implanted at the right subphrenic space, which we termed "left at right" liver transplantation (LAR-LT). The sequence of vascular and biliary reconstruction was performed as standard techniques, and no perioperative vascular complications related to LAR-LT were encountered. There were two mortalities in this series, one due to a small-for-size graft dysfunction and the other due to postoperative internal hemorrhage. Two recipients had biliary strictures that were successfully managed by percutaneous biliary dilatation and Roux-en-Y hepaticojejunostomy. The clinical characteristics and outcomes of patients undergoing LAR-LT were also compared with patients undergoing conventional orthotopic left liver LT (n = 14). Although the results showed no significant difference between the two groups, according to our experience, the satisfactory outcome and easier technical reconstruction suggest that the LAR-LT modification could be a feasible alternative to left liver LT.

Hypersensitivity syndrome associated with teicoplanin has rarely been reported. We report a case with a preceding episode of vancomyin-related neutropenia. A 47-year-old female with cervical spine infection was treated with vancomycin. Neutropenia occurred after 17 days of vancomycin therapy. Vancomycin was changed to teicoplanin, and the neutropenia resolved 4 days later. After 11 days of teicoplanin therapy, a new episode of hypersensitivity syndrome manifested as fever, bilateral neck lymphadenopathy, mild wheezing, hepatitis and increased CRP occurred. Neutropenia and thrombocytopenia developed 3 days later. The patient's symptoms settled over 1 week following withdrawal of teicoplanin. Naranjo's ADR algorithm categorized the neutropenia associated with vancomycin and the hypersensitivity syndrome associated with teicoplanin as 'probable'.

Objectives We sought to examine biliary complications in adult right-lobe living donor liver transplantation (LDLT) with duct-to-duct anastomosis (RL-LDLT-DD), evaluating the efficacy of endoscopic retrograde cholangiography (ERC) in the diagnosis and management of biliary complications following LDLT. Methods Ninety adult RL-LDLT-DD were performed from June 2004 to August 2007, including 21 (23.3%) cases of biliary complications. Results The endoscopic retrograde cholangiopancreatiography (ERCP) findings were stricture only (n = 8), stricture plus leakage (n = 9), and leakage only (n = 4). In the overall 13 cases of leakage, nine patients recovered after treatment by stent or endoscopic nasobiliary drainage. The time to resolution was 3.0 ± 1.3 months with 2.2 ± 1.3 endoscopic examinations. All bile duct complications were treated by ERC first. Among 17 cases with stricture, seven cases were successfully treated by endoscopy and three cases by percutaneous transhepatic cholangiography plus stent (PTCS). In the other seven cases, the treatment was still ongoing in five cases and two subjects died during treatment. The mean time to stricture resolution 7.2 ± 3.3 months with 3.9 ± 1.4 endoscopic examinations. The results of 21 cases were 5/21 mortalities (23.8%), successful ERC treatment in 9/21; (42.9%), successful PTCS treatment in 3/21 (14.3%), and ongoing ERC treatment in 5/21, (23.8%), including one case with successful ERC treatment who died of lung infection postoperatively. During follow-up (13.1 ± 9.9 months), there was no recurrence in the stricture or leak. Conclusions When compared with the literature, RL-LDLT-DD without biliary drainage does not increase the incidence of biliary complications. From our study, ERC and PTC play a complementary roles in the treatment of bile duct complications.

Luteinizing hormone-releasing hormone (LHRH) was first isolated in the mammalian hypothalamus and shown to be the primary regulator of the reproductive system through its initiation of pituitary gonadotropin release. Since its discovery, this form of LHRH (LHRH-I) has been shown to be one of many structural variants with a variety of roles in both the brain and peripheral tissues. Enormous interest has been focused on LHRH-I and LHRH-II and their cognate receptors as targets for designing therapies to treat cancers of the reproductive system. LHRH-I is processed by a zinc metalloendopeptidase EC 3.4.24.15 (EP24.15) that cleaves the hormone at the fifth and sixth bond of the decapeptide (Tyr5-Gly6) to form LHRH-( 1 – 5 ). We have previously reported that the autoregulation of LHRH gene expression can also be mediated by its processed peptide, LHRH-( 1 – 5 ). Furthermore, LHRH-( 1 – 5 ) has also been shown to be involved in cell proliferation. This review will focus on the possible roles of LHRH and its processed peptide, LHRH-( 1 – 5 ), in non-hypothalamic tissues.

The shape of core-stones remained in the weathering basalt column is an index to classify its weathered degree. In this paper, a roundness index (RI) like the box dimension using in fractal theory, was employed to quantitatively measure the shape of core-stone in various weathering grades. The rounded core-stone that is weathered seriously has a smaller RI value. According to the value of RI, the five classes shown in the Russell–Taylor–Pettijohn chart for visually classifying grain shape is available to approximately determine the weathered grades of core-stones remained in the basalt column in Taiwan. A slump test is preliminarily tested to show the difference in repose angle of a stability slope assembled by the grains in a similar shape. The collection of angular core-stones those are less weathered (with a higher RI value) indeed reveals a greater repose angle.

In the female rat, ovulation is preceded by a marked increase in the release of the decapeptide, LHRH, culminating in a preovulatory LH surge, which coincides with a period of sexual receptivity. The decapeptide, LHRH, is processed by a zinc metalloendopeptidase EC 3.4.24.15 (EP24.15) that cleaves the hormone at the Tyr(5)-Gly(6) bond. We have previously reported that the autoregulation of LHRH gene expression can also be mediated by its metabolite, LHRH-(1-5). Given the central function of LHRH in reproduction and reproductive behavior, we examined the role of the metabolite, LHRH-(1-5), in mediation of LHRH-facilitated reproductive behavior. Intracerebroventricular administration of LHRH-(1-5) facilitated sexual behavior responses, similar to those facilitated by the decapeptide LHRH, in ovariectomized estradiol-primed female rats. Furthermore, immunoneutralization of EP24.15 resulted in the inhibition of the LHRH-facilitated lordosis but had no inhibitory effects on LHRH-(1-5)-facilitated lordosis. The LHRH antagonist, Antide, was capable of inhibiting LHRH-facilitated lordosis, without affecting LHRH-(1-5)-facilitated lordosis. Collectively, these results suggest a role for LHRH metabolites in the facilitation of female receptive behavior in rats.

Metformin has been widely used in clinical type 2 diabetes treatment and prevention. The present study was designed to explore the effect on people with a sedentary lifestyle at therapeutic doses. Twenty-two physically-inactive volunteers with normal glucose tolerance were studied. Escalating doses of metformin in low-dose (250 mg), intermediate-dose (500 mg), and high-dose (750 mg) treatment three times per day were administrated into each subject for a three-week treatment period. Fasting plasma glucose, A1C, HOMA-IR for insulin resistance, lipid profile, and plasma beta-endorphin-like immunoreactivity (BER) were measured before treatment and weekly at the end of each dosing period. Metformin significantly reduced fasting plasma glucose and HOMA-IR in healthy humans after receiving this treatment at therapeutic doses including low-dose (5 %, 17 %), intermediate-dose (6 %, 25 %) and high-dose treatment (6 %, 21 %). Plasma BER was also increased from 135.46 +/- 61.73 pg/ml to 137.52 +/- 66.11 pg/ml by low-dosing (p = 0.39), to 139.17 +/- 64.08 pg/ml by intermediate-dosing (p = 0.32), and to 149.59 +/- 63.32 pg/ml by high-dosing (p < 0.05). Also, serum cholesterol decreased significantly using metformin at therapeutic doses including low-dose (4 %), intermediate-dose (8 %) and high-dose treatment (7 %). However, metformin failed to modify levels of serum HDL-cholesterol and C-reactive protein (CRP) in healthy subjects. Also, the reduction of serum cholesterol by metformin did not correlate to the increase in insulin sensitivity. In conclusion, metformin causes a significant parallel increase in insulin sensitivity and plasma beta-endorphin level in human subjects.

Introduction Acute humoral rejection (AHR), a rare complication in orthotopic liver transplantation (OLT), responds poorly to conventional therapies. Bortezomib, a proteasome inhibitor, has been shown to be effective in treating plasma cell–derived tumors and acute rejection episodes after renal transplantation. Herein, we have reported our clinical experience with bortezomib as a novel approach to treat AHR after OLT. Methods We retrospectively analyzed the 247 adult OLTs performed from January 2007 to April 2011. Patients with AHR who were treated with steroid pulses, rituximab (375 mg/m2), and plasmapheresis (PP) were assigned to group A. Group B subjects were prescribed steroid pulses, rituximab, PP, and bortezomib (1.3 mg/m2), after March 2009. Results Among the 9 patients (3.6%) diagnosed with AHR, all subjects in group A (n = 3) died within several days after AHR, whereas 4/6 (66.7%) group B patients were rescued and 3 (50%) survived at a mean follow-up 22.3 months (range, 18–26). Conclusion Proteasome inhibitor-based therapies provide a more effective strategy to treat AHR after OLT.

Polychlorinated biphenyls (PCBs) cause abnormal development and physiology of the reproductive system. We hypothesized that these effects may be mediated, at least in part, by neuroendocrine cells in the hypothalamus that integrate inputs to and outputs from the central nervous system and reproductive systems. The effects of two PCB mixtures, Aroclor 1221 and Aroclor 1254, were tested on the hypothalamic GT1-7 cells, which synthesize and secrete the key hypothalamic hormone, gonadotropin-releasing hormone (GnRH). GT1-7 cells were treated for 24 h in dose-response experiments and GnRH gene expression and release were quantified. Aroclor 1221 was stimulatory to GnRH gene expression, particularly at post-transcriptional levels (GnRH cytoplasmic mRNA), and increased GnRH peptide levels, suggesting a post-translational regulation of GnRH biosynthesis. It also caused a qualitative increase in GT1-7 neurite outgrowth and cell confluency. Aroclor 1254 had very different effects from Aroclor 1221. It inhibited GnRH nuclear mRNA levels at high dosages, and stimulated GnRH mRNA at low doses, suggesting a post-transcriptional mechanism of regulation. Aroclor 1254 did not alter GnRH peptide levels. Qualitatively, Aroclor 1254 caused a retraction of GT1-7 cell processes and neurotoxicity at high dosages. In order to gauge the involvement of the oestrogen receptor in these responses, the oestrogen receptor antagonist, ICI 182,780 (ICI) was coadministered in other studies with the PCBs. While effects of Aroclor 1221 on GnRH gene expression were not blocked by ICI, its effects on GnRH peptide levels were blocked by ICI, indicating that some but not all of the effects of Aroclor 1221 are mediated by the classical oestrogen receptor alpha and/or beta. The inhibitory effects of Aroclor 1254 on GnRH gene expression were not prevented by ICI, although ICI itself had stimulatory effects on GnRH gene expression that were blocked by cotreatment with Aroclor 1254. These results demonstrate a novel mechanism for effects of the two PCBs directly on GnRH gene expression, and indicate a hypothalamic level for endocrine disruption by these environmental toxicants.

This special issue of the Journal of Neuroendocrinology comprisesfive review articles, centred on the theme of the neuroendocrineregulation of homeostasis, and provides a snapshot of the sessionsat the 2013 International Workshop in Neuroendocrinology (IWNE).The workshop was held in Santa Clara Resort, in the town ofDourado, S~ao Paulo, Brazil, from 4–7 August 2013 and emergedfrom the unification of two independent neuroendocrine meetingsheld in August 2011: The First US–Latin American Workshop inNeuroendocrinology (Vi~na del Mar, Chile) and the First BrazilianInternational Symposium on Integrative Neuroendocrinology (Dourado,Brazil). The small, intimate venue not only facilitated scientificinteractions between Neuroendocrinologists from the United Statesand South America, but also provided graduate students and post-doctoral fellows with the opportunity to interact with each otherand with established investigators. It provided the unique opportu-nity for 11 competitively chosen young investigators to discusstheir research findings as an oral or poster presentation in aninformal setting. Several of these young investigators spearheadedthe writing and compilation of the review articles, with input fromthe established investigators.Stress coping mechanisms have evolved over phyla and play animportant role in the survival of the species. In adaptive responseto stress, living organisms redirect their physiological functionstowards the maintenance of homeostasis, by mobilising energystores and suppressing diverse processes such as feeding, bodyrepair, reproduction and behaviours. Glucocorticoids, the end prod-ucts of the stress-stimulated hypothalamic-pituitary-adrenal (HPA)axis, exert effects on multiple organ systems to regulate metabolic,cardiovascular, immune, behavioural and neuroendocrine activitiesto maintain homeostasis. Sex differences in stress reactivity as aresult of the activational effects of gonadal steroids are wellknown. The HPA and hypothalamic-pituitary-gonadal axes are inti-mately intertwined, wherein activation of the former affects thefunction of the latter and vice versa. In addition, the adaptive stressresponse is determined by genetic, environmental, nutritional anddevelopmental factors, which dictate the characteristics of themobilised defences against stressors throughout the lifespan. Thereviews in this special issue attempt to summarise current researchon various aspects related to the central theme of the neuroendocrineregulation of homeostasis.The first review by Uchoa et al. (1) discusses the current state ofknowledge about the regulation of the HPA axis by glucocorticoids,and elaborates the role of glucocorticoids in neural plasticity,immunomodulation and feeding behaviours. Toufexis et al. (2) out-line the complex interplay between the reproductive and stressaxes. Based on studies from rodents to primates, the review high-lights how stressors, during development and adulthood, disruptgonadal hormone-mediated neuroendocrine and behaviouralresponses and impair reproductive health and emotional wellbeing.The review by Boersma et al. (3) discusses how environmentalperturbations such as stress and nutrition during development canlead to epigenetic alterations and maladaptive consequences (i.e.obesity and heightened stress sensitivity) in adulthood. Amaralet al. (4) emphasise the importance of circadian rhythms in themaintenance of physiological homeostasis and discuss the impor-tance of hormonal and neural cues in the synchronisation of thecircadian timing system to the light/dark cycle. No discussion onneuroendocrine regulation can be complete without due consider-ation of the environmental effects of oestrogens on homeostasis.The review by Cruz et al. (5) discusses how neonatal exposure toenvironmental oestrogens can modify epigenetic programming andproduce alterations in reproductive function in adulthood.The topics covered in this issue on neuroendocrine regulation ofstress have important implications for the day-to-day lives of allliving organisms. Although neuroendocrinologists have begun tounravel the multifaceted and integrative mechanisms involved insuch regulation, we have barely touched the tip of the iceberg.Application of newer concepts and tools will potentially propel thefield into revealing the nuts and bolts biology of how stress exposurecan disrupt homeostatic functions, leading to pathophysiology.

A large-area high-density microwave plasma is successfully generated at low pressure by a tunable surface wave cavity which consists of a 12 period vane-type slow wave structure. This cavity is operated in the π mode and resonant at 2.45 GHz. The plasma area is in excess of 50 cm×25 cm with a uniformity of ±10% at pressures less than 30 mTorr. A plasma surface wave has been excited so that a plasma density as high as 1.0×1012 cm−3 can be achieved at 30 mTorr for a microwave power of 2.0 kW. The plasma temperature is ∼1.5 eV and the plasma potential is ∼12 V. Above all, the number of the periods of the π-mode cavity can be increased without changing the resonance frequency and the distribution of the microwave fields such that this plasma source is easy to up-scaled.

A linear theory model is developed to analyze traveling wave tubes (TWT) employing distributed wall loss. The loss can be a function of position. The electronic and circuit equation are derived, taking into account the spatial variation of the circuit loss. This model can be used to provide a first-cut design of the TWT.

In this study, a high power coupler designed for a tunable planar cavity is experimentally tested. The cavity consists of a periodical vane-type structure, of which the height of the vane can be mechanically adjusted so that the resonance frequency can be fine tuned. The cavity is designed to be operated at π mode and resonant at 2.45 GHz. The high power coupler is composed of a rectangular waveguide and a cylindrical ceramic rod with tapered ends. One end of the ceramic rod is intruded into the gap between two vanes of the cavity. Through this coupler, the TE10 mode of the rectangular waveguide is converted into the TE11 mode of the ceramic rod and then couples to the TEM mode in the gap between vanes of the cavity. Experimental results show that a microwave power up to 5 kW can be effectively transmitted to excite the π mode of the cavity . This cavity can be used to excite large area plasmas

In ongoing efforts to study the ontogeny of gonadotropin-releasing hormone (GnRH) neurons, we serendipitously observed that increasing times of incubation in antibodies enhanced signal detection. Here, we describe significant differences in the early migration pattern, population dynamics, and growth cone morphology from published reports. The first immunoreactive GnRH cells were detected in the mouse at E10.75 (7.6 +/- 2.8 cells; morning after mating = E0.5), prior to the closure of the olfactory placode. Although half of these cells were in the medial wall of the olfactory pit, the other half had already initiated their migration, and approximately one quarter had reached the telencephalic vesicle. Although the migratory pattern of the GnRH cells after E11.00 was identical to that described previously, these earliest migrating cells traveled singly rather than in cords, with some reaching the presumptive preoptic area (posterior to the ganglionic eminence) by E11.75. The number of GnRH cells increased significantly (p < 0.05) to 777 +/- 183 at E11.75 and peaked at 1949.6 +/- 161.6 (p < 0.05) at E12.75. The adult population was approximately 800 cells distributed between the central nervous system (CNS) and the nasal region. Hence, the population of GnRH neurons during early development is much larger than previously appreciated; mechanisms for its decline are discussed. Neuritic extensions on the earliest GnRH neurons are short (30-50 microm) and blunt and may represent the leading edge of the moving cell. By E12.75, GnRH axons in the CNS had a ribboned or beaded morphology and increasingly more complex growth cones were noted from this time until the day of birth. The most complex growth cones were associated with apparent choice points along the axons' trajectory. By E13.75, GnRH axons were seen at the presumptive median eminence in all animals, and it was at this stage that the axons began to branch profusely. Branching, as well as the presence of growth cones, continued post-natally. These results provide further insights into the pathfinding mechanisms of GnRH cells and axons.

The hypogonadal mouse is one of "nature's knockouts," bearing a specific deletion in the gene for gonadotropin-releasing hormone (GnRH), with the result that no GnRH peptide is detectable in the brain. The lack of reproductive development after birth provides an animal model that has proved fruitful in clarifying the role of GnRH in reproductive behavior and physiology. Behavioral studies with hypogonadal mice convincingly demonstrate that although GnRH may facilitate the appearance of sexual behavior, this peptide is not essential for either male or female sexual behavior in the mouse. Administration of GnRH to hypogonadal mice with regimens mimicking GnRH pulsatility initiates reproductive development. Surprisingly, continuous exposure to GnRH stimulates remarkable ovarian and uterine growth and increased FSH release, although pituitary content of LH and FSH remains unchanged. In contrast, when brain grafts of normal fetal preoptic area (POA), containing GnRH cells, are implanted in the third ventricle of adult hypogonadal mice, both pituitary and plasma gonadotropin levels increase. Grafted GnRH neurons innervate the median eminence of the host and support pulsatile LH secretion in the majority of animals with graft-associated gonadal development. Studies of hypogonadal mice with POA grafts demonstrate that distinct components of reproductive function are dissociable: hosts may demonstrate reflex but not spontaneous ovulation; others may show positive but not negative feedback. Activation of grafted GnRH cells in response to sensory input to the host, as revealed in Fos expression studies, is an example of the integration of the graft with the host brain that underlies such capabilities. A goal of these studies is to elucidate the specific connectivity underlying discrete aspects of reproductive function.

During development, an increase in gonadotropin-releasing hormone (GnRH) release occurs that is critical for the initiation of puberty. This increase is attributable, at least in part, to activation of the GnRH neurosecretory system by inputs from neurotransmitters, such as glutamate, acting via NMDA receptors. We examined changes in GnRH and NMDA-R1 gene expression by RNase protection assay of preoptic area-anterior hypothalamic (POA-AH) dissections of female rats undergoing normal puberty or in which precocious puberty was induced by treatment with the glutamate agonist NMA. GnRH mRNA levels increased significantly throughout normal development; this was accelerated by treatment with NMA. NMDA-R1 mRNA levels increased only between P10 and P20. The acceleration of the elevation in GnRH mRNA levels by NMDA suggests that a stimulation of GnRH gene expression may be a rate-limiting factor for the onset of puberty. This is attributable to a post-transcriptional mechanism because GnRH primary transcript levels, an index of proGnRH gene transcription, were not observed to change during puberty. Alterations in the colocalization of GnRH neurons with the NMDA-R1 subunit during puberty also were assessed immunocytochemically. The percentage of GnRH neurons that double-labeled with NMDA-R1 was 2% in prepubertal rats and 3% in pubertal rats; this increased to 19% in postpubertal rats. Taken together, these studies suggest that an increase in glutamatergic input to GnRH neurons plays a role in the increase in GnRH release and gene expression that occurs at the initiation of puberty.

SUMMARY We used FOS expression, widely accepted as a marker for neuronal activation, to evaluate physiologically induced activation of gonadotropin-releasing hormone (GnRH) neurons within intraventricular preoptic area grafts in hypogonadal (hpg) female mice. Hpg mice lack endogenous GnRH due to a mutated gene, but can respond to grafted GnRH neurons with reproductive development. The purpose of this study was to determine the degree to which the host brain regulates grafted GnRH neurons. FOS expression in grafted GnRH neurons was induced in progesterone-primed female mice paired with sexually active males. The degree of sexual activity did not affect the outcome, with 40.9 +- 12.2% of the grafted GnRH cells expressing FOS when male partners performed intromissions, and 47.5 f 10.2% when they also ejaculated. There was little or no FOS expression in the grafts of unprimed hpg mice paired with sexually active males, in unpaired mice primed with progesterone or sequential estradiol benzoate and progesterone, or in controls. The pattern of FOS expression in the brains of the female hpg mice engaged in mating behavior was similar to that reported in other species, with moderate to high expression in the medial preoptic area, ventromedial nucleus, and medial amygdala in females paired with males that ejaculated. The present results support the hypothesis that host-derived activation of grafted GnRH neurons underlies aspects of reproductive responses seen in hpg mice with grafts, and further, that at least a portion of the host-graft connectivity is steroid sensitive. o 1996

We have enhanced the luminance and the power efficiency of organic light-emitting devices with Hf-doped indium tin oxide (ITO) anodes instead of a CuPc layer. The Hf-doped ITO layer with a thickness of 15nm was deposited on top of the ITO anode. Less than 10mol.% of Hf was doped in ITO films by adjusting the sputtering rates of both sources. The highest work function of the Hf-doped ITO layers was 5.4eV at the Hf concentrations about 10mol.%. The driving voltages of the device have been reduced by 1V. A luminance of 1000cd∕m2 at 7mA∕cm2, a current efficiency of 14cd∕A, and a power efficiency of 6lm∕W at 6mA∕cm2 have been achieved in the device with a 4mol.% Hf-doped ITO layer (work function=5.2eV). In general, the performance was about 50% better than the device with a CuPc buffer layer.

Using a modified immunocytochemistry protocol with enhanced sensitivity, we were able to visualize a population of neurons in the tectum of the developing mouse that contained GnRH-like immunoreactivity. In microscopic studies conducted using 100 microns sections cut in sagittal or horizontal planes, 10-20 lightly-stained neurons were first detected in the tectum at E13.75 (morning of plug = E0.5). The number of immunostained cells increased exponentially reaching a peak at E15.75 before decreasing in number. No positive neurons were seen in the tectum at PN20 or later. The GnRH cells were located medially along the dorso-ventral axis of the tectum in a region of the brain distinct from that containing GnRH neurons that migrate into the CNS from the olfactory placode. To determine the nature of the immunoreactivity, two approaches were used. Analysis of tissue from an hpg mutant strongly supports the hypothesis that these cells make mammalian GnRH. Immunocytochemical data suggest that although the precursor protein is synthesized, the cleaved and amidated decapeptide may be absent or be present at an undetectable level. Our results demonstrate that in addition to the GnRH neurons from the placade, a population of GnRH neurons exists in the mouse tectum. This population is developmentally regulated, appearing only during embryonic and early postnatal ages but not in the adult.

The aim of this trial was to determine whether whole-body vibration (WBV) induced via a noninvasive oscillation platform could improve symptoms and health-related quality of life (HRQOL) in patients with chronic functional constipation.A single-blinded, randomized controlled trial was performed in a single hospital in Taiwan. Patients diagnosed with chronic functional constipation, as per the Rome III diagnostic criteria, were included and randomized to either the WBV treatment or no treatment (control) group. The treatment group received six 15-min sessions of WBV therapy over a 2-week period. Patients received vibrations of 2 mm in amplitude at a frequency of 12 Hz. The primary outcome was whether constipation symptoms improved, assessed by the constipation severity instrument (CSI) and the secondary outcome measure was whether there was an improvement in HRQOL.Whole-body vibration therapy over a 2-week period in patients with chronic functional constipation (n = 14) significantly reduced the total CSI and obstructive defaecation subscale scores compared with control (n = 13). However, WBV did not improve the pain and chronic inertia subscale scores of the CSI or HRQOL.These findings suggest that low-intensity WBV induced via a noninvasive oscillation platform may be an effective therapy for reducing symptom severity in patients with chronic functional constipation.

Steroid hormones are key modulators of the inter- and intra-cellular communications network used by the central nervous system. These hormones, although simple in structure, have the capacity to influence virtually all neural functions in a myriad of ways: from the programming, organization and maintenance of neurons and their connections during development, the activity and function of neurons in adulthood, to the death of neurons during aging and neuropathology. To stimulate scientific interactions between US and South American neuroendocrinologists interested in steroid hormone influences on a variety of physiological and behavioral events, including development, reproduction and energy homeostasis, the First US-South American Workshop in Neuroendocrinology was held in Vina del Mar, Chile from August 7–10, 2011. The site is known for its natural beauty and its historic importance in neuroscience [1] and provided an interesting backdrop for this important interchange. In a small and informal setting, this meeting fostered in-depth discussion of new ideas and interactions between young and established investigators using a wide array of model systems, strategies and technologies, from molecular to behavioral. It also provided a unique opportunity for 16 competitively chosen young investigators to present their research in oral or poster presentations and discuss their findings with established investigators in the field. This Special Issue of Hormone and Metabolic Research comprises the reviews and original articles that arose from this workshop. All have significant input from our promising young investigators who were in attendance. The meeting began with a keynote address by Jeffrey Blaustein (University of Massachusetts, Amherst) who explored the role of neuronal steroid hormone receptors as integrators of the internal and external environment [2]. The address provided a broad overview for this meeting and summarized key concepts that led to major advances in our understanding of how steroid hormone receptors are regulated in brain and influence behavior. He provided an overview of the neuroendocrine field, starting with the 1960s discovery of their regulation by steroid hormones, to the current day understanding of their regulation by neurotransmitters, membrane-initiated second messenger signaling pathways, and somatosensory inputs. Furthermore, he discussed how external factors, like stress, could have long-term effects on brain remodeling and steroid receptor regulation. Following his presentation, Victor Ramirez (University of Illinois, Urbana-Champagne) and Valeria Rettori (CEFYBO-CONICET-UBA, Buenos Aires, Argentina) provided a brief account of the rich interaction between the Americas over many decades. In particular, there was a tribute to the pioneers in the field, the late Samuel M. McCann, Charles H. Sawyer, and Bernardo Houssay whose scientific contributions had a tremendous impact across the continents. The discussion set the tone for the scientific sessions, which showcased presentations by young investigators alongside those of established investigators. Several of these young investigators are the lead authors of the reviews in this volume, which summarize the presentations within each of the sessions. Steroid sensitive neural circuits are implicated, not only in the control of reproductive hormone secretion and behaviors, but also in nonreproductive functions such as energy balance, stress and anxiety, emotion, aggression, cognition, metabolism, feeding, etc. The circuitry undergoes programming during development in a sex dependent manner that is dependent on genomic factors. In addition, environmental factors, both in utero and post-natal, also influence these functions throughout the lifespan. This issue attempts to encapsulate the current cutting-edge research on these various aspects that are related to steroid hormones. The reviews underscore some of these common themes. The first review discusses the current state of understanding of the molecular mechanisms of steroid hormone action [3]. Nugent et al. [4] integrates hormonal programming and function, from development through aging, on various tissue types including neurons, glia, and blood vessels. This review also discusses exciting genomic and epigenomic mechanisms that may work to alter the expression of critical hormone receptor genes. A discussion of steroid hormone action is never complete without a discussion of its role in regulating gonadotropin-releasing hormone (GnRH) and reproduction across species. Christiansen et al. [5] discuss several aspects of the regulation of GnRH by addressing a number of critical questions such as strategies involved in GnRH regulation and the internal and external conditions that modulate function and behavior. The review by Ismail et al. [6] demonstrates that a proper regulation of the stress axis relies on the complex interplay between genetic and environmental factors. Such influences could also affect the physiology and health of the offspring, including its role in metabolism as highlighted in the article by Boersma et al. [7]. The steroidal influences in not only metabolism, but neuropsychiatric health as well, rely on the interphase of the reproductive and stress axes as pointed out in the review by Fernandez-Guasti et al. [8]. How sex differences, programmed during development, and activated and subsequently modulated by gonadal steroids influence the outcome of risks to various psychiatric disorders are also discussed. Many challenges for this burgeoning field exist for the future. In the coming decade, important advances must be made in the field of neuroendocrinology using innovative technologies spanning the fields of molecular, computational, and systems biology to examine critical questions in the field. Such an integration of approaches is not that distant as exemplified by Sergio Ojeda (The Oregon Health Science University) in his presidential keynote address. His research on the basic mechanisms involved in GnRH regulation of puberty using novel systems biology approaches of high throughput screening has identified a highly organized hierarchical network of genes. Such powerful techniques have transformed our traditional views on regulation of puberty and the function of the brain. We are now witnessing the use of such novel approaches in the contributions of the young investigators in this volume. While the technologies available are certainly powerful, we cannot lose sight of the fact that traditional techniques will also find their place in the iterative process to define the function of the newly identified gene networks. We also cannot lose sight of the centralizty of neuroendocrinology modulation of most biological systems.

Reproduction is an event that requires the coordination of peripheral organs with the nervous system to ensure that the internal and external environments are optimal for successful procreation of the species. This is accomplished by the hypothalamic-pituitary-gonadal axis that coordinates reproductive behavior with ovulation. The primary signal from the central nervous system is gonadotropin-releasing hormone (GnRH), which modulates the activity of anterior pituitary gonadotropes regulating follicle stimulating hormone (FSH) and luteinizing hormone (LH) release. As ovarian follicles develop they release estradiol, which negatively regulates further release of GnRH and FSH. As estradiol concentrations peak they trigger the surge release of GnRH, which leads to LH release inducing ovulation. Release of GnRH within the central nervous system helps modulate reproductive behaviors providing a node at which control of reproduction is regulated. To address these issues, this review focuses on several critical questions. How is the HPG axis regulated in species with different reproductive strategies? What internal and external conditions modulate the synthesis and release of GnRH? How does GnRH modulate reproductive behavior within the hypothalamus? How does disease shift the activity of the HPG axis. Fil: Christensen, A.. University of California at Los Angeles; Estados Unidos Fil: Bentley, G. E.. University of California at Berkeley; Estados Unidos Fil: Cabrera Kreiker, Ricardo Jorge. Universidad de Mendoza; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Ortega, Hugo Hector. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Litoral; Argentina Fil: Perfito, N.. University of California at Berkeley; Estados Unidos Fil: Wu, T. J.. Uniformed Services University Of The Health Sciences; Estados Unidos Fil: Micevych, P.. University of California at Los Angeles; Estados Unidos

Objective The high rate of early major infections in liver transplantation recipients is due to their compromised immune-system. We examined the risk factors of early major infection in living donor liver transplantation (LDLT). Materials and methods From January 2004 to December 2010, 242 patients undergoing LDLT were enrolled in the prospective cohort. We prospectively collected their clinical and demographic variables, operative details, and posttransplant complications. Result One hundred thirty-nine patients (57.7%) experienced 252 episodes of early infection posttransplantation: bloodstream septicemia ( n = 46, 18.3%), urinary tract ( n = 34; 14.1%), pneumonia ( n = 64; 25.4%), peritonitis ( n = 62; 25.7%), and catheter related ( n = 46; 19%). The most frequent Gram-positive bacteria were coagulase-negative staphylococci ( n = 52; 16.9%), followed by Staphylococcus aureus ( n = 32; 10.4%). The most common Gram-negative bacteria were Escherichia coli ( n = 27; 8.8%); Acinetobacter baumannii ( n = 29; 9.4%), Pseudomonas aureos ( n = 18; 5.8%), and Sternotrophomonas maltophilia ( n = 18; 5.8%). Upon multivariate logistic regression analysis, the risk factors for early major infection were a high creatinine level (odds ratio = 1.481), a long anhepatic arterial phase (1.01), a reoperation (6.417), young age (1.040), and non-hepatocellular carcinoma recipient (2.141). Conclusion Early major infection after LDLT was high with Gram-positive bacteria, the most common etiologies. Prolonged anhepatic arterial phase, renal insufficiency, and reoperation were risk factors for an early major infection.

Background. Prolonged intubation results in ventilator-associated pneumonia (VAP), which contributes to significant mortality among patients on the waiting list. The aim of this study was to determine the risk factors for and clinical outcomes of VAP among patients into the intensive care unit (ICU). Methods. We enrolled 50 consecutive critically ill patients with end-stage liver disease admitted to the ICU from January 2005 through December 2010. All patients were intubated for more than 4 days; no definite infection was found initially. We evaluated potential risks factors for VAP and clinical outcomes. Results. Smoking, underlying liver disease, and lobar focal consolidations were significant factors for patients with versus without VAP. Fourteen-day mortality rates were 61.5% for VAP versus 40.5% for patients without VAP. Twenty-eight-day mortality rates for both groups were 92.3% and 86.5%, respectively. Multivariate analysis failed to identify independent predictors of early 14-day mortality. Conclusions. Underlying liver disease and lobar focal consolidations were risks factors for VAP in patients with prolonged intubation. Patients with prolonged intubation have a dismal prognosis even without VAP. The clinical outcomes of patients with versus without VAP were similar. However, early liver transplantation (14 days of intubation) improves the chance to rescue patients before development of VAP.

Purpose The aim of this study was to evaluate risk factors for an acute cellular rejection episode (ARE) among adult liver transplant (OLT) patients. Materials and methods We retrospectively reviewed 110 consecutive patients who underwent OLT between May 2007 and December 2010. The diagnosis of ARE was based upon clinical and biochemical data; liver biopsy was only performed when clinical presentation was equivocal. We recorded donor and recipient characteristics, perioperative immune status, and postoperative laboratory data. Forty patients (36.4%) who suffered a clinical rejection episode and received pulsed or recycled steroid therapy (R group), were compared with 70 (63.6%) free of rejection (N group). Results The mean age of R recipients was 46.61 ± 9.97 years, which was younger than the N group (51.86 ± 8.37, P = .005). R group patients displayed a lower pre-OLT creatinine (P = .016) and higher alanine aminotransferase (P = .048). Cox regression model showed recipient age to be the only significant factor to predict ARE (odds ratio = 1.071, P = .003). The cutpoint of age was 46 years by receiver operating characteristic analysis. Patients younger than 46 years showed higher initial CD8+ T-cell counts (P = .038). Conclusion Recipient age was significantly associated with ARE; younger patients showed higher CD8+ lymphocyte counts than older patients. More aggressive immunosuppression should be considered for younger recipients to prevent ARE.

Teicoplanin and vancomycin show similar clinical and bacteriological efficacy in clinical trials. Teicoplanin has been reported to have a lower adverse drug reaction (ADR) rate than vancomycin. Cross-reactivity between these two glycopeptides is controversial. Our aim was to study the cross-reactivity between teicoplanin and vancomycin through an assessment of all the reported ADRs of these drugs in our University hospital.Over a period of 2 years, 170 cases of vancomycin therapy, which were closely monitored by doctors and clinical pharmacists, were used to analyse ADRs. Teicoplanin therapy was used as an alternative in cases of vancomycin intolerance. When an ADR related to vancomycin or teicoplanin was suspected, specialists were consulted to confirm if these were true ADR and to determine whether the implicated drug should be stopped. All ADRs for the two glycopeptides were assessed for causality using the Naranjo probability scale.Thirty-eight of 170 patients (22·4%) treated with vancomycin developed ADRs. Twenty-four patients were switched to teicoplanin. However, 14 of those 24 patients (58·3%) developed ADRs. The time of onset of ADRs involving vancomycin was 12·7 ± 10·9 days (range, 1-46 days). The time of onset of sequential teicoplanin-induced ADRs was 11·7 ± 4·7 days (range, 2-20 days). Of the 14 patients with ADRs related to sequential teicoplanin therapy, six showed cross-reactivity between vancomycin and teicoplanin. The incidence of vancomycin-induced neutropenia was 4·7% (8/170), whereas the incidence of teicoplanin-induced neutropenia subsequent to vancomycin intolerance was as high as 33·3% (8/24). Furthermore, 71·4% (10/14) of the teicoplanin-induced ADRs were associated with haematological abnormalities such as neutropenia, thrombocytopenia or leucopenia.Teicoplanin, used as an alternative in cases of vancomycin intolerance, was associated with a high incidence of ADRs and haematological reactions, most notably neutropenia. This high rate of ADRs suggests cross-reactivity between the two glycopeptides.

Experiments were conducted to identify neurons in the bovine brain that express the LHRH gene and to determine whether LHRH mRNA levels are influenced by the ovaries. Two groups of postpubertal heifers were utilized: heifers killed during the mid-luteal phase of the estrous cycle (LUTEAL, n = 5) and heifers killed 14-16 wk following ovariectomy (OVX, n = 5). In situ hybridization was performed through use of a 52P-end-labeled deoxyoligonucleotide (59 mer) complementary to the human LHRH mRNA sequence. LHRH-expressing neurons were identified in the diagonal band of Broca, the preoptic area, and the anterior hypothalamus in a manner consistent with immunocytochemical localization. Reduced silver grains, proportional to LHRH mRNA content, were quantified (in pixels, 45x objective) with an image analysis system. Expected serum hormone concentration differences between endocrine states were confirmed by radioimmunoassay for progesterone (LUTEAL > OVX, p LUTEAL, p < 0.01). Compared to the OVX group, LUTEAL heifers had 34% fewer LHRH-expressing neurons (p < 0.05); on the average, these neurons possessed 28% fewer pixels/cell (p < 0.01), indicating fewer copies of LHRH mRNA per cell. When the numbers of pixels in all labeled cells were totalled, LUTEAL animals had 57% fewer pixels (p < 0.05) than did the OVX females-probably reflecting a decrease in LHRH synthetic capacity in the LUTEAL animals. Therefore, during the mid-luteal phase of the bovine estrous cycle, ovarian steroid (i.e., luteal progesterone) suppression of LHRH release (as reflected by serum LH) is coincident with decreased LHRH mRNA in the brain. In summary, the quantity of LHRH mRNA, as well as the number of detectable LHRH-expressing neurons in the bovine brain, is influenced by the ovaries.

Hypersensitivity syndrome associated with teicoplanin has rarely been reported. We report a case with a preceding episode of vancomyin-related neutropenia. A 47-year-old female with cervical spine infection was treated with vancomycin. Neutropenia occurred after 17 days of vancomycin therapy. Vancomycin was changed to teicoplanin, and the neutropenia resolved 4 days later. After 11 days of teicoplanin therapy, a new episode of hypersensitivity syndrome manifested as fever, bilateral neck lymphadenopathy, mild wheezing, hepatitis and increased CRP occurred. Neutropenia and thrombocytopenia developed 3 days later. The patient's symptoms settled over 1 week following withdrawal of teicoplanin. Naranjo's ADR algorithm categorized the neutropenia associated with vancomycin and the hypersensitivity syndrome associated with teicoplanin as 'probable'.

Overweight/obesity is currently a common health issue that may cause many diseases, even malignancies. The influence of steatosis on long-term results of surgical treatment for hepatocellular carcinoma (HCC) is not well known. The aim of this study is to analyze the results of hepatectomy for HCC patients with steatosis.The study included 1048 patients who underwent hepatectomy for HCC from 1999 to 2005. The patients were divided into two groups; group A patients without steatosis (n = 693) and group B patients with steatosis (n = 355). The clinicopathological data and long-term survival were analyzed.Mean tumor size in group B patients was smaller than that in group A patients (4.61 ± 3.40 vs. 5.91 ± 4.36 cm, p0.01). Group B patients showed lower tumor differentiation grade, lower vascular invasion rate and better 5-year overall survival compared to group A patients (61.2% vs. 50.1%, p = 0.001). By multivariate analysis, steatosis was found to be associated with well-differentiated, small-sized, and less α-fetoprotein productive tumors. When focusing on the tumors5 cm in diameter, group B patients had better survival rate than group A patients (p = 0.041). Vascular invasion and steatosis were independent prognostic factors for the overall survival.HCC in steatotic liver was less aggressive than that in non-steatotic liver. HCC patients with steatosis have better surgical outcomes than those without steatosis. Vascular invasion and steatosis were independent prognostic factors for the overall survival if tumors were5 cm in diameter.

Non-cirrhotic patients having acute liver decompensation in flares of hepatitis B can recover spontaneously or die without liver transplantation. Criteria for identifying patients in need of liver transplantation are lacking. Fifty-one non-cirrhotic patients having acute liver decompensation in flares of hepatitis B were retrospectively reviewed. The patients were divided into three groups: group A patients (n=18) recovered from acute liver decompensation spontaneously; group B patients (n=22) died of acute liver failure; and group C patients (n=11) had liver transplantation. Model of end-stage liver disease (MELD) scores were evaluated to identify the criteria for liver transplantation. The cut-off point of MELD scores for liver transplantation was evaluated by receiver operating characteristic (ROC) curve. Comparing group A and B patients, MELD score was an independent factor to predict prognosis. By analysing ROC curve, a MELD score30 was the most optimal cut-off point to indicate liver transplantation; however, the false positive rate was 11.1%. By weekly measurement of MELD scores, subsequent increase in MELD scores could help to avoid false positives. Moreover, a MELD score34 yielded 0% false positive rate and indicated the necessity of definite liver transplantation. For group C patients, ten of 11 patients were saved by liver transplantation. In conclusion, for the patients having acute liver decompensation in flares of hepatitis B, liver transplantation is definitely indicated by MELD scores34. Liver transplantation is also indicated if the MELD score increases in the subsequent 1-2 weeks. Liver transplantation has a good outcome if performed on time.

Hepatitis C recurrence after liver transplantation is universal and is a major cause of long-term graft failure. Improving the effectiveness of recurrent hepatitis C treatment is extremely important. We studied 35 anti-hepatitis C virus (HCV)-positive patients who underwent liver transplantation. Among the 35 patients, 25 patients had recurrent hepatitis C and received antiviral treatment. HCV RNA load after liver transplantation was increased by 3.68-fold. The antiviral treatment regimen comprised pegylated-interferon (180 μg) every 2 weeks and ribavirin at a dose of 200-400 mg every day. The treatment duration was flexible and individualized, and depended on viral response to treatment. The dosage of tacrolimus was decreased gradually to minimize immunocompromise. Median (interquartile) serum level of tacrolimus was 6.9 (6-8.9) ng/mL at initiation of treatment and 3.8 (3.6-5) ng/mL at the end of treatment. One patient (4.0%) was withdrawn from the study, and three patients (12%) died of infection during treatment. At end of treatment, 18 of 25 patients (72%) were negative for serum HCV RNA. After an additional 6 months following the end of treatment, 16 of the 25 patients (64%) had sustained viral response (SVR) and only two patients had HCV relapse. The 1-year, 3-year and 5-year survival rates were 91.4%, 84.5% and 84.5% for all patients and 88.0%, 82.8% and 82.8% for the 25 patients who received antiviral therapy. In conclusion, recurrent HCV infection is an important issue in liver transplantation. The flexible regimen of antiviral therapy and individualized immunosuppressive agents that was applied in this study achieved a SVR rate of 64%.

Murine CTL have seven serine proteases, known as granzymes, in their lytic granules. Despite considerable effort, convincing evidence that these enzymes play an obligatory role in the lytic process has not been presented. To investigate the function of one of these proteases, granzyme A (GA), we utilized an antisense expression vector to lower the level of the enzyme in the cells. An expression vector containing antisense cDNA for GA and the gene for hygromycin B resistance was constructed and electroporated into the murine CTL line, AR1. Transfectants were selected based on resistance to hygromycin B, and a number of stable lines were developed. One of the antisense lines had greatly reduced levels of GA mRNA, when compared to the parental cells or to control lines transfected with the vector lacking the antisense DNA. The message levels for two other CTL granule proteins, granzyme B and perforin, were unaffected by the antisense vector. The amount of GA, as measured by enzymatic activity, was 3- to 10-fold lower in the transfectant. Most significantly, this line also consistently showed 50 to 70% lower ability to lyse nucleated target cells and to degrade their DNA. Furthermore, it exhibited 90 to 95% lower lytic activity to anti-CD3-coated SRBC. Conjugate formation with target cells, however, was normal. These data provide strong evidence that GA plays an important role in the cytolytic cycle, and that the quantity of enzyme is a limiting factor in these cytolytic cells.

A study was conducted to further understand involvement of the endogenous opioid peptides in suckling-induced inhibition of LH release in ovariectomized rats. The first experiment was designed to determine the effect of an opioid antagonist, naloxone (NAL, 1.0 mg. kg-1h-1), on the increase in peripheral LH concentration 18 h after pup removal and on the decrease in LH concentration 18 h after pup return. Infusion of NAL during the 18 h after pup removal or during the 18 h after pup return neither accentuated nor attenuated serum LH concentrations. The second experiment was designed to determine the effect of NAL on peripheral LH concentrations in continuously suckled rats. Serum LH increased (p less than 0.10 and p less than 0.005, respectively) in response to 18 and 36 h of NAL infusion. The third experiment was designed to determine the effect of pup removal during NAL infusion on serum LH. Peripheral LH concentrations were not different in the rats treated with 36 h of NAL infusion whether they were suckled for the duration of the infusion or nonsuckled for the last 18 h of infusion. These results suggest that suckling may inhibit LH release through two mechanisms. The first may be an opioid-independent or enhanced opioid tone mechanism important for the initiation of the inhibitory effect of suckling on LH release, while the second may be an opioid-dependent mechanism important for the sustained inhibitory effect of suckling on LH release.