Seroepidemiological Studies of Arboviruses in Africa.

The literature on sero-epidemiological studies of flaviviral infections in the African continent is quite scarce. Much of the viral epidemiology studies have been focussing on diseases such as HIV/AIDS because of their sheer magnitude and impact on the lives of people in the various affected countries. Increasingly disease outbreaks caused by arboviruses such as the recent cases of chikungunya virus, dengue virus and yellow fever virus have prompted renewed interest in studying these viruses. International agencies from the US, several EU nations and China are starting to build collaborations to build capacity in many African countries together with established institutions to conduct these studies. The Tofo Advanced Study Week (TASW) was established to bring the best scientists from the world to the tiny seaside town of Praia do Tofo to rub shoulders with African virologists and discuss cutting-edge science and listen to the work of researchers in the field. In 2015 the 1st TASW focussed on Ebola virus. The collections of abstracts from participants at the 2nd TASW which focused on Dengue and Zika virus as well as presentations on other arboviruses are collated in this chapter.

[Gender-Specific Differences in Liver Transplantation]. / Genderspezifische Unterschiede im Rahmen der Lebertransplantation.

Liver transplantation is the treatment of choice for acute hepatic failure or endstage liver disease. Long-time outcome following liver transplantation has been increased as a result of improvements in surgical technique, perioperative management, organ procurement and immunuosuppression. Differences in liver disease, access and allocation to liver transplantation as outcome due to gender have been reported. This review highlights the important differences in the field of liver transplantation.

Melatonin induces transcriptional regulation of Bim by FoxO3a in HepG2 cells.

BACKGROUND: Melatonin induces apoptosis in many different cancer cell lines, including hepatocellular carcinoma cells. However, the responsible pathways have not been clearly elucidated. A member of the forkhead transcription factors' family, FoxO3a, has been implicated in the expression of the proapoptotic protein Bim (a Bcl-2-interacting mediator of cell death). In this study, we used human HepG2 liver cancer cells as an in vitro model to investigate whether melatonin treatment induces Bim through regulation by the transcription factor FoxO3a. METHODS: Cytotoxicity of melatonin was compared in HepG2 hepatoblastoma cells and primary human hepatocytes. Proapoptotic Bim expression was analysed by reverse transcriptase-polymerase chain reaction and western blot. Reporter gene assays and chromatin immunoprecipitation assays were performed to analyse whether FoxO3a transactivates the Bim promoter. Small interfering RNA (siRNA) was used to study the role of FoxO3a in Bim expression. Immunofluorescence was performed to analyse FoxO3a localisation in HepG2 cells. RESULTS: Melatonin treatment induces apoptosis in HepG2 cells, but not in primary human hepatocytes. The proapoptotic effect was mediated by increased expression of the BH3-only protein Bim. During melatonin treatment, we observed increased transcriptional activity of the forkhead-responsive element and could demonstrate that FoxO3a binds to a specific sequence within the Bim promoter. Furthermore, melatonin reduced phosphorylation of FoxO3a at Thr(32) and Ser(253), and induced its increased nuclear localisation. Moreover, silencing experiments with FoxO3a siRNA prevented Bim upregulation. CONCLUSION: This study shows that melatonin can induce apoptosis in HepG2 hepatocarcinoma cells through the upregulation of proapoptotic Bim mediated by nuclear translocation and activation of the transcription factor FoxO3a.

[Hilar cholangiocarcinoma: right versus left hepatectomy]. / Hiläres Cholangiokarzinom: rechts- versus linksseitige En-bloc-Resektion.

INTRODUCTION: Right-sided hepatectomy including segment 1 and right trisectionectomy are typical approaches to surgical treatment of hilar cholangiocarcinoma. In this study we have compared the oncological capacity of this approach to left-sided hepatectomy. PATIENTS AND PROCEDURES: In 223 patients referred to our institution 150 hepatic resections were performed: 14 hilar resections, 68 right and 68 left hepatectomies. RESULTS: Survival after curative (R0) and palliative surgery was significantly superior to that in patient with exploration or no surgery at all (p < 0.0001). 5- and 10-year survival after right versus left hepatectomy was 29 and 22 % versus 21 and 7 % (p = 0.204). If hospital mortality was eliminated, survival after right hepatectomy was marginally significantly superior to that after left-sided hepatectomy (p = 0.041). Hospital mortality was 13 % after right compared to 4 % after left hepatectomy (p = 0.069). The R situation was of prognostic importance following right and the N situation after left hepatectomy (p = 0.038 and 0.01, respectively). Vascular resection - in right-sided procedures performed as "hilar en bloc resection" - did not influence the outcome. CONCLUSIONS: Low perioperative mortality after left-sided resection and, obviously, inferior oncological radicality are features of left hepatectomy. These features do not detract from the importance of left hepatectomy which is an indispensable approach to surgically treated patients with hilar cholangiocarcinoma.

Structured diabetes self-management education and its association with perceived diabetes knowledge, information, and disease distress: Results of a nationwide population-based study.

OBJECTIVE: To evaluate, how participation in structured diabetes self-management education (DSME) programs is associated with perceived level of knowledge about diabetes, information needs, information sources and disease distress. METHODS: We included 796 ever- and 277 never-DSME participants of the population-based survey "Disease knowledge and information needs - Diabetes mellitus (2017)" from Germany. Data on perceived level of diabetes knowledge (12 items), information needs (11 items), information sources (13 items) and disease distress (2 indices) were collected. Multiple logistic regression analyses were used to examine the association of DSME-participation with these outcomes. RESULTS: DSME-participants showed a higher level of diabetes knowledge compared to never-DSME participants, particularly in aspects concerning diabetes in general (odds ratio 2.53; 95% confidence intervals 1.48-4.33), treatment (2.41; 1.36-4.26), acute complications (1.91; 1.07-3.41) and diabetes in everyday life (1.83; 1.04-3.22). DSME-participants showed higher information needs regarding late complications (1.51; 1.04-2.18) and acute complications (1.71; 1.71-2.48) than DSME never participants. DSME-participants more frequently consulted diabetologists (5.54; 3.56-8.60) and diabetes care specialists (5.62; 3.61-8.75) as information sources. DSME participation was not associated with disease distress. CONCLUSION: DSME is a valuable tool for improving individual knowledge about diabetes. However, DSME should focus more on psychosocial aspects to reduce the disease burden.

Liver transplantation for hepatocellular carcinoma--is there a risk of recurrence caused by intraoperative blood salvage autotransfusion?

BACKGROUND/AIMS: The use of intraoperative blood salvage autotransfusion (IBSA) during surgical approaches may contribute to tumour cell dissemination. Therefore, IBSA should be avoided in cases of malignancy. However, the risks of IBSA might be acceptable in liver transplantation (LT) for selected small hepatocellular carcinoma (HCC). METHODS: In total, 136 recipients of LT with histologically proven HCC in the explanted liver were included in this analysis. With regard to tumour recurrence, 40 patients receiving IBSA despite HCC (IBSA group) were compared to 96 patients without IBSA (non-IBSA group). RESULTS: Milan criteria as assessed in the explanted liver were fulfilled in 24 of 40 IBSA patients and 58 of 96 non-IBSA patients (p = 0.85). Five of 40 patients in the IBSA group and 18 of 96 patients in the non-IBSA group experienced tumour recurrence (p = 0.29). In spite the theoretical risk of tumour cell dissemination, the recurrence rate was not increased in the IBSA group. CONCLUSION: Our results indicate that IBSA does not modify the risk of HCC recurrence. Therefore, in highly selected HCC patients undergoing LT, the use of IBSA appears to be justified.

Acute renal failure and liver dysfunction after subcutaneous injection of 3-sn-phosphatidylcholine (Lipostabil®)-case report.

INTRODUCTION: Drug-induced tubulointerstitial nephritis and acute tubular necrosis are common, and are often caused by drugs especially antibiotics or non-steroidal anti-inflammatory drugs. Drug-induced liver dysfunction and renal failure after subcutaneous injection of phosphatidylcholine was not reported so far. 3-sn-Phosphatidylcholine has been described as a cell lysis reaction-inducing drug. Its in vitro data indicated a relevant toxicity potential. In particular human cell types such as fibroblast-like preadipocytes, vascular and skeletal muscle cells, or renal epithelial cells react more sensitive than other human cell types. CASE REPORT: We present a 28-year-old woman who received 3.5 g (70 mL) of 3-sn-phosphatidylcholine (Lipostabil®) at once subcutaneously (s. c.) in both gluteal regions. The drug was originally introduced to prevent fat embolism. Nevertheless, its off-label use in aesthetic therapy for treatment of localized fat deposits through subcutaneous administration is becoming increasingly common. Three hours after injection the patient suffered from severe nausea and emesis. Within 24 hours a dramatic increase of liver enzymes and a beginning liver dysfunction were observed. Subsequently, renal function deteriorated two days later making a temporary haemodialysis necessary. Hepatic improvement was observed after three days of treatment. Renal function was fully recovered after two weeks. CONCLUSION: To the best of our knowledge, this is the first reported patient presenting with acute liver dysfunction and renal failure after subcutaneous injection of 3-sn-phosphatidyl-choline (Lipostabil®) indicating the risk of an off-label use of this drug.

Murine cytomegalovirus inhibits interferon gamma-induced antigen presentation to CD4 T cells by macrophages via regulation of expression of major histocompatibility complex class II-associated genes.

CD4 T cells and interferon gamma (IFN-gamma) are required for clearance of murine cytomegalovirus (MCMV) infection from the salivary gland in a process taking weeks to months. To explain the inefficiency of salivary gland clearance we hypothesized that MCMV interferes with IFN-gamma induced antigen presentation to CD4 T cells. MCMV infection inhibited IFN-gamma-induced presentation of major histocompatibility complex (MHC) class II associated peptide antigen by differentiated bone marrow macrophages (BMMphis) to a T cell hybridoma via impairment of MHC class II cell surface expression. This effect was independent of IFN-alpha/beta induction by MCMV infection, and required direct infection of the BMMphis with live virus. Inhibition of MHC class II cell surface expression was associated with a six- to eightfold reduction in IFN-gamma induced IAb mRNA levels, and comparable decreases in IFN-gamma induced expression of invariant chain (Ii), H-2Ma, and H-2Mb mRNAs. Steady state levels of several constitutive host mRNAs, including beta-actin, cyclophilin, and CD45 were not significantly decreased by MCMV infection, ruling out a general effect of MCMV infection on mRNA levels. MCMV effects were specific to certain MHC genes since IFN-gamma-induced transporter associated with antigen presentation (TAP)2 mRNA levels were minimally altered in infected cells. Analysis of early upstream events in the IFN-gamma signaling pathway revealed that MCMV did not affect activation and nuclear translocation of STAT1alpha, and had minor effects on the early induction of IRF-1 mRNA and protein. We conclude that MCMV infection interferes with IFN-gamma-mediated induction of specific MHC genes and the Ii at a stage subsequent to STAT1alpha activation and nuclear translocation. This impairs antigen presentation to CD4 T cells, and may contribute to the capacity of MCMV to spread and persist within the infected host.

[Management of complications after liver resection]. / Management von Komplikationen nach Leberresektionen.

Hepatic resections represent a standard procedure for both benign and malignant liver diseases. Nevertheless, typical complications arise follow-ing hepatic surgery. Besides common problems, such as bile leakage or impaired wound healing, rare complications, like progressive liver failure or portal vein thrombosis are observed. Mortality and morbidity after liver resection depend on the preoperative constitution of the patient, on the state of the liver parenchyma and on the re-main-ing liver volume. In particular, a marked steatosis increases both morbidity and mortality of hepatic resections. The advances of modern chemotherapy increases the number of surgical patients, who were previously not resectable. However, the chemotherapy induced hepatotoxicity implies additional problems, thus increasing the morbidity of liver resections. Therefore, before planning hepatic surgery, the individual situation of the patient has to be evaluated in order to maximise the security of the operative procedure.

[Procurement of abdominal organs]. / Abdominale Organentnahme.

Solid organ transplantation is frequently carried out in this society. Under these circumstances the basic principles are altruistic organ donation and abidance by the law, which are regulated by the German Transplantation Act and by directives of the Federal Medical Council from which process instructions of the German Organ Transplantation Foundation are derived. The organ allocation is carried out by the Eurotransplant International Foundation (ET) located in Leiden, the Netherlands. Organ procurement is an essential component of the process of organ donation. This article highlights the procedure for harvesting of abdominal organs and also nonsurgical issues in the process of organ donation.

Influence of relative gas humidity on the inactivation efficiency of a low temperature gas plasma.

AIMS: To investigate the effect of relative gas humidity on the inactivation efficiency of a cascaded dielectric barrier discharge (CDBD) in air against Aspergillus niger and Bacillus subtilis spores on PET foils. METHODS AND RESULTS: The inactivation kinetics as a function of treatment time were determined using synthetic air with different relative humidity as the process gas. Spores of A. niger and B. subtilis respectively were evenly sprayed on PET foils for use as bioindicators. In the case of A. niger, increased spore mortality was found at a high relative gas humidity of 70% (approx. 2 log(10)). This effect was more evident at prolonged treatment times. In contrast, B. subtilis showed slightly poorer inactivation at high gas humidity. CONCLUSIONS: Water molecules in the process gas significantly affect the inactivation efficiency of CDBD in air. SIGNIFICANCE AND IMPACT OF THE STUDY: Modifying simple process parameters such as the relative gas humidity can be used to optimize plasma treatment to improve inactivation of resistant micro-organisms such as conidiospores of A. niger.

Localized spirals in Taylor-Couette flow.

We present a type of spiral vortex state that appears from a supercritical Hopf bifurcation below the linear instability of circular Couette flow in a Taylor-Couette system with rigid end plates. These spirals have been found experimentally as well as numerically as "pure" states but also coexist with "classical" spirals (or axially standing waves for smaller systems) which typically appear from linear instability in counterrotating Taylor-Couette flow. These spiral states have an axial distribution of the strongly localized amplitude in the vicinity of the rigid end plates that confine the system in the axial direction. Furthermore, they show significantly different oscillation frequencies compared to the critical spiral frequencies. Despite the localization of the amplitude near the ends, the states appear as global states with spirals that propagate either toward the middle from each end of the system or vice versa. In contrast to classical spirals, these states exhibit a spatial or a spatiotemporal reflection symmetry.

Social touch during development: Long-term effects on brain and behavior.

In this paper, our goal is to explore what is known about the role of social touch during development. We first address the neural substrates of social touch and the role of tactile experience in neural development. We discuss natural variation in early exposure to social touch, followed by a discussion on experimental manipulations of social touch during development and "natural experiments", such as early institutionalization. We then consider the role of other developmental and experiential variables that predict social touch in adults. Throughout, we propose and consider new theoretical models of the role of social touch during development on later behavior and neurobiology.

Imperfect Hopf bifurcation in spiral Poiseuille flow.

We present the results of an experimental study on the transition to spiral vortices in flow between concentric counter-rotating cylinders in the presence of an axial through-flow, i.e., in spiral Poiseuille flow. The experiments were performed in an apparatus having an aspect ratio Gamma=L/d=22.8 ( L axial length, d gap width between cylinders) and end plates enabling an in and outflow of mass. As a result of an applied axial through-flow the "classical" Hopf bifurcation to spiral vortices (SPI) splits up and a primary and secondary branch of down and upstream propagating SPI, respectively, as well as a transient quasiperiodic flow appear. Downstream propagating SPI resulting from the primary supercritical Hopf bifurcation are either convectively or absolutely unstable. The bifurcation structure observed in this open flow experiment is in qualitative agreement with predictions from theory of Hopf bifurcation with broken reflection symmetry [J. D. Crawford and E. Knobloch, Nonlinearity 1, 617 (1988)] and also in quantitative agreement with results from recent numerical calculations [A. Pinter, M. Lücke, and C. Hoffmann, Phys. Rev. E 67, 026318 (2003); C. Hoffmann, M. Lücke, and A. Pinter, Phys. Rev. E 69, 056309 (2004)].

Transarterial chemoembolization before liver transplantation in 60 patients with hepatocellular carcinoma.

Tumor recurrence is a major problem after orthotopic liver transplantation (OLT) in patients with hepatocellular carcinoma (HCC). In 60 patients OLT was performed for HCC after pretreatment by repeated transarterial chemoembolization (TACE). Forty-four recipients exceeded the Milan criteria. Recurrence-free 5-year survival was 65.2% and 5-year freedom from recurrence was 73.2%. During the waiting time, 14 patients experienced minimal change, which did not fulfill the definition of tumor progression according to official oncological criteria. Five-year freedom from recurrence among patients with stable compared with progressive disease was 93.3% versus 28.1%, respectively (P = .0001). A strict TACE pretreatment protocol may select patients with obviously biologically less aggressive tumors, who are suitable for OLT even if the HCC exceeds the commonly accepted listing criteria.

Dengue Virus Envelope Dimer Epitope Monoclonal Antibodies Isolated from Dengue Patients Are Protective against Zika Virus.

UNLABELLED: Zika virus (ZIKV) is a mosquito-borne flavivirus responsible for thousands of cases of severe fetal malformations and neurological disease since its introduction to Brazil in 2013. Antibodies to flaviviruses can be protective, resulting in lifelong immunity to reinfection by homologous virus. However, cross-reactive antibodies can complicate flavivirus diagnostics and promote more severe disease, as noted after serial dengue virus (DENV) infections. The endemic circulation of DENV in South America and elsewhere raises concerns that preexisting flavivirus immunity may modulate ZIKV disease and transmission potential. Here, we report on the ability of human monoclonal antibodies and immune sera derived from dengue patients to neutralize contemporary epidemic ZIKV strains. We demonstrate that a class of human monoclonal antibodies isolated from DENV patients neutralizes ZIKV in cell culture and is protective in a lethal murine model. We also tested a large panel of convalescent-phase immune sera from humans exposed to primary and repeat DENV infection. Although ZIKV is most closely related to DENV compared to other human-pathogenic flaviviruses, most DENV immune sera (73%) failed to neutralize ZIKV, while others had low (50% effective concentration [EC50], <1:100 serum dilution; 18%) or moderate to high (EC50, >1:100 serum dilution; 9%) levels of cross-neutralizing antibodies. Our results establish that ZIKV and DENV share epitopes that are targeted by neutralizing, protective human antibodies. The availability of potently neutralizing human monoclonal antibodies provides an immunotherapeutic approach to control life-threatening ZIKV infection and also points to the possibility of repurposing DENV vaccines to induce cross-protective immunity to ZIKV. IMPORTANCE: ZIKV is an emerging arbovirus that has been associated with severe neurological birth defects and fetal loss in pregnant women and Guillain-Barré syndrome in adults. Currently, there is no vaccine or therapeutic for ZIKV. The identification of a class of antibodies (envelope dimer epitope 1 [EDE1]) that potently neutralizes ZIKV in addition to all four DENV serotypes points to a potential immunotherapeutic to combat ZIKV. This is especially salient given the precedent of antibody therapy to treat pregnant women infected with other viruses associated with microcephaly, such as cytomegalovirus and rubella virus. Furthermore, the identification of a functionally conserved epitope between ZIKV and DENV raises the possibility that a vaccine may be able to elicit neutralizing antibodies against both viruses.

Liver transplantation for hepatocellular carcinoma in cirrhosis: prognostic parameters.

Selection of patients suffering from hepatocellular carcinoma (HCC) in cirrhosis for liver transplantation is based upon the number and diameter of tumor nodules but not with vascular invasion. From 1989 to 2003, 1619 liver transplantations were performed in 1471 patients, including 163 patients with an HCC in cirrhosis. Selection criteria were a maximal diameter of up to 5 cm when the tumor appeared to be uninodular, or up to 3 cm in the case of two or three nodules and no vascular invasion prior to transplantation. The postoperative mortality rate was 1.7%. One-, 5- and 10-year survivals were 88%, 62%, and 51%, respectively. Among 1307 transplantations without HCC, the rates were 90%, 84%, and 76%, respectively (P < .0001). Multivariate analysis identified histopathological grading and vascular invasion to predict survival. A subgroup analysis showed 5-year survivals of 67% and 57% for well versus moderately differentiated tumors with vascular invasion. Liver transplantation is a safe and effective long-term treatment for small HCC in cirrhosis. Exeptions from the morphometric rules may be justified for patients with HCC in cirrhosis who show well or moderately differentiated tumors with vascular invasion.

Liver transplantation for treatment of intrahepatic Osler's disease: first experiences.

BACKGROUND: Intrahepatic Osler's disease with multiple arteriovenous malformations and high intrahepatic shunting may lead to secondary pulmonary hypertension followed by right-heart stress and insufficiency. Until now, therapy with arterial embolization, banding, or ligation of the hepatic arteries is still limited and provides unsatisfactory long-term results. Liver transplantation offers another therapeutic option. METHODS: We report on four patients with intrahepatic involvement of Osler's disease who were liver transplanted between 1995 and 1999. All patients suffered from restricted liver function and right-heart insufficiency with multiple cardiac decompensations. One patient received one course of embolization, and another received six courses of embolization and then banding of the main hepatic artery before transplantation. In both patients, the clinical symptoms improved for only a few months. RESULTS: All patients had high degrees of intrahepatic arteriovenous shunting, and cardiac output measurements were between 8.0 to 13.3 L/min preoperatively. Preoperative mean pulmonary artery pressure was between 24 to 35 mmHg. After liver transplantation, cardiac output and right-heart diameter decreased or normalized and pulmonary pressure reached the normal range after 2 months. All patients received tacrolimus and steroids for primary immunosuppression. In one case, temporary hemodialysis was necessary for 2 weeks after transplantation, but renal function recovered completely. After follow-up time of 12 to 65 months, all patients had normal graft function and good cardiopulmonary condition. CONCLUSIONS: Indication for liver transplantation should be considered in patients with intrahepatic Osler's disease, high arteriovenous shunting with right-heart stress, and restricted liver function before irreversible fixed pulmonary hypertension leads to severe right-heart insufficiency or failure. Our therapeutic regimen of early liver transplantation in the case of intrahepatic Osler's disease in four patients has promising results.

Rosiglitazone reduces urinary albumin excretion in type II diabetes.

This study examines the effect of rosiglitazone on urinary albumin excretion (UAE) in patients with type II diabetes. Urinary albumin: creatinine ratio (ACR) was measured in a 52-week, open-label, cardiac safety study comparing rosiglitazone and glyburide. Patients were randomised to treatment with rosiglitazone 4 mg b.i.d. or glyburide. ACR was measured at baseline and after 28 and 52 weeks of treatment. Statistically significant reductions from baseline in ACR were observed in both treatment groups at week 28. By week 52, only the rosiglitazone group showed a significant reduction from baseline. Similar results were observed for the overall study population and for the subset of patients with baseline microalbuminuria. For patients with microalbuminuria at baseline, reductions in ACR did not correlate strongly with reductions in glycosylated haemoglobin, or fasting plasma glucose, but showed strong correlation with changes in mean 24-h systolic and diastolic blood pressure for rosiglitazone-treated patients (deltaACR vs deltamean 24-h systolic blood pressure, r=0.875; deltaACR vs deltamean 24-h diastolic blood pressure, r=0.755; P < 0.05 for both). No such correlation was observed for glyburide-treated patients. In conclusion, rosiglitazone treatment was associated with a decrease in urinary albumin excretion. These findings suggest a potential beneficial effect of rosiglitazone in the treatment or prevention of renal and vascular complications of type II diabetes.

Assessment of doxylamine influence on mixed function oxidase activity upon multiple dose oral administration to normal volunteers.

The primary purpose of this study was to assess the influence of doxylamine and phenobarbital on antipyrine/metabolites pharmacokinetics and 6 beta-hydroxycortisol urinary excretion. This study was conducted in 48 healthy male human volunteers (16 per treatment group) using a parallel study design. Treatment groups consisted of 12.5 mg of doxylamine succinate, placebo, or 30 mg of phenobarbital administered orally every 6 h for 17 days. Results indicate that no statistically significant differences were observed between the doxylamine and placebo groups that are indicative of enzyme induction. For the phenobarbital group, a significant increase for antipyrine total (36 versus 45 mL/h/kg) and nonrenal (35 versus 44 mL/h/kg) clearances and 6 beta-hydroxycortisol excretion (338 versus 529 micrograms) and a significant decrease in the terminal exponential half-life (11 versus 9 h) of antipyrine were observed.