Retrospective study of the incidence, risk factors, treatment outcomes of bacterial infections at uncommon sites in cirrhotic patients

BACKGROUND Bacterial infections(BI)negatively affect the natural course of cirrhosis.The most frequent BI are urinary tract infections(UTI),pneumonia,and spontaneousbacterial peritonitis(SBP).AIM To assess the relevance of bacterial infections beyond the commonly recognized types in patients with cirrhosis and to investigate their relationship with other clinical variables.METHODS We retrospectively analyzed patients with cirrhosis and BI treated between 2015 and 2018 at our tertiary care center.BIs were classified as typical and atypical,and clinical as well as laboratory parameters were compared between the two groups.RESULTS In a cohort of 488 patients with cirrhosis,we identified 225 typical BI(95 UTI,73 SBP,72 pulmonary infections)and 74 atypical BIs,predominantly cholangitis and soft tissue infections(21 each),followed by intra-abdominal BIs(n=9),cholecystitis(n=6),head/throat BIs(n=6),osteoarticular BIs(n=5),and endocarditis(n=3).We did not observe differences concerning age,sex,or etiology of cirrhosis in patients with typical vs atypical BI.Atypical BIs were more common in patients with more advanced cirrhosis,as evidenced by Model of End Stage Liver Disease(15.1±7.4 vs 12.9±5.1;P=0.005)and Child-Pugh scores(8.6±2.5 vs 8.0±2;P=0.05).CONCLUSION Atypical BIs in cirrhosis patients exhibit a distinct spectrum and are associated with more advanced stages of the disease.Hence,the work-up of cirrhosis patients with suspected BI requires detailed work-up to elucidate whether typical BI can be identified.

Cell atlas of CCl_(4)-induced progressive liver fibrosis reveals stage-specific responses

Chronic liver injury leads to progressive liver fibrosis and ultimately cirrhosis,a major cause of morbidity and mortality worldwide.However,there are currently no effective anti-fibrotic therapies available,especially for latestage patients,which is partly attributed to the major knowledge gap regarding liver cell heterogeneity and cellspecific responses in different fibrosis stages.To reveal the multicellular networks regulating mammalian liver fibrosis from mild to severe phenotypes,we generated a single-nucleus transcriptomic atlas encompassing 49919nuclei corresponding to all main liver cell types at different stages of murine carbon tetrachloride(CCl_(4))-induced progressive liver fibrosis.Integrative analysis distinguished the sequential responses to injury of hepatocytes,hepatic stellate cells and endothelial cells.Moreover,we reconstructed the cell-cell interactions and gene regulatory networks implicated in these processes.These integrative analyses uncovered previously overlooked aspects of hepatocyte proliferation exhaustion and disrupted pericentral metabolic functions,dysfunction for clearance by apoptosis of activated hepatic stellate cells,accumulation of pro-fibrotic signals,and the switch from an anti-angiogenic to a pro-angiogenic program during CCl_(4)-induced progressive liver fibrosis.Our dataset thus constitutes a useful resource for understanding the molecular basis of progressive liver fibrosis using a relevant animal model.

CDP-choline to promote remyelination in multiple sclerosis:the need for a clinical trial

Multiple sclerosis is a multifactorial chronic inflammatory disease of the central nervous system that leads to demyelination and neuronal cell death,resulting in functional disability.Remyelination is the natural repair process of demyelination,but it is often incomplete or fails in multiple sclerosis.Available therapies reduce the inflammatory state and prevent clinical relapses.However,therapeutic approaches to increase myelin repair in humans are not yet available.The substance cytidine-5′-diphosphocholine,CDP-choline,is ubiquitously present in eukaryotic cells and plays a crucial role in the synthesis of cellular phospholipids.Regenerative properties have been shown in various animal models of diseases of the central nervous system.We have already shown that the compound CDPcholine improves myelin regeneration in two animal models of multiple sclerosis.However,the results from the animal models have not yet been studied in patients with multiple sclerosis.In this review,we summarise the beneficial effects of CDP-choline on biolipid metabolism and turnover with regard to inflammatory and regenerative processes.We also explain changes in phospholipid and sphingolipid homeostasis in multiple sclerosis and suggest a possible therapeutic link to CDP-choline.

COVID-19:Insights into long-term manifestations and lockdown impacts

Coronaviruses are pathogens thought to primarily affect the respiratory tracts of humans.The outbreak of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)in 2019 was also marked mainly by its symptoms of respiratory illness,which were named coronavirus disease 2019(COVID-19).Since its initial discovery,many other symptoms have been linked to acute SARS-CoV-2 infections as well as to the long-term outcomes of COVID-19 patients.Among these symptoms are different categories of cardiovascular diseases(CVDs),which continue to be the main cause of death worldwide.The World Health Organization estimates that 17.9 million people die from CVDs each year,accounting for~32%of all deaths globally.Physical inactivity is one of the most important behavioral risk factors for CVDs.The COVID-19 pandemic has affected CVDs as well as the physical activity in different ways.Here,we provide an overview of the current status as well as future challenges and possible solutions.

Having a Partner and Having Children:Comparisons of Adults with Congenital Heart Disease and the General Population:A 15-Year Case-Control Study

Objectives:To examine whether patients with congenital heart disease(CHD)are less likely to have a partner or children than individuals from the general population.Methods:Longitudinal study with two assessments of the same patients(n=244)from a hospital population and controls(n=238)from the German Socio-Economic Panel(GSOEP)using parental education,patients age,and sex as matching criteria.The first patient study was conducted between 5/2003 and 6/2004,the second one between 5/2017 and 4/2019.Controls were drawn from GSOEP-surveys 2004 and 2018.CHD-severity was classified according to type of surgery:curative,reparative,or palliative.Living single was used as outcome measure,for offspring the outcome was having children or not.Results:Among women with CHD the rate of those living single was higher than among controls with the differences depending on disease complexity(curative:OR=5.5;reparative:OR=1.9;palliative:OR=2.7).No statistically significant differences between patients and controls emerged in the male study population.With respect to children a marked difference emerged between women with CHD and controls.Among patients the odds of having children were lower than among controls(curative:OR=0.3;reparative:OR=0.3;palliative:OR=0.2).The rate of patients with children with CHD(women:5.6%;men:4.9%)was higher than expected(1%)if compared with the general population.Conclusions:Using partnership and children as outcome criteria,patients with CHD are disadvantaged if compared to subjects from the general population.In female patients the social consequences of the disease turned out as more pervasive than in women.

Transarterial chemoembolization using degradable starch microspheres and iodized oil in the treatment of advanced hepatocellular carcinoma: evaluation of tumor response, toxicity, and survival

BACKGROUND: In a multidisciplinary conference patients with advanced non-resectable hepatocellular carcinoma (HCC) were stratified according to their clinical status and tumor extent to different regional modalities or to best supportive care. The present study evaluated all patients who were stratified to repeated transarterial chemoembolization (TACE) from 1999 until 2003 in terms of tumor response, toxicity, and survival. A moderate embolizing approach was chosen using a combination of degradable starch microspheres (DSM) and iodized oil (Lipiodol) in order to combine anti-tumoral efficiency and low toxicity. METHODS: Fourty-seven patients were followed up prospectively. TACE treatment consisted of cisplatin (50 mg/m2), doxorubicin (50 mg/m2), 450-900 mg DSM, and 5-30 ml Lipiodol. DSM and Lipiodol were administered according to tumor vascularization. Patient characteristics,toxicity, and complications were outlined. In multivariate regression analyses of pre-treatment variables from a prospective database, predictors for tumor response and survival after TACE were determined. RESULTS: 112 TACE courses were performed (2.4±1.5 courses per patient). Mean maximum tumor size was 75 (± 43) mm, in 68% there was bilobar disease. Best response to TACE treatment was: progressive disease (PD) 9%, stable disease (SD) 55%, partial remission (PR) 36%, and complete remission (CR) 0%. Multivariate regression analyses identified tumor size ≤75 mm, tumor number ≤5, and tumor hypervascularization as predictors for PR. The overall 1-, 2-, and 3-year-survival rates were 75%, 59%, and 41%, respectively, and the median survival was 26 months. Low α-fetoprotein levels (<400 ng/ml) (Odds ratio=3.3) and PR as best response to TACE (Odds ratio=6.7) were significantly associated with long term survival (>30 months, R2=36%). Grade 3 toxicity occurred in 7.1% (n=8), and grade 4 toxicity in 3.6% (n=4) of all courses in terms of reversible leukopenia and thrombocytopenia. The incidence of major complications was 5.4% (n=6). All complications were managed conservatively. The mortality within 6 weeks after TACE was 2.1% (one patient). CONCLUSIONS: DSM and Lipiodol were combined successfully in the palliative TACE treatment of advanced HCC resulting in high rates of tumor response and survival at limited toxicity. Favourable tumor response was associated with tumor extent and vascularization. TACE using DSM and Lipiodol can be considered a suitable palliative measure in patients who might not tolerate long acting embolizing agents.

Combination of repeated single-session percutaneous ethanol injection and transarterial chemoembolisation compared to repeated single-session percutaneous ethanol injection in patients with non-resectable hepatocellular carcinoma

瞄准：为病人评估经皮的乙醇注射(PEI ) 的治疗效果与先进， non-resectable HCC 与 transarterial chemoembolisation 的联合相比(不作声) 并且重复单个会议的 PEI，独自重复了单个会议的 PEI，重复不作声独自一个，或最好的支持的照顾。方法：在学习时期期间接受了 PEI 治疗的所有病人根据物理地位和肿瘤程度被包括并且成层到下列治疗形式之一：联合不作声并且重复单个会议的 PEI，独自重复了单个会议的 PEI，重复不作声独自一个，或最好的支持的照顾。包括Okuda分类，门静脉血栓的存在，腹水的存在，肿瘤的数字，最大的肿瘤直径，和假胆硷酯酶( CHE )的临床的参数的预示的价值，以及孩子呸上演， alpha-fetoprotein (法新社)，发烧，复杂并发症的发生在这些组之间被估计并且比较。幸存用 Kaplan-Meier 被决定，多，变量回归分析。结果：所有病人的 1 年、 3 年的幸存是 73% 和 47% 。在亚群分析，联合不作声， PEI (1 ) 与更长的幸存被联系(1- ， 3- ， 5 年的幸存：90% ， 52% ，和 43%) 与 PEI 治疗相比独自一个(2 )(1- ， 3- ， 5 年的幸存：65% ， 50% ，和 37%) 。(3 ) 在起始的层化以后的第二等的 PEI 产出可比较的结果不作声(1- ， 3- ， 5 年的幸存：91% ， 40% ，和 30%) 当在到最好的支持的照顾(4 ) 的层化以后的 PEI 与减少的幸存被联系时(1- ， 3- ， 5 年的幸存：50% ， 23% ， 12%) 。除了选择治疗形式，为更好的幸存的预言者是肿瘤数字(n 【 5 ) ，肿瘤尺寸(【 5 厘米) ，在 PEI 前的没有腹水，和在 PEI 以后的稳定的假胆硷酯酶(P 【 0.05 ) 。在在 PEI 以后的 2 wk 以内的死亡是 2.8%(n = 3 ) 。有 24 (8.9%) 主修在包括部分肝梗塞，焦点的肝坏死，和肝脓肿的 PEI 以后的复杂并发症。所有复杂并发症能非通过手术被管理。结论：重复单个会议的 PEI 在有以可接受、可管理的复杂并发症率的先进 HCC 的病人是有效的。病人们成层到联合不作声， PEI 能比那些独自成层到重复 PEI 期望更长的幸存。而且，有在好临床的地位的大或多重的肿瘤的病人可以也从联合获利不作声并且为第二等的 PEI 的再考虑。

Heme oxygenase-1 as a therapeutic target in inflammatory disorders of the gastrointestinal tract

Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. HO-1 not only protects against oxidative stress and apoptosis, but has received a great deal of attention in recent years because ofits potent anti-inflammatory functions. Studies with HO-1 knockout animal models have led to major advances in the understanding of how HO-1 might regulate inflammatory immune responses, although little is known on the underlying mechanisms. Due to its beneficial effects the targeted induction of this enzyme is considered to have major therapeutic po- tential for the treatment ofinflammatory disorders. This review discusses current knowledge on the mechanisms that mediate anti-inflammatory protection by HO-1. More specifically, the article deals with the role of HO-1 in the pathophysiology of viral hepatitis, inflammatorybowel disease, and pancreatitis. The effects of specific HO-1 modulation as a potential therapeutic strategy in experimental cell culture and animal models of these gastrointestinal disorders are summarized. In conclusion, targeted regulation of HO-1 holds major promise for future clinical interventions in inflammatory diseases of the gastrointestinal tract.

Direct ex vivo analysis of dendritic cells in patients with hepatocellular carcinoma

瞄准：与肝细胞癌(HCC ) 从病人分析树枝状的房间(DC ) 的显型和功能以便在这疾病理解他们的角色。方法：骨髓的的树枝状的房间在 HCC 病人的外部血被枚举。从外部血的天真、刺激的骨髓的的树枝状的房间上的 CD80， CD83， CD86 和 HLA 医生表示被分析。骨髓的的树枝状的房间从外部血被孤立，他们的功能被测试。吞噬作用用 FITC 葡聚糖祷告被分析，肽特殊刺激，在多形核白细胞 dI:dC 之上刺激 allogeneic T 房间和 cytokines 的分泌物的能力被测试。结果：骨髓的的树枝状的房间与 HCC 在病人被减少。在 CD80， CD83， CD86 和 HLA 医生表示的差别都没从 HCC 病人和健康控制在天真、刺激的骨髓的的树枝状的房间上被发现。肽 specific T 房间的正常吞噬作用或刺激与一个损害 allo-stimulatory 能力和减少的 IL-12 分泌物相对照被观察。结论：在病人的 mDCs 的损害 IL-12 生产能导致建议指导治疗可以提高的那 IL-12 的天真的 T 房间的一个损害 stimulatory 能力在 HCC 病人的肿瘤 specific 免疫者回答。

Benign liver tumors in pediatric patients-Review with emphasis on imaging features

Benign hepatic tumors are commonly observed in adults,but rarely reported in children.The reasons for this remain speculative and the exact data concerning the incidence of these lesions are lacking.Benign hepatic tumors represent a diverse group of epithelial and mesenchymal tumors.In pediatric patients,most benign focal liver lesions are inborn and may grow like the rest of the body.Knowledge of pediatric liver diseases and their imaging appearances is essential in order to make an appropriate differential diagnosis.Selection of the appropriate imaging test is challenging,since it depends on a number of age-related factors.This paper will discuss the most frequently encountered benign liver tumors in children(infantile hepatic hemangioendothelioma,mesenchymal hamartoma,focal nodular hyperplasia,nodular regenerative hyperplasia,and hepatocellular adenoma),as well as a comparison to the current knowledge regarding such tumors in adult patients.The current emphasis is on imaging features,which are helpful not only for the initial diagnosis,but also for pre- and posttreatment evaluation and follow-up.In addition,future perspectives of contrast-enhanced ultrasound(CEUS) in pediatric patients are highlighted,with descriptions of enhancement patterns for each lesion being discussed.The role of advanced imaging tests such as CEUS and magnetic resonance imaging,which allow for non-invasive assessment of liver tumors,is of utmost importance in pediatric patients,especially when repeated imaging tests are needed and radiation exposure should be avoided.

Laparoscopic splenectomy:Current concepts

Since early 1990's,when it was inaugurally introduced,laparoscopic splenectomy has been performed with excellent results in terms of intraoperative and postoperative complications.Nowadays laparoscopic splenectomy is the approach of choice for both benign and malignant diseases of the spleen.However some contraindications still apply.The evolution of the technology has allowed though,cases which were considered to be absolute contraindications for performing a minimal invasive procedure to be treated with modified laparoscopic approaches.Moreover,the introduction of advanced laparoscopic tools for ligation resulted in less intraoperative complications.Today,laparoscopic splenectomy is considered safe,with better outcomes in comparison to open splenectomy,and the increased experience of surgeons allows operative times comparable to those of an open splenectomy.In this review we discuss the indications and the contraindications of laparoscopic splenectomy.Moreover we analyze the standard and modified surgical approaches,and we evaluate the short-term and long-term outcomes.

Modification of tubular chitosan-based peripheral nerve implants: applications for simple or more complex approaches

Surgical treatment of peripheral nerve injuries is still a major challenge in human clinic.Up to now,none of the well-developed microsurgical treatment options is able to guarantee a complete restoration of nerve function.This restriction is also effective for novel clinically approved artificial nerve guides.In this review,we compare surgical repair techniques primarily for digital nerve injuries reported with relatively high prevalence to be valuable attempts in clinical digital nerve repair and point out their advantages and shortcomings.We furthermore discuss the use of artificial nerve grafts with a focus on chitosan-based nerve guides,for which our own studies contributed to their approval for clinical use.In the second part of this review,very recent future perspectives for the enhancement of tubular(commonly hollow)nerve guides are discussed in terms of their clinical translatability and ability to form three-dimensional constructs that biomimick the natural nerve structure.This includes materials that have already shown their beneficial potential in in vivo studies like fibrous intraluminal guidance structures,hydrogels,growth factors,and approaches of cell transplantation.Additionally,we highlight upcoming future perspectives comprising co-application of stem cell secretome.From our overview,we conclude that already simple attempts are highly effective to increase the regeneration supporting properties of nerve guides in experimental studies.But for bringing nerve repair with bioartificial nerve grafts to the next level,e.g.repair of defects>3 cm in human patients,more complex intraluminal guidance structures such as innovatively manufactured hydrogels and likely supplementation of stem cells or their secretome for therapeutic purposes may represent promising future perspectives.

Biliary complications following liver transplantation: Singlecenter experience over three decades and recent risk factors

AIM To identify independent risk factors for biliary complications in a center with three decades of experience in liver transplantation.METHODS A total of 1607 consecutive liver transplantations were analyzed in a retrospective study. Detailed subset analysis was performed in 417 patients, which have been transplanted since the introduction of Model of End-Stage Liver Disease(MELD)-based liver allocation. Risk factors for the onset of anastomotic biliary complications were identified with multivariable binary logisticregression analyses. The identified risk factors in regression analyses were compiled into a prognostic model. The applicability was evaluated with receiver operating characteristic curve analyses. Furthermore, Kaplan-Meier analyses with the log rank test were applied where appropriate. RESULTS Biliary complications were observed in 227 cases(14.1%). Four hundred and seventeen(26%) transplantations were performed after the introduction of MELD-based donor organ allocation. Since then, 21%(n = 89) of the patients suffered from biliary complications, which are further categorized into anastomotic bile leaks [46%(n = 41)], anastomotic strictures [25%(n = 22)], cholangitis [8%(n = 7)] and non-anastomotic strictures [3%(n = 3)]. The remaining 18%(n = 16) were not further classified. After adjustment for all univariably significant variables, the recipient MELD-score at transplantation(P = 0.006; OR = 1.035; 95%CI: 1.010-1.060), the development of hepatic artery thrombosis post-operatively(P = 0.019; OR = 3.543; 95%CI: 1.233-10.178), as well as the donor creatinine prior to explantation(P = 0.010; OR = 1.003; 95%CI: 1.001-1.006) were revealed as independent risk factors for biliary complications. The compilation of these identified risk factors into a prognostic model was shown to have good prognostic abilities in the investigated cohort with an area under the receiver operating curve of 0.702.CONCLUSION The parallel occurrence of high recipient MELD and impaired donor kidney function should be avoided. Risk is especially increased when post-transplant hepatic artery thrombosis occurs.

Decision modelling for economic evaluation of liver transplantation

As the gap between a shortage of organs and the immense demand for liver grafts persists, every available donor liver needs to be optimized for utility, urgency and equity. To overcome this challenge, decision modelling might allow us to gather evidence from previous studies as well as compare the costs and consequences of alternative options. For public health policy and clinical intervention assessment, it is a potentially powerful tool. The most commonly used types of decision analytical models include decision trees, the Markov model, microsimulation, discrete event simulation and the system dynamic model. Analytic models could support decision makers in the field of liver transplantation when facing specific problems by synthesizing evidence, comprising all relevant options, generalizing results to other contexts, extending the time horizon and exploring the uncertainty. For modeling studies of economic evaluation for transplantation, understanding the current nature of the disease is crucial, as well as the selection of appropriate modelling techniques. The quality and availability of data is another key element for the selection and development of decision analytical models. In addition, good practice guidelines should be complied, which is important for standardization and comparability between economic outputs.

Stem cell autotomy and niche interaction in different systems

The best known cases of cell autotomy are the formation of erythrocytes and thrombocytes(platelets) from progenitor cells that reside in special niches. Recently, autotomy of stem cells and its enigmatic interaction with the niche has been reported from male germline stem cells(GSCs) in several insect species. First described in lepidopterans, the silkmoth, followed by the gipsy moth and consecutively in hemipterans, foremost the milkweed bug. In both, moths and the milkweed bug, GSCs form finger-like projections toward the niche, the apical cells(homologs of the hub cells in Drosophila). Whereas in the milkweed bug the projection terminals remain at the surface of the niche cells, in the gipsy moth they protrude deeply into the singular niche cell. In both cases, the projections undergo serial retrograde fragmentation with progressing signs of autophagy. In the gipsy moth, the autotomized vesicles are phagocytized and digested by the niche cell. In the milkweed bug the autotomized vesicles accumulate at the niche surface and disintegrate. Autotomy and sprouting of new projections appears to occur continuously. The significance of the GSC-niche interactions, however, remains enigmatic. Our concept on the signaling relationship between stem cell-niche in general and GSC and niche(hub cells and cyst stem cells) in particular has been greatly shaped by Drosophila melanogaster. In comparing the interactions of GSCs with their niche in Drosophila with those in species exhibiting GSC autotomy it is obvious that additional or alternative modes of stem cell-niche communication exist. Thus, essential signaling pathways, including niche-stem cell adhesion(E-cadherin) and the direction of asymmetrical GSC division- as they were found in Drosophila- can hardly be translated into the systems where GSC autotomywas reported. It is shown here that the serial autotomy of GSC projections shows remarkable similarities with Wallerian axonal destruction, developmental axon pruning and dying-back degeneration in neurodegenerative diseases. Especially the hypothesis of an existing evolutionary conserved "autodestruction program" in axons that might also be active in GSC projections appears attractive. Investigations on the underlying signaling pathways have to be carried out. There are two other well known cases of programmed cell autotomy: the enucleation of erythroblasts in the process of erythrocyte maturation and the segregation of thousands of thrombocytes(platelets) from one megakaryocyte. Both progenitor cell types- erythroblasts and megakaryocytes- are associated with a niche in the bone marrow, erythroblasts with a macrophage, which they surround, and the megakaryocytes with the endothelial cells of sinusoids and their extracellular matrix. Although the regulatory mechanisms may be specific in each case, there is one aspect that connects all described processes of programmed cell autotomy and neuronal autodestruction: apoptotic pathways play always a prominent role. Studies on the role of male GSC autotomy in stem cell-niche interaction have just started but are expected to reveal hitherto unknown ways of signal exchange. Spermatogenesis in mammals advance our understanding of insect spermatogenesis. Mammal and insect spermatogenesis share some broad principles, but a comparison of the signaling pathways is difficult. We have intimate knowledge from Drosophila, but of almost no other insect, and we have only limited knowledge from mammals. The discovery of stem cell autotomy as part of the interaction with the niche promises new general insights into the complicated stem cell-niche interdependence.

S-Nitroso-N-acetyl-L-cysteine ethyl ester(SNACET) and N-acetyl-L-cysteine ethyl ester(NACET)–Cysteine-based drug candidates with unique pharmacological profiles for oral use as NO, H_2S and GSH suppliers and as antioxidants: Results and overview

S-Nitrosothiols or thionitrites with the general formula RSNO are formally composed of the nitrosyl cation(NOt) and a thiolate(RSà), the base of the corresponding acids RSH. The smallest S-nitrosothiol is HSNO and derives from hydrogen sulfide(HSH, H_2S). The most common physiological S-nitrosothiols are derived from the amino acid L-cysteine(Cys SH). Thus, the simplest S-nitrosothiol is S-nitroso-L-cysteine(Cys SNO). Cys SNO is a spontaneous potent donor of nitric oxide(NO) which activates soluble guanylyl cyclase to form cyclic guanosine monophosphate(c GMP). This activation is associated with multiple biological actions that include relaxation of smooth muscle cells and inhibition of platelet aggregation.Like NO, Cys SNO is a short-lived species and occurs physiologically at concentrations around 1 n M in human blood. Cys SNO can be formed from Cys SH and higher oxides of NO including nitrous acid(HONO)and its anhydride(N_2O_3). The most characteristic feature of RSNO is the S-transnitrosation reaction by which the NOtgroup is reversibly transferred to another thiolate. By this way numerous RSNO can be formed such as the low-molecular-mass S-nitroso-N-acetyl-L-cysteine(SNAC) and S-nitroso-glutathione(GSNO), and the high-molecular-mass S-nitrosol-L-cysteine hemoglobin(Hb Cys SNO) present in erythrocytes and S-nitrosol-L-cysteine albumin(Alb Cys SNO) present in plasma at concentrations of the order of 200 n M. All above mentioned RSNO exert NO-related biological activity, but they must be administered intravenously. This important drawback can be overcome by lipophilic charge-free RSNO.Thus, we prepared the ethyl ester of SNAC, the S-nitroso-N-acetyl-L-cysteine ethyl ester(SNACET), from synthetic N-acetyl-L-cysteine ethyl ester(NACET). Both NACET and SNACET have improved pharmacological features over N-acetyl-L-cysteine(NAC) and S-nitroso-N-acetyl-L-cysteine(SNAC), respectively,including higher oral bioavailability. SNACET exerts NO-related activities which can be utilized in the urogenital tract and in the cardiovascular system. NACET, with high oral bioavailability, is a strong antioxidant and abundant precursor of GSH, unlike its free acid N-acetyl-L-cysteine(NAC). Here, we review the chemical and pharmacological properties of SNACET and NACET as well as their analytical chemistry.We also report new results from the ingestion of S-[^(15) N]nitroso-N-acetyl-L-cysteine ethyl ester(S^(15) NACET) demonstrating the favorable pharmacological profile of SNACET.

Hepatic encephalopathy before and neurological complications after liver transplantation have no impact on the employment status 1 year after transplantation

AIM To investigate the impact of hepatic encephalopathybefore orthotopic liver transplantation(OLT) and neurological complications after OLT on employment after OLT.METHODS One hundred and fourteen patients with chronic liver disease aged 18-60 years underwent neurological examination to identify neurological complications, neuropsychological tests comprising the PSE-SyndromeTest yielding the psychometric hepatic encephalopathy score, the critical flicker frequency and the Repeatable Battery for the Assessment of Neuropsychological Status(RBANS), completed a questionnaire concerning their occupation and filled in the short form 36(SF-36) to assess health-related quality of life before OLT and 12 mo after OLT, if possible. Sixty-eight(59.6%) patients were recruited before OLT, while on the waiting list for OLT at Hannover Medical School [age: 48.7 ± 10.2 years, 45(66.2%) male], and 46(40.4%) patients were included directly after OLT. RESULTS Before OLT 43.0% of the patients were employed. The patients not employed before OLT were more often non-academics(employed: Academic/non-academic 16(34.0%)/31 vs not employed 10(17.6%)/52, P = 0.04), had more frequently a history of hepatic encephalopathy(HE)(yes/no; employed 15(30.6%)/34 vs not employed 32(49.2%)/33, P = 0.05) and achieved worse results in psychometric tests(RBANS sum score mean ± SD employed 472.1 ± 44.5 vs not employed 443.1 ± 56.7, P = 0.04) than those employed. Ten patients(18.2%), who were not employed before OLT, resumed work afterwards. The patients employed after OLT were younger [age median(range, min-max) employed 47(42, 18-60) vs not employed 50(31, 29-60), P = 0.01], achieved better results in the psychometric tests(RBANS sum score mean ± SD employed 490.7 ± 48.2 vs not employed 461.0 ± 54.5, P = 0.02) and had a higher health-related quality of life(SF 36 sum score mean ± SD employed 627.0 ± 138.1 vs not employed 433.7 ± 160.8; P < 0.001) compared to patients not employed after OLT. Employment before OLT(P < 0.001), age(P < 0.01) and SF-36 sum score 12 mo after OLT(P < 0.01) but not HE before OLT or neurological complications after OLT were independent predictors of the employment status after OLT.CONCLUSION HE before and neurological complications after OLT have no impact on the employment status 12 mo after OLT. Instead younger age and employment before OLT predict employment one year after OLT.

Overweight and obesity in hip and knee arthroplasty:Evaluation of 6078 cases

AIM: To evaluate a possible association between thevarious levels of obesity and peri-operative characteristics of the procedure in patients who underwent endoprosthetic joint replacement in hip and knee joints. METHODS: We hypothesized that obese patients were treated for later stage of osteoarthritis, that more conservative implants were used, and the intraand perioperative complications increased for such patients. We evaluated all patients with body mass index(BMI) ≥ 25 who were treated in our institution from January 2011 to September 2013 for a primary total hip arthroplasty(THA) or total knee arthroplasty(TKA). Patients were split up by the levels of obesity according to the classification of the World Health Organization. Average age at the time of primary arthroplasty, preoperative Harris Hip Score(HHS), Hospital for Special Surgery score(HSS), gender, type of implanted prosthesis, and intra-and postoperative complications were evaluated.RESULTS: Six thousand and seventy-eight patients with a BMI ≥ 25 were treated with a primary THA or TKA. Age decreased significantly(P < 0.001) by increasing obesity in both the THA and TKA. HHS and HSS were at significantly lower levels at the time of treatment in the super-obese population(P < 0.001). Distribution patterns of the type of endoprostheses used changed with an increasing BMI. Peri- and postoperative complications were similar in form and quantity to those of the normal population. CONCLUSION: Higher BMI leads to endoprosthetic treatment in younger age, which is carried out at significantly lower levels of preoperative joint function.

Preeclampsia from a renal point of view:Insides into disease models,biomarkers and therapy

Proteinuria is a frequently detected symptom,found in 20% of pregnancies.A common reason for proteinuria in pregnancy is preeclampsia.To diagnose preeclampsia clinically and to get new insights into the pathophysiology of the disease it is at first essential to be familiar with conditions in normal pregnancy.Animal models and biomarkers can help to learn more about disease conditions and to find new treatment strategies.In this article we review the changes in kidney function during normal pregnancy and the differential diagnosis of proteinuria in pregnancy.We summarize different pathophysiological theories of preeclampsia with a special focus on the renal facets of the disease.We describe the current animal models and give a broad overview of different biomarkers that were reported to predict preeclampsia or have a prognostic value in preeclampsia cases.We end with a summary of treatment options for preeclampsia related symptoms including the use of plasmapheresis as a rescue therapy for so far refractory preeclampsia.Most of these novel biomarkers for preeclampsia are not yet implemented in clinical use.Therefore,we recommend using proteinuria(measured by UPC ratio) as a screening parameter for preeclampsia.Delivery is the only curative treatment for preeclampsia.In earlypreeclampsia the primary therapy goal is to prolong pregnancy until a state were the child has an acceptable chance of survival after delivery.

Transition after pediatric liver transplantation-Perceptions of adults, adolescents and parents

AIM To develop a locally adapted, patient-focused transitionprogram, we evaluated the perceptions of adult and adolescent patients and parents regarding transitionprograms and transfer.METHODS We evaluated these perceptions by analyzing the responses of pre-transfer adolescents(n = 57), their parents(n = 57) and post-transfer adults(n = 138) from a cohort of pediatric-liver-transplant-patients using a self-designed questionnaire. Furthermore, we compared a responder group with a non-responder group as well as the provided answers with baseline characteristics and clinical outcomes to exclude selection bias, characterize high-risk patients for nonadherence and test for gender differences. Included in our study were all pre-transfer liver transplant and combined liver-kidney transplant recipients aged 11-19 currently under our care and their parents, as well as all post-transfer liver transplant and combined liverkidney transplant recipients aged ≥ 17 years who had received a liver transplant and were treated at our center during childhood.RESULTS Fifty-seven(24 female) pre-transfer patients who received a transplant in the previous 8-186 mo(mean 93.9 mo, median 92 mo, SD 53.8 mo) and 138(57 female) post-transfer patients who received a transplant in the preceding 2-29 years(mean 15.6 years, median 17, SD 6.90) met the inclusion criteria. A total of 67% of pre-transfer patients(71% of female; 64% of male; P = 0.78) and their parents replied. Additionally, 54% of post-transfer patients(26% of female; 48% of male; P = 0.01) replied. No differences in clinical outcomes were observed between the responder and non-responder groups, and responses did not differ significantly based on clinical complication rates, although they did differ based on gender and the location of medical follow-up after transfer. Adolescents were generally ambivalent toward transition programs. However, adults strongly supported transition programs. CONCLUSION Transition programs need to be developed in close collaboration with adolescents. The best clinical practices regarding transition should respect local circumstances, gender and the location of post-transfer medical follow-up.