Pathological features of primary sclerosing cholangitis identified by bile proteomic analysis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown origin. Previous bile proteomic analyses in patients with PSC have revealed changes in disease activity specific to malignant transformation. In this study, we established a reference bile duct-derived bile proteome for PSC that can be used to evaluate biliary pathophysiology. Samples were collected from patients with PSC or with choledocholithiasis (control) (n=6 each). Furthermore, patients with PSC-associated cholangiocarcinoma (CC) and with CC without concomitant PSC were analyzed. None of the patients showed signs of inflammation or infection based on clinical and laboratory examinations. Proteins overexpressed in patients with PSC relative to control patients were detected by two-dimensional difference gel electrophoresis and identified by liquid chromatography-tandem mass spectrometry. Functional proteomic analysis was performed using STRING software. A total of 101 proteins were overexpressed in the bile fluid of patients with PSC but not in those of controls; the majority of these were predicted to be intracellular and related to the ribosomal and proteasomal pathways. On the other hand, 91 proteins were found only in the bile fluid of controls; most were derived from the extracellular space and were linked to cell adhesion, the complement system, and the coagulation cascade. In addition, proteins associated with inflammation and the innate immune response-e.g., cluster of differentiation 14, annexin-2, and components of the complement system-were upregulated in PSC. The most prominent pathways in PSC/CC-patients were inflammation associated cytokine and chemokine pathways, whereas in CC-patients the Wnt signaling pathway was upregulated. In PSC/CC-patients DIGE-analysis revealed biliary CD14 and Annexin-4 expression, among others, as the most prominent protein that discriminates between both cohorts. Thus, the bile-duct bile proteome of patients with PSC shows disease-specific changes associated with inflammation and the innate immune response even in the absence of obvious clinical signs of cholangitis, malignancy, or inflammation. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni and Peter Jansen.

[Expert recommendations: Hepatitis C and transplantation]. / Empfehlungen zur antiviralen Therapie der chronischen Hepatitis C bei Patienten auf der Warteliste und nach Transplantation.

With the approval of new direct acting antiviral agents (DAA), therapeutic options for patients with chronic hepatitis C virus (HCV) infection are now generally available before and after liver transplantation (LT). Interferon-free DAA regimens are highly effective therapies and provide a good safety profile. However, the body of clinical evidence in this patient population is limited and the best treatment strategies for patients on the waiting list with (de)compensated cirrhosis and after LT are not well defined. The following recommendations for antiviral therapy in the context of LT are based on the currently available literature and clinical experience of experts in the field, and have been discussed in an expert meeting. The aim of this article is to guide clinicians in the decision making when treating patients before and after LT with DAAs.

UKPMC: a full text article resource for the life sciences.

UK PubMed Central (UKPMC) is a full-text article database that extends the functionality of the original PubMed Central (PMC) repository. The UKPMC project was launched as the first 'mirror' site to PMC, which in analogy to the International Nucleotide Sequence Database Collaboration, aims to provide international preservation of the open and free-access biomedical literature. UKPMC (http://ukpmc.ac.uk) has undergone considerable development since its inception in 2007 and now includes both a UKPMC and PubMed search, as well as access to other records such as Agricola, Patents and recent biomedical theses. UKPMC also differs from PubMed/PMC in that the full text and abstract information can be searched in an integrated manner from one input box. Furthermore, UKPMC contains 'Cited By' information as an alternative way to navigate the literature and has incorporated text-mining approaches to semantically enrich content and integrate it with related database resources. Finally, UKPMC also offers added-value services (UKPMC+) that enable grantees to deposit manuscripts, link papers to grants, publish online portfolios and view citation information on their papers. Here we describe UKPMC and clarify the relationship between PMC and UKPMC, providing historical context and future directions, 10 years on from when PMC was first launched.

Detecting experimental techniques and selecting relevant documents for protein-protein interactions from biomedical literature.

BACKGROUND: The selection of relevant articles for curation, and linking those articles to experimental techniques confirming the findings became one of the primary subjects of the recent BioCreative III contest. The contest's Protein-Protein Interaction (PPI) task consisted of two sub-tasks: Article Classification Task (ACT) and Interaction Method Task (IMT). ACT aimed to automatically select relevant documents for PPI curation, whereas the goal of IMT was to recognise the methods used in experiments for identifying the interactions in full-text articles. RESULTS: We proposed and compared several classification-based methods for both tasks, employing rich contextual features as well as features extracted from external knowledge sources. For IMT, a new method that classifies pair-wise relations between every text phrase and candidate interaction method obtained promising results with an F1 score of 64.49%, as tested on the task's development dataset. We also explored ways to combine this new approach and more conventional, multi-label document classification methods. For ACT, our classifiers exploited automatically detected named entities and other linguistic information. The evaluation results on the BioCreative III PPI test datasets showed that our systems were very competitive: one of our IMT methods yielded the best performance among all participants, as measured by F1 score, Matthew's Correlation Coefficient and AUC iP/R; whereas for ACT, our best classifier was ranked second as measured by AUC iP/R, and also competitive according to other metrics. CONCLUSIONS: Our novel approach that converts the multi-class, multi-label classification problem to a binary classification problem showed much promise in IMT. Nevertheless, on the test dataset the best performance was achieved by taking the union of the output of this method and that of a multi-class, multi-label document classifier, which indicates that the two types of systems complement each other in terms of recall. For ACT, our system exploited a rich set of features and also obtained encouraging results. We examined the features with respect to their contributions to the classification results, and concluded that contextual words surrounding named entities, as well as the MeSH headings associated with the documents were among the main contributors to the performance.

The BioLexicon: a large-scale terminological resource for biomedical text mining.

BACKGROUND: Due to the rapidly expanding body of biomedical literature, biologists require increasingly sophisticated and efficient systems to help them to search for relevant information. Such systems should account for the multiple written variants used to represent biomedical concepts, and allow the user to search for specific pieces of knowledge (or events) involving these concepts, e.g., protein-protein interactions. Such functionality requires access to detailed information about words used in the biomedical literature. Existing databases and ontologies often have a specific focus and are oriented towards human use. Consequently, biological knowledge is dispersed amongst many resources, which often do not attempt to account for the large and frequently changing set of variants that appear in the literature. Additionally, such resources typically do not provide information about how terms relate to each other in texts to describe events. RESULTS: This article provides an overview of the design, construction and evaluation of a large-scale lexical and conceptual resource for the biomedical domain, the BioLexicon. The resource can be exploited by text mining tools at several levels, e.g., part-of-speech tagging, recognition of biomedical entities, and the extraction of events in which they are involved. As such, the BioLexicon must account for real usage of words in biomedical texts. In particular, the BioLexicon gathers together different types of terms from several existing data resources into a single, unified repository, and augments them with new term variants automatically extracted from biomedical literature. Extraction of events is facilitated through the inclusion of biologically pertinent verbs (around which events are typically organized) together with information about typical patterns of grammatical and semantic behaviour, which are acquired from domain-specific texts. In order to foster interoperability, the BioLexicon is modelled using the Lexical Markup Framework, an ISO standard. CONCLUSIONS: The BioLexicon contains over 2.2 M lexical entries and over 1.8 M terminological variants, as well as over 3.3 M semantic relations, including over 2 M synonymy relations. Its exploitation can benefit both application developers and users. We demonstrate some such benefits by describing integration of the resource into a number of different tools, and evaluating improvements in performance that this can bring.

Eating disorders in men: current features and childhood factors.

BACKGROUND: Disturbed interactions with one's body and with other persons are two major features in eating disorders. This study was designed to assess current and childhood characteristics of eating-disordered men. METHODS: The authors interviewed 32 men with eating disorders (anorexia nervosa: N=9, bulimia nervosa: N=15, eating disorders not otherwise specified: N=8) and 43 control participants with no such history similar in age and educational status. The Structured Clinical Interview for DSM-IV was used to assess Axis I disorders and a self-designed interview to assess actual social and sexual characteristics and childhood body-focused and social behaviors including sexual and physical abuse. RESULTS: The two groups differed significantly with regard to clinical, sexual and social features, with a three times higher rate of psychiatric disorders, fewer sexual and social relationships in the index group than in the controls. Eating-disordered men differed significantly from controls on most measures of body-focused and social behaviors, displaying higher rates of thumb sucking, nail biting, auto-aggressive behavior, and nudity as a familial taboo during childhood, as well as less parental bodily caressing than did controls. The index group reported significantly poorer relationships to their parents, fewer friends and persons of trust, and more often had adjustment problems at school than did their counterparts. CONCLUSIONS: Our data show that disturbed interactions with one's body and with other persons in eating-disordered men are associated with a body-denying and distant family climate and an auto-aggressive, anxious and inhibited social behavior during childhood.

Effect of mycophenolic acid on inosine monophosphate dehydrogenase (IMPDH) activity in liver transplant patients.

BACKGROUND: Due to the development of immunosuppressants, the focus in transplanted patients has shifted from short-term to long-term survival as well as a better adjustment of these drugs in order to prevent over- and under-immunosuppression. Mycophenolic acid (MPA) is a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) and approved for prophylaxis of acute rejection after kidney, heart, and liver transplantation, where it has become a part of the standard therapy. Targeting inosine monophosphate IMPDH activity as a surrogate pharmacodynamic marker of MPA-induced immunosuppression may allow a more accurate assessment of efficacy and aid in limiting toxicity in liver transplanted patients. AIM: Assess IMPDH-inhibition in liver transplant recipients and its impact on biliary/infectious complications, acute cellular rejection (ACR) and liver dependent survival. METHODS: This observational cohort study comprises 117 liver transplanted patients that were treated with mycophenolate mofetil (MMF) for at least 3 months. Blood samples (BS) were collected and MPA serum level and IMPDH activity were measured before (t(0)), 30minutes (t(30)) and 2h after (t(120)) MMF morning dose administration. Regarding MPA, we assessed the area under the curve (AUC). Patients were prospectively followed up for one year and assessed for infectious and biliary complications, episodes of ACR and liver dependent survival. RESULTS: The MPA levels showed a broad interindividual variability at t(0) (2.0±1.8ng/ml), t(30) (12.7±9.0ng/ml) and t(120) (7.5±4.3ng/ml). Corresponding IMPDH activity was at t(o) (23.2±9.5 nmol/h/mg), at t(30) (16.3±8.8 nmol/h/mg) and t(120) (18.2±8.7 nmol/h/mg). With regard to MPA level we found no correlation with infectious or biliary complications within the follow-up period. Patients with baseline IMPDH(a) below the median had significant more viral infections (6 (10.2%) vs. 17 (29.3%); P=0.009) with especially more cytomegalovirus (CMV) infections (1 (3.4%) vs. 6 (21.4%); P=0.03)). Furthermore, patients with baseline IMPDH(a) above the median developed more often non-anastomotic biliary strictures (8 (13.6%) vs. 1 (1.7%), P=0.03). We found the group reaching the combined clinical endpoint of death and re-transplantation showing significantly lower MPA baseline values (t(0) 0.9±0.7 vs. 2.1±1.8µg/ml Mann-Whitney-U: P=0.02). We calculated a simplified MPA(AUC) with the MPA level at baseline, 30 and 120minutes after MPA administration. Whereas we found no differences with regard to baseline characteristics at entry into the study patients with MPA (AUC) below the median experienced significantly more often the combined clinical endpoint (12.1% (7/58) vs. 0.0% (0/57); P=0.002) and had a reduced actuarial re-transplantation-free survival (1.0 year vs. 0.58 years; Log-rank: P=0.007) during the prospective one-year follow-up period. In univariate and multivariate analysis including gender, age, BMI, ACR, MPA (AUC) and IMPDH(a) only BMI, MPA (AUC) and IMPDH(a) were independently associated with reduced actuarial re-transplantation-free survival. CONCLUSION: MPA-levels and IMPDH-activity in liver transplanted patients allows individual risk assessment. Patients with higher IMPDH inhibition acquire more often viral infections. Insufficient IMPDH inhibition is associated with development of non-anastomotic bile duct strictures and reduced re-transplantation-free survival.

First principles study of Si-doped BC2N nanotubes.

Spin polarized density functional theory is used to investigate the incorporation of substitutional Si atoms in the zigzag (5,0) and in the armchair (3,3) BC(2)N nanotubes (NTs). Our results show that the Si impurities in BC(2)N NTs have lower formation energy when compared to Si in carbon and boron nitride NTs. In neutral charge state, Si in the boron site (Si(B)) presents a spin split with two electronic levels within the NT band gap and it gives rise to a net spin magnetic moment net of 1mu(B). Si in the nitrogen site (Si(N)) introduces electronic levels near the top of the valence band that lead the system to exhibit acceptor properties, which suggest the formation of defect-induced type-p BC(2)N NTs. The defective levels for Si in the two nonequivalent carbon atom sites (Si(CI) and Si(CII)) are resonant with the valence and conduction bands, respectively. The calculations of formation energy in charge state show that for all the available values of the electronic chemical potential, Si(CI) and Si(CII) have lower formation energy in neutral charge state, while Si(B) and Si(N) present lower formation energy in neutral or single negative charge state depending on the position of the electronic chemical potential.

A screen for genes required for meiosis and spore formation based on whole-genome expression.

BACKGROUND: Meiosis is the process by which gametes are generated with half the ploidy of somatic cells. This reduction is achieved by three major differences in chromosome behavior during meiosis as compared to mitosis: the production of chiasmata by recombination, the protection of centromere-proximal sister chromatid cohesion, and the monoorientation of sister kinetochores during meiosis I. Mistakes in any of these processes lead to chromosome missegregation. RESULTS: To identify genes involved in meiotic chromosome behavior in Saccharomyces cerevisiae, we deleted 301 open reading frames (ORFs) which are preferentially expressed in meiotic cells according to microarray gene expression data. To facilitate the detection of chromosome missegregation mutants, chromosome V of the parental strain was marked by GFP. Thirty-three ORFs were required for the formation of wild-type asci, eight of which were needed for proper chromosome segregation. One of these (MAM1) is essential for the monoorientation of sister kinetochores during meiosis I. Two genes (MND1 and MND2) are implicated in the recombination process and another two (SMA1 and SMA2) in prospore membrane formation. CONCLUSIONS: Reverse genetics using gene expression data is an effective method for identifying new genes involved in specific cellular processes.

Cardiac volume overload and pulmonary hypertension in long-term follow-up of patients with a transjugular intrahepatic portosystemic shunt.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPSS) cause haemodynamic changes in patients with cirrhosis, yet little is known about long-term cardiopulmonary outcomes. AIM: To evaluate the long-term cardiopulmonary outcome after TIPSS. METHODS: We evaluated cardiopulmonary parameters including echocardiography during long-term follow-up after TIPSS. Results at 1-5 years after TIPSS were compared to those of cirrhotic controls. Pulmonary hypertension (PH) diagnoses rates were included. Endothelin 1, thromboxane B2 and serotonin were measured. RESULTS: We found significant differences 1-5 years after TIPSS compared to pre-implantation values: median left atrial diameter (LAD) increased from 37 mm [interquartile range (IQR): 33-43] to 40 mm (IQR: 37-47, P = 0.001), left ventricular end-diastolic diameter (LV-EDD) increased from 45 mm (range: 41-49) to 48 mm (IQR: 45-52, P < 0.001), pulmonary artery systolic pressure (PASP) increased from 25 mmHg (IQR: 22-33) to 30 mmHg (IQR: 25-36, P = 0.038). Comparing results 1-5 years post-implantation to the comparison cohort revealed significantly higher (P < 0.05) LAD, LV-EDD and PASP values in TIPSS patients. PH prevalence was higher in the shunt group (4.43%) compared to controls (0.91%, P = 0.150). Thromboxane B2 levels correlated with PASP in the TIPSS cohort (P = 0.033). There was no transhepatic gradient observed for the vasoactive substances analysed. CONCLUSIONS: TIPSS placement is accompanied by long-term cardiovascular changes, including cardiac volume overload, and is associated with an increased rate of pulmonary hypertension. The need for regular cardiac follow-up after TIPSS requires further evaluation.

Inhibition of fibrin polymerization by fragment d is affected by calcium, Gly-Pro-Arg and Gly-His-Arg.

Fibrinopeptides A and B were removed from purified human fibrinogen by bovine thrombin, whereas the snake venom protease batroxobin only split fibrinopeptide A from fibrinogen. Aggregation of the resulting desAB- and desA-fibrin monomers was evaluated by recording the turbidity of incubation mixtures. Fibrin assembly was strongly accelerated by increasing the calcium concentration from 10(-5) to 10(-3) M. Fragment D was obtained from fibrinogen by proteolytic degradation with plasmin in the presence of Ca2+. At a 4-fold molar concentration relative to fibrinogen, fragment D dramatically inhibited fibrin polymerization at up to 10(-4) M Ca2+. This anticlotting activity was, however, much less pronounced at 10(-3) M Ca2+. The thrombin clotting time, measured on human plasma, was prolonged by fragment D in a dose-dependent manner. In citrate-containing plasma, the fibrinogen clotting was significantly delayed by an equimolar concentration of fragment D. In barium sulfate-adsorbed oxalated plasma, containing 2.5 mM Ca2+, the same amount of fragment D hardly affected fibrin polymerization. We conclude that fragment D has no important anticlotting effect under physiological conditions. The synthetic peptide Gly-Pro-Arg, corresponding to the amino-terminal sequence of the fibrin alpha-chain, inhibited aggregation of both desA-fibrin and desAB-fibrin at 10(-3) M Ca2+. The inhibition of desAB-fibrin polymerization by Gly-Pro-Arg was abolished at 10(-5) M Ca2+. In addition, Gly-Pro-Arg depressed the anticlotting activity of fragment D at low calcium concentration. An analogue of the amino-terminus of fibrin beta-chain, Gly-His-Arg, strongly accelerated aggregation of desA-fibrin monomers, but only moderately enhanced polymerization of desAB-fibrin monomers at 10(-5) M Ca2+, both in the presence and in the absence of fragment D. This activating effect of Gly-His-Arg was abolished at 10(-3) M Ca2+. It is suggested that the binding of calcium, Gly-His-Arg, and possibly also Gly-Pro-Arg, induces a conformational change in fibrin monomers and thus accelerates the polymerization process.

Acute hypersensitivity reactions to etoposide in a VEPA regimen for Hodgkin's disease.

PURPOSE: We report an unexpectedly high incidence of hypersensitivity to etoposide among 45 patients with newly diagnosed Hodgkin's disease treated with vinblastine, etoposide, prednisone, and doxorubicin (VEPA) plus radiation. PATIENTS AND METHODS: Twenty-three of 45 patients (51%) had one or more acute hypersensitivity reactions to etoposide administration. The 23 patients were 8 to 18 years of age (median, 15 years); 12 were males. Four patients had experienced prior allergic reactions to antibiotics or intravenous contrast media. RESULTS: Hypersensitivity reactions followed the first or second dose of VEPA in most cases. The reactions occurred at a median time of 5 minutes (range, 3 to 120) from the start of the etoposide infusion. Fifteen patients reacted early (within 10 minutes), four midway through the infusion, and four after completion of the infusion. Signs and symptoms included flushing, respiratory problems, changes in blood pressure, and abdominal pain with or without nausea and vomiting. Respiratory problems included dyspnea, chest pain/tightness, bronchospasm, and cyanosis. Symptoms were alleviated by discontinuing the etoposide infusions and administering diphenhydramine and/or hydrocortisone; epinephrine was required to reverse bronchospasm in three cases. All 23 patients recovered without adverse sequelae and were rechallenged with etoposide. Fifteen patients tolerated subsequent etoposide infused at a slower rate, with antihistamine and/or corticosteroid premedication; five had recurrent hypersensitivity despite these measures. Three of these five developed similar symptoms when teniposide was substituted for etoposide. Three patients who had isolated episodes of hypotension on completion of the etoposide infusion successfully received subsequent infusions without premedication or change in infusion rate or concentration. CONCLUSION: Despite this unexpectedly high incidence of hypersensitivity among Hodgkin's disease patients treated with etoposide, rechallenge with the drug was successful in 78% of cases.

IGFBP7, a novel tumor stroma marker, with growth-promoting effects in colon cancer through a paracrine tumor-stroma interaction.

The activated tumor stroma participates in many processes that control tumorigenesis, including tumor cell growth, invasion and metastasis. Cancer-associated fibroblasts (CAFs) represent the major cellular component of the stroma and are the main source for connective tissue components of the extracellular matrix and various classes of proteolytic enzymes. The signaling pathways involved in the interactions between tumor and stromal cells and the molecular characteristics that distinguish normal 'resting' fibroblasts from cancer-associated or '-activated' fibroblasts remain poorly defined. Recent studies emphasized the prognostic and therapeutic significance of CAF-related molecular signatures and a number of those genes have been shown to serve as putative therapeutic targets. We have used immuno-laser capture microdissection and whole-genome Affymetrix GeneChip analysis to obtain transcriptional signatures from the activated tumor stroma of colon carcinomas that were compared with normal resting colonic fibroblasts. Several members of the Wnt-signaling pathway and gene sets related to hypoxia, epithelial-to-mesenchymal transition (EMT) and transforming growth factor-ß (TGFß) pathway activation were induced in CAFs. The putative TGFß-target IGFBP7 was identified as a tumor stroma marker of epithelial cancers and as a tumor antigen in mesenchyme-derived sarcomas. We show here that in contrast to its tumor-suppressor function in epithelial cells, IGFPB7 can promote anchorage-independent growth in malignant mesenchymal cells and in epithelial cells with an EMT phenotype when IGFBP7 is expressed by the tumor cells themselves and can induce colony formation in colon cancer cells co-cultured with IGFBP7-expressing CAFs by a paracrine tumor-stroma interaction.

Inhibition of 12-O-tetradecanoylphorbol-13-acetate and other skin tumor-promoter-caused induction of epidermal interleukin-1 alpha mRNA and protein expression in SENCAR mice by green tea polyphenols.

Recent studies have shown that topical application of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) to murine skin results in increased expression of the highly inflammatory cytokine interleukin (IL)-1 alpha in the epidermis. This has led to the suggestion that IL-1 alpha directly or indirectly mediates the inflammatory and hyperplastic responses elicited by TPA and possibly by other skin tumor promoters. In the current study, we investigated the effect of skin application of a polyphenolic fraction isolated from green tea (GTP) to SENCAR mice on skin tumor-promoter-caused induction of cutaneous edema and hyperplasia, and IL-1 alpha mRNA expression. Pretreatment of the skin with GTP 30 min before that of anthralin, benzoyl peroxide, mezerein, and TPA resulted in a significant (p < 0.05) inhibition of cutaneous edema and epidermal hyperplasia caused by each of these tumor promoters. Northern blot analysis indicated that topical application of TPA, anthralin, mezerein, or benzoyl peroxide to SENCAR mice resulted in an increased expression of epidermal IL-1 alpha mRNA. Pretreatment of the skin with GTP or individual epicatechin derivatives (ECDs) present therein, 30 min before that of TPA, resulted in a significant inhibition of enhanced expression of epidermal IL-1 alpha mRNA caused by skin application of TPA. These inhibitory effects were found to be dependent on the dose of GTP. Among four epicatechin derivatives present in GTP, (-)-epicatechin-3-gallate and (-)-epigallocatechin-3-gallate were more effective than (-)-epigallocatechin and (-)-epicatechin in affording this inhibition. Preapplication of GTP was also found to afford inhibition against anthralin-, benzoyl peroxide-, and mezerein-caused increased expression of epidermal IL-1 alpha mRNA and protein. Our study suggests that the inhibition of tumor-promoter-induced IL-1 alpha mRNA and protein expression in mouse epidermis by green tea in combination with other inhibitory effects may be responsible for the anti-tumor-promoting and anti-inflammatory effects of GTP.

Effect of calcium and synthetic peptides on fibrin polymerization.

Human fibrinogen was subjected to limited proteolytic attack by thrombin, batroxobin or Agkistrodon contortrix thrombin-like enzyme, yielding desAB-, desA- or desB-fibrin monomers, respectively. Turbidity curves demonstrated that, with all three enzymes, the polymerization process was strongly accelerated by increasing the calcium concentration from 10(-5) M to 10(-4) M. Synthetic peptide Gly-His-Arg (5 mM), an analogue of the aminoterminal sequence of fibrin beta-chain, inhibited aggregation of desB-fibrin monomers at physiological calcium concentration whereas it enhanced aggregation of desA- and desAB-fibrin monomers at calcium concentrations below 10(-4) M. On the other hand, Gly-Pro-Arg (1 mM) corresponding to the amino-terminus of fibrin alpha-chain, dramatically inhibited aggregation of both desA- and desB-fibrins, but it only moderately affected the polymerization of thrombin-induced monomers. We conclude that the observed effects of Gly-Pro-Arg and Gly-His-Arg are not due solely to their competition with fibrin amino-termini for the respective binding sites in the D-domain, but rather reflect conformational changes in fibrin monomers which affect the polymerization process.

Calcium and phosphorus in neonatal parenteral nutrition solutions.

Due to calcium and phosphorus solubility problems in parenteral nutrition solutions, it is difficult to provide the premature infant with enough of these two minerals for adequate bone mineralization. In order to determine the maximum amounts of both Ca and P soluble in neonatal parenteral nutrition solutions, we employed the following procedure: (1) using concentrations of dextrose 10 to 25% and amino acid 0.5 to 4.0% with standard electrolyte and vitamin concentrations, Ca and P additions were sequentially made to determine the critical concentrations at which precipitates formed; (2) the pH of each test solution was determined; (3) all test solutions were incubated for 30 hr at room temperature; (4) following incubation, all tests were visually observed for calcium-phosphate crystals; (5) the solutions not obviously precipitated were filtered using black Millipore filters to determine the presence of any microprecipitates. Multiple graphs of Ca and P solubility in various dextrose/amino acid solutions were prepared from data generated by the study. The Ca and P interaction is primarily pH sensitive. Factors affecting the solution pH include both dextrose and amino acid concentrations. Our study showed that increases in amino acid concentrations enabled us to increase both Ca and P in the solutions.

Measurement and prediction of thermal behavior and acute assessment of injury in a pig model of renal cryosurgery.

PURPOSE: To analyze in vivo end temperatures and histologic injury in a standardized cryo-iceball using a porcine kidney model in order to establish the threshold temperature for tissue ablation. To evaluate the ability to predict end temperatures using a thermal finite element model. MATERIALS AND METHODS: A single freeze/thaw cryolesion was created in five pig kidneys and the temperature history recorded. End temperature was calculated using a thermal finite element model. The threshold temperature for tissue injury was established by directly correlating end temperature and histologic injury. RESULTS: Reproducible geometry and temperature profiles of the cryo-iceball were found. End temperature could be accurately predicted through thermal modeling, and correlation with histologic injury revealed a threshold temperature of -16.1 degrees C for complete tissue ablation. CONCLUSION: Thermal modeling may accurately predict end temperature within a cryo-iceball. Provided threshold temperatures for tissue destruction are known, modeling may become a powerful tool in cryosurgery, improving the assessment of damage in normal and malignant tissue.

[Malignant mesothelioma of the tunica vaginalis testis]. / Malignes Mesotheliom der Tunica vaginalis testis.

A case of malignant mesothelioma of the tunica vaginalis testis is reported in a 77-year-old male patient. There was no history of asbestos exposure. Recurrent right hydrocele with a papillar inguinal mass was the main clinical feature. An inguinal radical orchiectomy with en bloc resection of the surrounding tissue was performed. The therapeutic options for this rare, but aggressive neoplasm are discussed. Because of the disappointing results of antineoplastic chemotherapy or radiation therapy, the importance of initial radical surgical treatment with complete excision is emphasized.

[Life expectancy of the drug addict]. / Lebenserwartung des Drogenkonsumenten.

The exact characterization of the epidemiology of drug-related mortality demands investigations of cross-sectional dates and the pursuit of trends under scientifically correct conditions. At the moment the possibilities of research in this field are limited. This is the reason why conclusions concerning the life expectancy of drug-addicts should be drawn with caution. Although systemic studies are not available and--for different reasons--cannot be expected in the FRG few sample surveys do exist which may be considered indicative of certain trends in mortality. Besides the Netherlands the FRG has become the most important market characterized by a rapid increase in illegal drug traffic. The number of drug-related deaths dramatically rises and the elder age-groups are increasingly concerned with the age-group from 20 top 30 years displaying a significantly increased mortality in connection with drug abuse. The epidemiologic development described so far is supposed even to be aggravated because the i.v.-drug-addicts are at high risk to acquire a hepatitis or HIV-infection.

Reduction in alkaline phosphatase is associated with longer survival in primary sclerosing cholangitis, independent of dominant stenosis.

BACKGROUND: Alkaline phosphatase (ALP) is an important serum marker in primary sclerosing cholangitis (PSC). Patients with obstruction of the large bile ducts due to dominant strictures (DS) are a special, clinically important phenotype. AIM: To determine the impact of ALP reduction on liver transplantation-free survival in PSC patients with DS. METHODS: Prospective cohort study in 215 PSC patients. We performed subgroup analysis for patients without DS (no DS, n = 84), DS at first presentation (DS early, n = 72) and development of DS during the course of the study (DS late, n = 59). We evaluated two scores of ALP reduction. ALP reduction 1 was defined as ALP normalisation, 50% reduction compared with baseline values, or reduction below 1.5 times of upper limit of normal (ULN) within 6 months. ALP reduction 2 was defined as ALP reduction below 1.5 times of ULN within 12 months. RESULTS: Of the patients, 59.5% reached an ALP reduction 1 and 56.7% according to ALP reduction 2. Achievement of each score was associated with longer transplantation-free survival in all three groups (ALP reduction 1: no DS P = 0.001; DS early P < 0.001; DS late P = 0.022; ALP reduction 2: no DS P = 0.014; DS early P = 0.001; DS late P = 0.002). Cox-regression analysis revealed each score as an independent predictor for improved transplantation-free survival (ALP reduction 1 and 2 P < 0.001 each). We further analysed previously published scores of ALP improvement in PSC showing also improved survival in patients with ALP normalisation or a reduction below 1.5 times of ULN (P = 0.003, P = 0.001, respectively), whereas the score determined by 40% reduction did not show significant differences in survival (P = 0.55). CONCLUSIONS: Reduction in alkaline phosphatase values within the first year is associated with improved transplantation-free survival in patients with primary sclerosing cholangitis independent of the presence of dominant strictures. Alkaline phosphatase might be an adequate surrogate marker for outcome assessment in clinical studies both for patients with and without dominant strictures.