PATRIC: the VBI PathoSystems Resource Integration Center.

The PathoSystems Resource Integration Center (PATRIC) is one of eight Bioinformatics Resource Centers (BRCs) funded by the National Institute of Allergy and Infection Diseases (NIAID) to create a data and analysis resource for selected NIAID priority pathogens, specifically proteobacteria of the genera Brucella, Rickettsia and Coxiella, and corona-, calici- and lyssaviruses and viruses associated with hepatitis A and E. The goal of the project is to provide a comprehensive bioinformatics resource for these pathogens, including consistently annotated genome, proteome and metabolic pathway data to facilitate research into counter-measures, including drugs, vaccines and diagnostics. The project's curation strategy has three prongs: 'breadth first' beginning with whole-genome and proteome curation using standardized protocols, a 'targeted' approach addressing the specific needs of researchers and an integrative strategy to leverage high-throughput experimental data (e.g. microarrays, proteomics) and literature. The PATRIC infrastructure consists of a relational database, analytical pipelines and a website which supports browsing, querying, data visualization and the ability to download raw and curated data in standard formats. At present, the site warehouses complete sequences for 17 bacterial and 332 viral genomes. The PATRIC website (https://patric.vbi.vt.edu) will continually grow with the addition of data, analysis and functionality over the course of the project.

PIML: the Pathogen Information Markup Language.

MOTIVATION: A vast amount of information about human, animal and plant pathogens has been acquired, stored and displayed in varied formats through different resources, both electronically and otherwise. However, there is no community standard format for organizing this information or agreement on machine-readable format(s) for data exchange, thereby hampering interoperation efforts across information systems harboring such infectious disease data. RESULTS: The Pathogen Information Markup Language (PIML) is a free, open, XML-based format for representing pathogen information. XSLT-based visual presentations of valid PIML documents were developed and can be accessed through the PathInfo website or as part of the interoperable web services federation known as ToolBus/PathPort. Currently, detailed PIML documents are available for 21 pathogens deemed of high priority with regard to public health and national biological defense. A dynamic query system allows simple queries as well as comparisons among these pathogens. Continuing efforts are being taken to include other groups' supporting PIML and to develop more PIML documents. AVAILABILITY: All the PIML-related information is accessible from http://www.vbi.vt.edu/pathport/pathinfo/

Farming exposure in childhood, exposure to markers of infections and the development of atopy in rural subjects.

BACKGROUND: Within the context of the hygiene hypothesis, we aimed to study the potential association between farming-related risk factors and Toxoplasma gondii (T. gondii) as well as Helicobacter pylori (H. pylori) seropositivity. METHODS: The study included questionnaire data and serum samples of 321 young adults living in a rural environment. Serum samples were analysed for specific IgE to a common panel of aeroallergens (SX1) as well as IgG against T. gondii and H. pylori. RESULTS: Regular contact with animal stables before the age of 3 years (odds ratio (OR) (95% confidence interval): 2.0 [1.0; 4.0]) and unpasteurized milk consumption at age 6 years (1.8 [1.0; 3.3]) were the strongest risk factors for T. gondii infection. None of the farming-related factors were significantly associated with H. pylori infection. Current consumption of raw farm milk was not significantly associated with H. pylori infection (2.1 [0.8; 5.3]). Regular contact with animal houses before the age of 7 years was the strongest predictor for atopy (0.49 [0.26-0.96]). The reduction in risk could not be further decreased by any other factor under consideration. After adjustment for animal house contact, the OR for atopy was decreased by raw milk consumption and H. pylori infection in an additive manner. CONCLUSION: Exposure to farming environments in childhood might predict T. gondii seropositivity in rural subjects. Nevertheless, the strongest predictor for atopy in rural subjects seems to be regular contact with farm animals. Whether T. gondii infection is an intermediate factor in the association between farm contact and atopy needs to be confirmed in larger studies.

A life scientist's gateway to distributed data management and computing: the PathPort/ToolBus framework.

The emergent needs of the bioinformatics community challenge current information systems. The pace of biological data generation far outstrips Moore's Law. Therefore, a gap continues to widen between the capabilities to produce biological (molecular and cell) data sets and the capability to manage and analyze these data sets. As a result, Federal investments in large data set generation produces diminishing returns in terms of the community's capabilities of understanding biology and leveraging that understanding to make scientific and technological advances that improve society. We are building an open framework to address various data management issues including data and tool interoperability, nomenclature and data communication standardization, and database integration. PathPort, short for Pathogen Portal, employs a generic, web-services based framework to deal with some of the problems identified by the bioinformatics community. The motivating research goal of a scalable system to provide data management and analysis for key pathosystems, especially relating to molecular data, has resulted in a generic framework using two major components. On the server-side, we employ web-services. On the client-side, a Java application called ToolBus acts as a client-side "bus" for contacting data and tools and viewing results through a single, consistent user interface.

Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock: a multicenter, randomized, placebo-controlled, dose-ranging study.

OBJECTIVE: To investigate the safety, biological effects, and efficacy of the anti-tumor necrosis factor (TNF) antibody fragment, MAK 195F, in a phase II trial in patient with severe sepsis. DESIGN: Prospective, randomized, open label, placebo-controlled, dose-ranging, multicenter, multinational clinical trial. SETTING: Sixteen academic medical centers' intensive care units in six European countries. PATIENTS: One hundred twenty-two patients with severe sepsis or septic shock who received standard supportive care and antimicrobial therapy. INTERVENTIONS: Patients received one of three different doses of the anti-TNF antibody (0.1 mg/kg, 0.3 mg/kg, or 1.0 mg/kg) or placebo; the antibody or placebo was given in nine doses at 8-hr intervals over 3 days. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in mortality rates among the groups receiving various doses of the anti-TNF antibody or placebo, but patients with baseline serum interleukin (IL)-6 concentrations of > 1000 pg/mL appeared to benefit from MAK 195F in a dose-dependent fashion. Increased circulating IL-6 concentrations, but not TNF concentrations, were found to be important prognostic indicators for mortality for the patients in the placebo and the two lower dosage groups but not in the high dosage group (1 mg/kg). IL-6 concentrations decreased during the first 24 hrs of treatment in all three anti-TNF groups but not in the placebo group. MAK 195F was well tolerated by all patients. Human antimurine antibodies developed in 40% of the patients receiving the antibody. CONCLUSIONS: There was no increase in survival from sepsis for the patients receiving anti-TNF treatment in the overall study population. Retrospective stratification of patients by IL-6 concentrations suggests beneficial effects of the drug for patients with baseline circulating IL-6 concentrations of > 1000 pg/mL. This hypothesis requires validation in a larger, blinded, prospective study.

[Fructose vs. glucose in total parenteral nutrition in critically ill patients]. / Fruktose vs. Glukose in der total parenteralen Ernährung kritisch kranker Patienten.

UNLABELLED: Parenteral nutrition required following surgery or injury should not only meet post-aggression caloric requirements but also match the specific metabolic needs so as not to worsen the metabolic disruptions already present in this situation. The primary objective of parenteral nutrition is body protein maintenance or restoration by reduction of protein catabolism or promotion of protein synthesis or both. Whether all parenteral energy donors, ie., glucose, fructose, other polyols, and lipid emulsions, are equally capable of achieving this objective continues to be a controversial issue. The objective of the present study was to answer the following questions: (1) Do glucose and fructose differ in their effects on the metabolic changes seen following surgery or injury, the changes in glucose metabolism in particular? (2) Can the observation of poorer glucose utilization in the presence of lipids be confirmed in ICU patients? PATIENTS, MATERIALS AND METHODS: A prospective, randomized clinical trial has been conducted in 20 aseptic surgical ICU patients to generate an objective database along these lines by performing a detailed analysis of the metabolic responses to different parenteral nutrition protocols. The effects of a glucose solution+lipid emulsion regimen vs fructose solution+lipid emulsion regimen on a number of carbohydrate and lipid metabolism variables were evaluated for an isocaloric (carbohydrates: 0.25 g/kg body weight/h; lipids: 0.166g/kg body weight/h) and isonitrogenous (amino acids: 0.0625 g/kg body weight/h) total nutrient supply over a 10-h study period. RESULTS: A significantly smaller rise in blood glucose concentrations (increase from baseline: glucose+lipids P<0.001 vs fructose+lipids n.s.) suggested that fructose had a small effect, if any at all, on glucose metabolism. Serum insulin activity showed significant differences as a function of carbohydrate regimen, i.e. infusion of fructose instead of glucose produced a less pronounced increase in insulin activity (increase from baseline: glucose+lipids P<0.001 vs fructose+lipids P<0.01). Impairment of glucose utilization by concomitant administration of lipids was observed neither in patients who first received glucose nor in those who first received fructose. CONCLUSIONS: As demonstrated, parenteral fructose, unlike parenteral glucose, has a significantly less adverse impact than glucose on the glucose balance, which is disrupted initially in the post-aggression state. In addition, the less pronounced increase in insulin activity during fructose infusion than during glucose infusion can be assumed to facilitate mobilization of endogenous lipid stores and lipid oxidation. Earlier workers pointed out that any rise in free fatty acid and ketone body concentrations in the serum produces inhibition of muscular glucose uptake and oxidation, and of glycolysis. These findings were recorded in a rat model and could not be confirmed in our post-aggression state patients receiving lipid doses commensurate with the usual clinical infusion rates. The serious complications that can result from hereditary fructose intolerance are completely avoidable if a careful patient history is taken before the first parenteral use of fructose. If the patient or family members and close friends, are simply asked whether he/she can tolerate fruit and sweet dishes, hereditary fructose intolerance can be ruled out beyond all reasonable doubt. Only in the extremely rare situations in which it is not possible to question either the patient or any significant other, a test dose will have to be administered to exclude fructose intolerance. The benefits of fructose-specific metabolic effects reported in the literature and corroborated by the results of out own study suggest that fructose is an important nutrient that contributes to metabolic stabilization, especially in the post-aggression phase and in septic patients. Hyperglycaemic states are largely prevented and fewer patients require ex

Time constant/volume relationship of passive expiration in mechanically ventilated ARDS patients.

Since the adult respiratory distress syndrome (ARDS) lung is known to be inhomogeneous, one could expect an uneven distribution of expiratory time constant during uninterrupted mechanical ventilation. We investigated the time constant/volume relationship of passive expiration, and their modification by external resistive elements. In 12 paralysed intubated ARDS patients, we determined the expiratory time constant (tau E) as a function of the expired volume (VE) during uninterrupted mechanical ventilation. Mean expiratory time was 2.9 +/- 0.3 s (+/- SD). VE was divided into five equal volume slices (portions) and a mean tau E calculated from the expiratory tidal volume/flow curve for each slice. The mean values of tau E for each volume slice did not differ significantly throughout expiration, averaging 690 +/- 218 ms (mean +/- SD of five slices and 12 patients). We show that the flow-dependent resistance of the endotracheal tube (RETT) is mainly responsible for the observed time constant homogeneity. We conclude that in ARDS patients during uninterrupted mechanical ventilation the time constants of passive expiration are markedly modified by the flow-dependent resistance of the endotracheal tube (RETT), and also by the external resistance of tubing and ventilator (REX). RETT and REX render tau E about three times larger than the time constant of the patient's respiratory system alone.

[Can administration of trasylol in reduced Hammersmith dosage with simultaneous transfusion of autologous blood meet the requirements of open heart surgery?]. / Kann die Gabe von Trasylol in einer verringerten Hammersmith-Dosierung bei gleichzeitiger Applikation von Eigenblutspenden den Ansprüchen der offenen Herzchirurgie entsprechen?

PROBLEM: The general positive effect of the proteinase inhibitor trasylol on blood loss and transfusion demand in cardiac surgery has been demonstrated in several placebo-controlled studies. Given the possibility of cardiac and renal side effects associated with a high dose of trasylol (Hammersmith dosage: 6 x 10(6) kallikrein inactivator units KIU), the question of a dose reduction was raised. METHODS: Being designed as a randomized double-blind comparative group study, the investigation included 120 patients with elective primary cardiac surgery from November 1990 to April 1992. One characteristic aspect of this study was the combined administration of trasylol and autologous blood transfusions. To compare the efficacy and safety of different doses of trasylol, two groups, each with 60 patients, were created: the former with the full Hammersmith dose (high dose group = HD group), the latter with half of the Hammersmith dose (los dose group = LD group). A placebo group had to be excluded for ethical reasons. RESULTS: The trasylol plasma levels showed a good dose correlation for the complete interval. The intra-operative bleeding tendency, as judged by the surgeons in charge, did not show any statistical significant difference between the HD group and the LD group. As to the post-operative blood loss via thoracic drainage, the early collection periods did not show any difference between both study groups. Starting at 6 hours post-operatively, the drainage losses showed a tendency towards lower volumes in the HD group. This difference was statistically significant for the time period "6-12 hours post-operatively". The analysis of the post-operative complications did not show any difference. SUMMARY: In this study with a high percentage of autologous blood transfusions, a lower dose of trasylol seemed to be nearly as effective as a full Hammersmith dose. However, such a reduced dose did not demonstrate any advantage regarding the complication rate in comparison with the conventional high dose.

Intrinsic PEEP monitored in the ventilated ARDS patient with a mathematical method.

Under mechanical volume-controlled ventilation, the intensive care patient can develop intrinsic positive end-expiratory pressure (iPEEP); that is, the passive expiration is terminated by the following inspiration before the alveolar pressure comes to its physical equilibrium value. We present a mathematical method to estimate this alveolar dynamic iPEEP breath by breath, without the need of a maneuver. We tested it in paralyzed patients ventilated for adult respiratory distress syndrome after multiple trauma and/or sepsis, and we compared the results obtained with the new mathematical method with those from the occlusion method introduced by Pepe and Marini. The results agreed well (median difference of 0.8 mbar in 201 investigations in 12 patients). However, the mathematically determined values, representing dynamic iPEEP, are systematically slightly smaller than those measured by the occlusion maneuver. A variation of expiratory time suggests that this difference might be due to mechanical time-constant inhomogeneity, viscoelastic processes, or other mechanisms showing time dependence.

[Initial experiences with rigid angled optical systems as intubation aids in difficult intubation]. / Erste Erfahrungen mit starren Winkeloptiken als Intubationshilfe bei der schwierigen Intubation.

Referring to a classification by Cormack, difficult laryngoscopy of Grade 3 (only the epiglottis or a part of it can be seen) was simulated in 16 patients by lowering the blade of the laryngoscope, so that the epiglottis was pushed down and thus covered up the vocal cords. The object of the study was to test whether a newly developed rigid endoscope is a useful tool during intubation in cases of laryngoscopical view Grade 3. After simulation of Grade 3 as mentioned above, using a clip, an angle optic was fixed to the vertical part of the blade, so that the movement of the optic in the sagittal level was still possible. If an improvement of the laryngoscopical view was possible, the tracheal tube was inserted via the nasal route until the top of the tube could be seen in the oropharynx. The tracheal tube was inserted into the trachea, under endoscopic control. With this new method, naso-tracheal intubation under endoscopic control in all 16 patients was successful, without affecting the pharynx and the vocal cords.

[Energy requirements of surgically treated, injured and infected patients]. / Der Energiebedarf operierter, verletzter und septischer Patienten.

There is always a distinct increase in energy expenditure in postoperative, posttraumatic and septic patients. In order to predict this increase in energy expenditure an enormous number of formulas have been developed. However, the problem with all these formulas is that they cannot sufficiently take into account the peculiarities of the underlying disease, the general and nutritional condition or the varying influence of the phase of disease. Furthermore, all these patients continuously show a considerable change in body weight which can be attributed to a shifting of the water balance. In all of these cases any calculation of energy expenditure based on body weight will inevitably be incorrect. Therefore, it is recommended that predicting formulas only be used as orienting guidelines in all uncomplicated postoperative or posttraumatic courses. In patients with multiple injuries or septic complications the real energy expenditure should be measured by indirect calorimetry in order to adapt energy intake during enteral or parenteral nutrition to the very different metabolic situations.