Animal model for sport-related concussion; ICP and cognitive function.

BACKGROUND: We have recently developed and characterized a rat model of mild traumatic brain injury which simulates the concussive injuries frequently encountered by players in American professional football. OBJECTIVES: To study the effect of multiple impacts to the head on intracranial pressure, cognitive function, and exploratory behavior. MATERIALS AND METHODS: The model was employed to cause concussion. Intracranial pressure, cognitive function, and exploratory behavior were examined following the multiple impacts of a 50 or 100 g projectile at a velocity of 9.3 or 11.2 m/s to the helmet protected head. RESULTS: Intracranial pressure measured at 6 and 10 h, and 1, 2, 3, 5, and 7 days. It was maximally elevated 10 h after impact and returned to the control levels 7 days later. Morris Water Maze assessment, 48 h after impact, revealed impaired cognitive function. Open field testing 2-4 days and 1 and 2 weeks after impacts indicated consistently reduced spontaneous exploratory activity. CONCLUSION: Multiple impacts to the head raise intracranial pressure and impair cognitive function and exploratory activity in this animal model.

The folic acid metabolite L-5-methyltetrahydrofolate effectively reduces total serum homocysteine level in orthotopic liver transplant recipients: a double-blind placebo-controlled study.

OBJECTIVE: Hyperhomocysteinemia is a described risk factor of cardiovascular diseases. The aim of this study was the treatment of hyperhomocysteinemia in liver transplant recipients with L-5-methyltetrahydrofolate (L-5-MTHF; 1 mg) vs folic acid (1 mg) vs placebo in a double-blind placebo-controlled study and to compare the relative responsiveness of these patients to L-5-MTHF and folic acid. SUBJECTS/METHODS: Patients were recruited from Hepatology-Transplantation-Unit at Johann Wolfgang Goethe-University, Frankfurt. Sixty patients were included in this study and 12 patients dropped out for different reasons. The patients were treated over 8 weeks with supplemental L-5-MTHF or folic acid or placebo. Serum homocysteine (HCY) was analyzed with high-performance liquid chromatography (HPLC) beside routine lab tests. RESULTS: We observed only a significant decrease of total serum HCY in the L-5-MTHF group during the study period (at week 0: 15+/-7.7 microM; after 8 weeks treatment: 9.41+/-2.6 microM, P<0.001). There was no significant decrease of total serum HCY neither in the folic acid group nor in the placebo group. CONCLUSION: The effects of L-5-MTHF are significantly more potent than folic acid itself. Therefore, lowering serum HCY in liver transplant recipients is effective with L-5-MTHF.

Transcriptional noise and cellular heterogeneity in mammalian macrophages.

Transcriptional noise is known to play a crucial role in heterogeneity in bacteria and yeast. Mammalian macrophages are known to exhibit cell-to-cell variation in their responses to pathogens, but the source of this heterogeneity is not known. We have developed a detailed stochastic model of gene expression that takes into account scaling effects due to cell size and genome complexity. We report the results of applying this model to simulating gene expression variability in mammalian macrophages, demonstrating a possible molecular basis for heterogeneity in macrophage signalling responses. We note that the nature of predicted transcriptional noise in macrophages is different from that in yeast and bacteria. Some molecular interactions in yeast and bacteria are thought to have evolved to minimize the effects of the high-frequency noise observed in these species. Transcriptional noise in macrophages results in slow changes to gene expression levels and would not require the type of spike-filtering circuits observed in yeast and bacteria.

Evolution of 'design' principles in biochemical networks.

Computer modelling and simulation are commonly used to analyse engineered systems. Biological systems differ in that they often cannot be accurately characterised, so simulations are far from exact. Nonetheless, we argue in this paper that evolution results in recurring, dynamic organisational principles in biological systems, and that simulation can help to identify them and analyse their dynamic properties. As a specific example, we present a dynamic model of the galactose utilisation pathway in yeast, and highlight several features of the model that embody such 'design principles'.

The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models.

MOTIVATION: Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. RESULTS: We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others. AVAILABILITY: The specification of SBML Level 1 is freely available from http://www.sbml.org/

The ERATO Systems Biology Workbench: enabling interaction and exchange between software tools for computational biology.

Researchers in computational biology today make use of a large number of different software packages for modeling, analysis, and data manipulation and visualization. In this paper, we describe the ERATO Systems Biology Workbench (SBW), a software framework that allows these heterogeneous application components--written in diverse programming languages and running on different platforms--to communicate and use each others' data and algorithmic capabilities. Our goal is to create a simple, open-source software infrastructure which is effective, easy to implement and easy to understand. SBW uses a broker-based architecture and enables applications (potentially running on separate, distributed computers) to communicate via a simple network protocol. The interfaces to the system are encapsulated in client-side libraries that we provide for different programming languages. We describe the SBW architecture and the current set of modules, as well as alternative implementation technologies.

Cis-regulatory logic in the endo16 gene: switching from a specification to a differentiation mode of control.

The endo16 gene of Strongylocentrotus purpuratus encodes a secreted protein of the embryonic and larval midgut. The overall functional organization of the spatial and temporal control system of this gene are relatively well known from a series of earlier cis-regulatory studies. Our recent computational model for the logic operations of the proximal region of the endo16 control system (Module A) specifies the function of interactions at each transcription factor target site of Module A. Here, we extend sequence level functional analysis to the adjacent cis-regulatory region, Module B. The computational logic model is broadened to include B/A interactions as well as other Module B functions. Module B drives expression later in development and its major activator is responsible for a sharp, gut-specific increase in transcription after gastrulation. As shown earlier, Module B output undergoes a synergistic amplification that requires interactions within Module A. The interactions within Module B that are required to generate and transmit its output to Module A are identified. Logic considerations predicted an internal cis-regulatory switch by which spatial control of endo16 expression is shifted from Module A (early) to Module B (later). This prediction was confirmed experimentally and a distinct set of interactions in Module B that mediate the switch function was demonstrated. The endo16 computational model now provides a detailed explanation of the information processing functions executed by the cis-regulatory system of this gene throughout embryogenesis. Early in development the gene participates in the specification events that define the endomesoderm; later it functions as a gut-specific differentiation gene. The cis-regulatory switch mediates this functional change.

Identification of complex shapes using a self organizing neural system.

We present a multilayer hierarchical neural system for automatic classification of complex contour patterns. The system consists of a neocognitron-like network structure combined with self-organizing maps to automatically determine feature classes. We present results showing that multilayer hierarchical networks are able to tolerate pattern distortion considerably better than standard neural network implementations.

Myeloablative radiochemotherapy followed by reinfusion of purged autologous stem cells for Waldenström's macroglobulinaemia.

Waldenström's macroglobulinaemia (WM) is an incurable lymphoproliferative disorder. The purpose of this study was to investigate the role of autologous peripheral blood stem cell transplantation (ASCT) for the treatment of WM. Seven patients (untreated or after first-line therapy) with symptomatic WM underwent two or three cycles of Dexa-BEAM chemotherapy + G-CSF with stem cell harvesting and proceeded to total body irradiation and high-dose cyclophosphamide followed by reinfusion of ex-vivo B-cell-depleted stem cells. Engraftment was prompt, and procedure-related deaths did not occur. A strong reduction or normalization of BM infiltration and serum IgM levels occurred in all evaluable patients, but immunofixation electrophoresis revealed persistent paraproteinaemia in five of them. With 3-30 months of follow-up, all patients are alive without clinical or serological signs of disease progression. This pilot trial shows for the first time that high-dose radiochemotherapy with purged stem cells is effective and may improve the course of patients with WM. In the majority of cases, however, complete eradication of the disease does not appear to be possible with ASCT alone.

Genomic cis-regulatory logic: experimental and computational analysis of a sea urchin gene.

The genomic regulatory network that controls gene expression ultimately determines form and function in each species. The operational nature of the regulatory programming specified in cis-regulatory DNA sequence was determined from a detailed functional analysis of a sea urchin control element that directs the expression of a gene in the endoderm during development. Spatial expression and repression, and the changing rate of transcription of this gene, are mediated by a complex and extended cis-regulatory system. The system may be typical of developmental cis-regulatory apparatus. All of its activities are integrated in the proximal element, which contains seven target sites for DNA binding proteins. A quantitative computational model of this regulatory element was constructed that explicitly reveals the logical interrelations hard-wired into the DNA.

Arrhythmia recognition strategies and hardware decisions for the implantable cardioverter-defibrillator--a review.

The avoidance of inappropriate shocks from the implantable cardioverter-defibrillator (ICD), together with its need to apply antitachycardia pacing to either atria or ventricles, demands considerable sophistication in the design of algorithms to interpret electrical or other cardiac signals in real-time. Methods based on rate and using single short-gap bipolar leads lack discrimination. Right ventricular electrogram morphology algorithms offer improvement but no universal algorithm exists; however, for any given patient an optimum algorithm of this type might be found. One improvement would be to provide atrial information in addition, by employing more than one electrode or a long-gap single bipolar lead. Alternatively, transducer signals could be included, once their efficacy and reliability have been improved. A different approach would be to use the much more sophisticated algorithms at present being tried with surface electrocardiograms. Integrated Circuit technology is reaching the point where this could be done but the requirement for exceptionally high reliability means that special system structures, such as a Memory Intensive Computer Architecture, may be required. When decisions on these approaches are to be made, it must also be remembered that ICDs will soon be implanted and programmed as a routine rather than a highly specialized procedure.

Graft-versus-leukemia activity after bone marrow transplantation does not require graft-versus-host disease.

Clinical data have suggested that graft-versus-host disease (GVHD) plays a crucial role in the antileukemic effects of bone marrow grafts. We investigated (a) whether bone marrow cells unable to induce GVHD can effect graft-versus-leukemia (GVL) activity and (b) whether such antileukemic capacity depends on the presence of T lymphocytes in the graft. Balb/c mice were inoculated with A20 cells, a B-cell lymphoma/leukemia of Balb/c origin. Four weeks after tumor inoculation the animals were lethally irradiated and received a bone marrow graft. Cells from (Balb/c x C57) F1 or (C3H x Balb/c) F1 hybrids were transplanted into parental-strain Balb/c mice. Since lymphocytes from F1 hybrids are unable to cause graft-versus-host reactivity against a parental-strain animal, we used this experimental setting to explore GVL effects in a GVHD-free system. In vitro incubation with monoclonal anti-Thy-1.2 antibody plus complement was used to eliminate Thy-1+ cells. After syngeneic transplantation, the death rate due to leukemia remained unchanged (91%) compared with that among untreated animals (86%). Following transplantation of F1 marrow cells of either (C57 x Balb/c) F1 or (C3H x Balb/c) F1 origin, death rates of 40% and 50% were observed; these were significantly lower. Depletion of Thy 1+ cells from bone marrow graft caused only a slight increase in the leukemic death rate after transplantation of bone marrow of (C57 x Balb/c) F1 hybrid origin (50%), but a high leukemic death rate was seen after transplantation of (C3H x Balb/c) F1 bone marrow (100%). Additional experiments with fully allogeneic, T-cell-depleted C57 bone marrow transplantation suggest an antileukemic effect that is comparable to that seen after transplantation of unmanipulated F1 bone marrow. Taken together, our results indicate that GVL activity can be dissociated from graft-versus-host reaction.