Integrated Multiscale Modeling of the Nervous System: Predicting Changes in Hippocampal Network Activity by a Positive AMPA Receptor Modulator

One of the fundamental characteristics of the brain is its hierarchical organization. Scales in both space and time that must be considered when integrating across hierarchies of the nervous system are sufficiently great as to have impeded the development of routine multilevel modeling methodologies. Complex molecular interactions at the level of receptors and channels regulate activity at the level of neurons; interactions between multiple populations of neurons ultimately give rise to complex neural systems function and behavior. This spatial complexity takes place in the context of a composite temporal integration of multiple, different events unfolding at the millisecond, second, minute, hour, and longer time scales. In this study, we present a multiscale modeling methodology that integrates synaptic models into single neuron, and multineuron, network models. We have applied this approach to the specific problem of how changes at the level of kinetic parameters of a receptor-channel model are translated into changes in the temporal firing pattern of a single neuron, and ultimately, changes in the spatiotemporal activity of a network of neurons. These results demonstrate how this powerful methodology can be applied to understand the effects of a given local process within multiple hierarchical levels of the nervous system

Simulation of Postsynaptic Glutamate Receptors Reveals Critical Features of Glutamatergic Transmission

Activation of several subtypes of glutamate receptors contributes to changes in postsynaptic calcium concentration at hippocampal synapses, resulting in various types of changes in synaptic strength. Thus, while activation of NMDA receptors has been shown to be critical for long-term potentiation (LTP) and long term depression (LTD) of synaptic transmission, activation of metabotropic glutamate receptors (mGluRs) has been linked to either LTP or LTD. While it is generally admitted that dynamic changes in postsynaptic calcium concentration represent the critical elements to determine the direction and amplitude of the changes in synaptic strength, it has been difficult to quantitatively estimate the relative contribution of the different types of glutamate receptors to these changes under different experimental conditions. Here we present a detailed model of a postsynaptic glutamatergic synapse that incorporates ionotropic and mGluR type I receptors, and we use this model to determine the role of the different receptors to the dynamics of postsynaptic calcium with different patterns of presynaptic activation. Our modeling framework includes glutamate vesicular release and diffusion in the cleft and a glutamate transporter that modulates extracellular glutamate concentration. Our results indicate that the contribution of mGluRs to changes in postsynaptic calcium concentration is minimal under basal stimulation conditions and becomes apparent only at high frequency of stimulation. Furthermore, the location of mGluRs in the postsynaptic membrane is also a critical factor, as activation of distant receptors contributes significantly less to calcium dynamics than more centrally located ones. These results confirm the important role of glutamate transporters and of the localization of mGluRs in postsynaptic sites in their signaling properties, and further strengthen the notion that mGluR activation significantly contributes to postsynaptic calcium dynamics only following high-frequency stimulation. They also provide a new tool to analyze the interactions between metabotropic and ionotropic glutamate receptors

Unexpected Massive Hemothorax After Pancreatic Islet Transplantation: A Case Report

The percutaneous transhepatic portal approach is the most commonly used technique for islet transplantation, largely owing to its safety and minimally invasive characteristic. Bleeding complications after islet transplantation are rare and include portal vein thrombosis and subcapsular liver hematoma. We report a massive hemothorax after portal vein catheterization in a patient with brittle type 1 diabetes undergoing hepatic islet embolization. The patient was under long-term aspirin therapy because of vascular complications and received heparin in low doses to prevent the instant blood-mediated inflammatory reaction and reduce the risk of portal vein thrombosis. The present case illustrates the particular risk of bleeding complications in patients with brittle type 1 diabetes, who represent a frail population. This uncommon adverse event highlights the importance of close monitoring in the first days following islet transplantation

Biliary strictures after liver transplantation: is percutaneous treatment indicated?

Biliary complications are common after orthotopic liver transplantation. Our study's aim is to evaluate the efficacy of percutaneous treatment of biliary strictures after orthotopic liver transplantation (OLT).Sixty-five patients with biliary anastomotic strictures received percutaneous transhepatic balloon cholangioplasty (PTBC). Three dilatations were performed with a 2- to 4-week period between the procedures. Primary and secondary patency were evaluated, with a follow-up between 6 months and 6 years.PTBC successfully treated strictures in 52.3\% (34/65) of cases. The normalization of clinical and biological features was noted at 2.3 months on average. Neither intercurrent episodes of sepsis nor a worsening of liver function were noted during the treatment; a significant complication was recorded in 8 patients. No patient needed surgery for the treatment of complications after PTBC. Factors related to a successful PTBC included older age at transplantation and single-site stricture. There were 7 recurrent strictures after PTBC, all successfully treated by nonsurgical procedures. The number of dilatations performed affected both the likelihood of success and the long-term risk of stricture recurrence. Of the 31 PTBC failures, 19 underwent subsequent surgical revision, 8 were treated endoscopically, and 4 were re-transplanted. Multifocal stenoses, central hepatic duct involvement, and intrahepatic localization resulted associated with treatment failure.PTBC should be considered as a first choice option for treatment of biliary strictures after liver transplantation as well as endoscopic treatment. For solitary extrahepatic strictures that fail PTBC and ERCP, surgical revision provides good results

Combined pancreatic islets-lung transplantation in cystic fibrosis-related diabetes: case reports

We report two cases of percutaneous portal embolization of pancreatic islets performed after double lung transplantation in cystic fibrosis (CF) patients using the pancreas of the same donor. CASE 1: A 19-year-old man with CF had insulin-dependent diabetes, which was poorly controlled despite an external insulin pump (96 IU/d): HbA(1c) = 9.8% and 1 to 3 hypoglycemic events per day. On October 29, 2007, he received a double lung graft because of chronic respiratory failure. For days after lung transplantation, 149,000 cultured IEQ (Islet EQuivalent) were injected by percutaneous intraportal infusion under local anesthesia. Immunosuppression consisted of steroids, cyclosporine, and azathioprine. Two years later, the forced expiratory volume (FEV) was 83%; C peptide level reached 1.4 mug/L, and the diabetes was satisfactorily controlled with an HbA(1c) of 7.5% and a decrease in insulin requirements to 30 U/d in the absence of hypoglycemic events. CASE 2: On July 10, 2006, a 32-year-old man with CF-related diabetes received a double lung graft because of chronic respiratory failure. Under multiple insulin injections, the HbA(1c) was 9.6% with numerous hypoglycemic events. On March 11, 2008, he again received a double lung graft because of persistent humoral rejection. Despite severe bleeding during the postoperative course, 234,000 IEQ were injected via the portal vein one week after lung transplantation. Immunosuppression consisted of steroids, tacrolimus, and mycophenolate mofetil. Eighteen months after the combined graft, the FEV was 52%; the plasma C-peptide reached 0.79 mug/L, the HbA(1c), 6% and the insulin requirements decreased to 55 U/d in the absence of hypoglycemic events. CONCLUSION: Combined lung-islet transplantation for patients with CF-related diabetes improved pulmonary and metabolic function

Studies of Circulating Microparticle Release in Peripheral Blood After Pancreatic Islet Transplantation

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Modeling and simulation of organophosphate-induced neurotoxicity: Prediction and validation by experimental studies

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