Safety Constraints in an Artificial Pancreatic β Cell: An Implementation of Model Predictive Control with Insulin on Board

Background

Type 1 diabetes mellitus (T1DM) is characterized by the destruction of pancreatic β cells, resulting in the inability to produce sufficient insulin to maintain normoglycemia. As a result, people with T1DM depend on exogenous insulin that is given either by multiple daily injections or by an insulin pump to control their blood glucose. A challenging task is to design the next step in T1DM therapy: a fully automated insulin delivery system consisting of an artificial pancreatic β cell that shall provide both safe and effective therapy. The core of such a system is a control algorithm that calculates the insulin dose based on automated glucose measurements.

Methods

A model predictive control (MPC) algorithm was designed to control glycemia by controlling exogenous insulin delivery. The MPC algorithm contained a dynamic safety constraint, insulin on board (IOB), which incorporated the clinical values of correction factor and insulin-to-carbohydrate ratio along with estimated insulin action decay curves as part of the optimal control solution.

Results

The results emphasized the ability of the IOB constraint to significantly improve the glucose/insulin control trajectories in the presence of aggressive control actions. The simulation results indicated that 50% of the simulations conducted without the IOB constraint resulted in hypoglycemic events, compared to 10% of the simulations that included the IOB constraint.

Conclusions

Achieving both efficacy and safety in an artificial pancreatic β cell calls for an IOB safety constraint that is able to override aggressive control moves (large insulin doses), thereby minimizing the risk of hypoglycemia.     

Differences in Affinity of Variant β Chains for a Chains: A Possible Explanation for the Variation in the Percentages of β Chain Variants in Heterozygotes

The a and β chains of the hemoglobins A, S, Leslie and N-Baltimore have been isolated as PMB derivates by CM-cellulose and DEAE-cellulose chromatography. The relative affinities of the β^A, β^s, β^Leslie and β^N-Baltimore chains for α chains were measured through quantitation by chromatography of Che hemoglobins A and Leslie, A and S, and A and N-Baltimore that were formed when variable amounts of α chains were added to a mixture of equal amounts of the appropriate β chains. The data indicate a greatly decreased affinity of β^Leslie chains for a chains; a similar preference of a chains for β^A chains was observed for mixtures Involving α, β^A, and β^s chains, but the affinity of β^s chains for a chains was higher than that of β^Leslie chains. The _βN-Baltimore chains assembled with a chains at a similar rate as β^A chains. The data as Interpreted Indicate that the affinity of certain β chains for a chains can be a major post-translatlonal control mechanism which regulates the level of a β chain variant in heterozygotes.     

Pancreatic metastasis of leiomyosarcoma in the right thigh： A case report

Pancreatic tumors are primary in most of the cases.Pancreatic metastases associated with other primary malignancies,especially pancreatic metastasis of leiomyosarcoma,are uncommon.A 66-year-old woman underwent surgical resection of malignant mesenchymoma(70% osteosarcoma and 30% leiomyosarcoma)in the right thigh.In the postoperative period,a pancreatic mass was identified radiologically by abdominal computed tomography.Pylorus-preserving pancreaticoduodenectomy was performed.The surgical specimen revealed leiomyosarcoma metastasized to the pancreas.A metastatic nodule on the remnant pancreatic tail was discovered 9 mo after the first pancreatic resection,and distal pancreatectomy was performed.Cases of pancreatic metastasis from leiomyosarcoma are extremely rare,especially when the tumor was resectable.We report here a unique case of pancreatic metastasis from a leiomyosarcoma in the right thigh that had been treated surgically.     

A Phase I Clinical Trial of the Treatment of Crohn’s Fistula by Adipose Mesenchymal Stem Cell Transplantation

PURPOSE The effective management of fistulas in patients with Crohn’s disease presents an extremely challenging problem. Mesenchymal adult stem cells extracted from certain tissues, such as adipose tissue, can differentiate into various cell types. Therefore, we have tried to use such cells to stimulate healing of Crohn’s fistulas.METHODS We designed a prospective Phase I clinical trial, involving five patients with Crohn’s disease, to test the feasibility and safety of autologous stem cells transplantation in the treatment of fistulas. We also studied the expression of various cell markers and the growth rates of the lipoaspirate-derived cells that were used for transplantation.RESULTS One patient was excluded because of bacterial contamination of cultured cells. We inoculated nine fistulas in four patients with autologous adipose tissue-derived stem cells at Passage 3 or earlier. Eight inoculated fistulas were followed weekly for at least eight weeks. In six fistulas, the external opening was covered with epithelium at the end of Week 8, and, thus, these fistulas were considered healed (75 percent). In the other two fistulas, there was only incomplete closure of the external opening, with a decrease in output flow (not healed; 25 percent). No adverse effects were observed in any patient at the end of the follow-up period (minimum follow-up,12 months; maximum follow-up, 30 months; follow-up average, 22 months).CONCLUSIONS To our knowledge, this is the first report of a clinical trial of cell therapy using autologous stem cells obtained from a lipoaspirate. Our results indicate that our protocol is feasible and safe for the treatment of fistulas in Crohn’s disease. The number of patients included and the uncontrolled nature of Phase I clinical trials do not allow demonstration of the effectiveness of the treatment. However, the results of the present study encourage to perform further studies in Phase II.Presented in part at IFATS-2004, Pittsburgh, Pennsylvania, October 3 to 5, 2004.     

Swallowing Apraxia: A Disorder of the Praxis System?

The purpose of this review is to evaluate the disorder of swallowing apraxia and determine how it fits into the praxis system. Swallowing apraxia, a proposed disorder of lingual, labial, and mandibular coordination, has been observed before bolus transfer during the oral stage of swallowing. Although frequently discussed anecdotally in dysphagia literature, the possible mechanisms and neural networks of swallowing apraxia have not been elucidated. Similarities and differences of swallowing apraxia with buccofacial, speech, and limb apraxias are evident. Critical review of the literature has identified possible similarities as greater occurrence upon command, transitive nature of the action, and evidence of spatial errors. Conversely, differences such as hemispheric lateralization and multiple gesture assessment may exist between swallowing apraxia and more traditional forms of apraxia. Until discrete error patterns of swallowing apraxia are identified and precisely measured, the nature of this disorder and its relationship with the praxis system will continue to remain elusive.     

Detection of Hb-Papio B,a Silent Mutation of the Baboon β Chain,by High Performance Liquid Chromatography. Improved Procedures for the Separation of Globin Chains by Hplc

A silent mutant of the β chain of the baboon (Papio cynocephalus) was detected by high performance liquid chromatography of the globin chains. The substitution is β13 Ala → Thr. The inclusion of nonylamine in the developers for HPLC results not only in an improved separation of baboon globin chains but also in the complete resolution of the human G_γ, A_γ, and A_γT chains and some common human variant β chains.     

Super-Resolution Microscopy: A Virus’ Eye View of the Cell

It is difficult to observe the molecular choreography between viruses and host cell components, as they exist on a spatial scale beyond the reach of conventional microscopy. However, novel super-resolution microscopy techniques have cast aside technical limitations to reveal a nanoscale view of virus replication and cell biology. This article provides an introduction to super-resolution imaging; in particular, localisation microscopy, and explores the application of such technologies to the study of viruses and tetraspanins, the topic of this special issue.     

Harnessing the Immunomodulatory and Tissue Repair Properties of Mesenchymal Stem Cells to Restore β Cell Function

Islet cell transplantation has therapeutic potential to cure type 1 diabetes (T1D), which is characterized by autoimmune-mediated destruction of insulin-producing β cells. However, current success rates are limited by long-term decline in islet graft function resulting partially from poor revascularization and immune destruction. Mesenchymal stem cells (MSCs) have the potential to enhance islet transplantation and prevent disease progression by a multifaceted approach. MSCs have been shown to be effective at inhibiting inflammatory-mediated immune responses and at promoting tissue regeneration. The immunomodulatory and tissue repairing properties of MSCs may benefit β cell regeneration in the context of T1D. This review will elucidate how MSCs can minimize β cell damage by providing survival signals and simultaneously modulate the immune response by inhibiting activation, and proliferation of several immune cell types. In addition, MSCs can enhance islet graft revascularization, maintaining long-term β cell viability and function.     

Effect of a group of genetic markers around the 5′ regulatory regions of the β globin gene cluster linked to high HbF on the clinical severity of β thalassemia

The clinical and hematological course of β thalassemia intermedia is influenced by a number of genetic factors which play a role in increasing fetal haemoglobin levels. Several polymorphisms located in the promoters of β and γ globin gene are involved in influencing the disease severity. Our objective was to study the effect of cis-DNA haplotypes, motifs, or polymorphisms (Pre G γ globin gene haplotypes, Aγ–δ intergenic region haplotypes XmnI and (AT)_x(T)_y polymorphisms, β-LCR HS2 and HS3 site motifs) that may contribute to higher HbF levels and a milder clinical course. We found that a combination of T haplotype of the Aγ–δ intergenic region, TAG Pre-Gγ haplotype, presence of the XmnI polymorphism along with the (AT)₉(T)₅ motif constitutes a topography that co-relates with raised HbF levels which may contribute in ameliorating the disease severity.     

Are the Results of a Regional ST-Elevation Myocardial Infarction System Reproducible?

Primary percutaneous coronary intervention (PCI) is the preferred reperfusion method in patients with ST-elevation myocardial infarction (STEMI) if it can be performed in a timely manner in high-volume centers. Regional STEMI networks improve timely access to PCI but are frequently criticized for being single center. To determine if results of regional STEMI systems could be replicated and achieve similar outcomes in 2 separate geographic regions, we examined the prospective databases of 2 large regional STEMI networks that use identical standardized protocols and integrated transfer systems. The Minneapolis Heart Institute (MHI) database included 2,266 patients with STEMI from 31 hospitals (498 at the PCI hospital, 1,033 transferred from 11 hospitals <60 miles away, and 735 transferred from 19 hospitals 60 to 210 miles away). The Iowa Heart Center (IHC) database included 1,206 patients with STEMI from 24 hospitals (710 at the PCI hospital, 266 transferred from 10 hospitals <60 miles away, and 230 transferred from 13 hospitals 60 to 120 miles away). Median total door-to-balloon times for the PCI hospital, zone 1, and zone 2 patients were 64, 95, and 123 minutes for the MHI and 59, 102, and 136 for the IHC (p <0.05 for each comparison between MHI and IHC). Overall in-hospital, 30-day, and 1-year mortalities was 4.8%, 5.4%, and 8.0% respectively (p = NS for each comparison between MHI and IHC). In conclusion, the use of identical protocols in 2 large regional STEMI systems in geographically separate locations produced nearly identical outcomes, adding to evidence that regional STEMI centers expand timely access to PCI.     

Do Genetic Variants of the Renin-Angiotensin System Predict Blood Pressure Response to Renin-Angiotensin System–Blocking Drugs? A Systematic Review of Pharmacogenomics in the Renin-Angiotensin System

The concept of “pharmacogenomics” or “pharmacogenetics” promises to offer the ultimate in personalized medicine, and the renin-angiotensin system (RAS) is one of the most plausible candidates for the application of this approach in the area of hypertension. For the past two decades, genetic variants of the RAS have been tested for association with blood pressure response, but the results have been inconsistent. The problems have been attributed to many issues, but the most fundamental concern is thought to be the statistical power of the studies. Therefore, we have tried to put together a new systematic review using a database search including only recent reports with adequate numbers of subjects, and 11 reports were identified. From the results, we were able to draw conclusions with nearly consistent findings that the conventional genetic variants of the system (i.e., the ACE I/D, AGT M235T, AT1 A1166C, and AT2 variant) are not associated with antihypertensive effects by RAS blockade, at least by one individual SNP. By contrast, significant associations have been reported (by one report each) for AGT rs7079, AT1 haplotype, REN, and ACE2. For these variants, further evaluations and confirmation are anticipated.     

Is a Preoperative Assessment of the Early Recurrence of Pancreatic Cancer Possible after Complete Surgical Resection?

Background/Aims

The prognosis of pancreatic adenocarcinoma (PAC) is poor. The serum carbohydrate antigen 19-9 (CA 19-9) level has been identified as a prognostic indicator of recurrence and reduced overall survival. The aim of this study was to identify preoperative prognostic factors and to create a prognostic model able to assess the early recurrence risk for patients with resectable PAC.

Methods

A series of 177 patients with PAC treated surgically at the St. Andrea Hospital of Rome between January 2003 and December 2011 were reviewed retrospectively. Univariate and multivariate analyses were utilized to identify preoperative prognostic indicators.

Results

A preoperative CA 19-9 level >228 U/mL, tumor size >3.1 cm, and the presence of pathological preoperative lymph nodes statistically correlated with early recurrence. Together, these three factors predicted the possibility of an early recurrence with 90.4% accuracy. The combination of these three preoperative conditions was identified as an independent parameter for early recurrence based on multivariate analysis (p=0.0314; hazard ratio, 3.9811; 95% confidence interval, 1.1745 to 15.3245).

Conclusions

PAC patient candidates for surgical resection should undergo an assessment of early recurrence risk to avoid unnecessary and ineffective resection and to identify patients for whom palliative or alternative treatment may be the treatment of choice.