Gradient-based parameter optimization method to determine membrane ionic current composition in human induced pluripotent stem cell-derived cardiomyocytes

Premature cardiac myocytes derived from human induced pluripotent stem cells (hiPSC-CMs) show heterogeneous action potentials (APs), probably due to different expression patterns of membrane ionic currents. We developed a method for determining expression patterns of functional channels in terms of whole-cell ionic conductance (Gx) using individual spontaneous AP configurations. It has been suggested that apparently identical AP configurations can be obtained using different sets of ionic currents in mathematical models of cardiac membrane excitation. If so, the inverse problem of Gx estimation might not be solved. We computationally tested the feasibility of the gradient-based optimization method. For a realistic examination, conventional 'cell-specific models' were prepared by superimposing the model output of AP on each experimental AP recorded by conventional manual adjustment of Gxs of the baseline model. Gxs of 4–6 major ionic currents of the 'cell-specific models' were randomized within a range of ± 5–15% and used as an initial parameter set for the gradient-based automatic Gxs recovery by decreasing the mean square error (MSE) between the target and model output. Plotting all data points of the MSE–Gx relationship during optimization revealed progressive convergence of the randomized population of Gxs to the original value of the cell-specific model with decreasing MSE. The absence of any other local minimum in the global search space was confirmed by mapping the MSE by randomizing Gxs over a range of 0.1–10 times the control. No additional local minimum MSE was obvious in the whole parameter space, in addition to the global minimum of MSE at the default model parameter

Postoperative Course of Crohn\u27s Disease -In regard to Recurrence and Residual Disease at Anastomosis -

Twenty-seven patients with Crohn\u27s disease who were operated on at the First Department of Surgery, Nagasaki University School of Medicine and followed-up after surgery were reviewed. Involved portion of intestinal tract were 10 in small bowel only, 14 in both small and large bowels, and 3 in large bowel. Major indication for surgery were obstruction, fistula, peritonitis and intractability of medical therapy. Twenty-two patients underwent radical resection and the other 5 patients had the disease left behind at anastomosis. The recurrence rate was 25.9% (7 out of 22), and early recurrence was found in small bowel diseases with longitudinal ulcerations or multiple aphthoid ulcers. Initial recurrence occured near the suture line, which showed no wide spreading in subsequent periods. Two cases with both small and large bowel disease required reoperation over 5 years after initial surgery because of stenosis. Three out of five cases with residual disease at the intestinal resection margin had a good condition, but the other three cases with skip sigmoid disease were intractable for medical therapy. Most suture line recurrence and residual disease at anastomosis were sufficiently managed by postoperative medication for long periods of time. Long-term follow-up study showed a good quality of life in about 75% of these cases. In conclusion, conservative resection rather than the sacrifice of normal bowel should be recommended for an extended disease of small bowel

DNA Analysis from Biopsied Specimens for Carcinomas of the Esophagus

Surgical outcome for advanced esophageal cancer patients is not satisfactory in spite of improvements of diagnostic tools, operative techniques, postoperative cares and adjuvant chemotherapy. Postoperative prognosis used to be predicted by the grades of histologic disease progression. However, it is limited to accurate prediction of its prognosis. Recent studies have been focused on biologic behavior of malignant cells, in particular, nuclear DNA contents which play an important role in cell proliferation and metabolizm. Clinical use of flow-cytometric measurement of nuclear DNA is now prevalent to assess the grades of malignancy for malignant tumors. In contrast, it is difficult to know nuclear DNA contents preoperatively. The purpose of this study is to clarify whether or not preoperative biologic behaviors is clinically feasible, from biopsied specimens in comparison with that from the surgical specimens

Serum Wisteria Floribunda Agglutinin-Positive Mac-2 Binding Protein Values Predict the Development of Hepatocellular Carcinoma among Patients with Chronic Hepatitis C after Sustained Virological Response

Measurement of Wisteria floribundaagglutinin-positive human Mac-2 binding protein (WFA+-M2BP) in serum was recently shown to be a noninvasive method to assess liver fibrosis. The aim of this study was to evaluate the utility of serum WFA+-M2BP values to predict the development of hepatocellular carcinoma (HCC) in patients who achieved a sustained virological response (SVR) by interferon treatment. For this purpose, we retrospectively analyzed 238 patients with SVR who were treated with interferon in our department. Serum WFA+-M2BP values were measured at pre-treatment (pre-Tx), post-treatment (24 weeks after completion of interferon; post-Tx), the time of HCC diagnosis, and the last clinical visit. Of 238 patients with SVR, HCC developed in 16 (6.8%) patients. The average follow-up period was 9.1 years. The cumulative incidence of HCC was 3.4% at 5 years and 7.5% at 10 years. The median pre-Tx and post-Tx WFA+-M2BP values were 1.69 (range: 0.28 to 12.04 cutoff index (COI)) and 0.80 (range: 0.17 to 5.29 COI), respectively. The WFA+-M2BP values decreased significantly after SVR (P 60 years), sex (male), pre-Tx platelet count ( 2.0 COI) were associated with the development of HCC after SVR. Conclusion: Post-Tx WFA+-M2BP (> 2.0 COI) is associated with the risk for development of HCC among patients with SVR. The WFA+-M2BP values could be a new predictor for HCC after SVR

Sistema Especialista Bayesiano aplicado em Análise de Riscos

TCC (graduação) - Universidade Federal de Santa Catarina. Centro Tecnológico. Curso de Ciências da Computação.Uso do redes bayesianas para o gerenciamento de operações de risco na perfuração de poços de petróle

Double SCN5A mutation underlying asymptomatic Brugada syndrome

Objectives: The purpose of this study was to identify risk markers in patients with Brugada syndrome. Background: Patients with Brugada syndrome who experience syncope or aborted sudden death are at high risk for recurrent lethal arrhythmias. The prognosis and therapeutic approaches in asymptomatic individuals with a Brugada-type ECG (asymptomatic Brugada syndrome) are controversial. Methods: We genetically screened 30 asymptomatic probands (29 men and 1 woman; mean age 47.1 years) exhibiting a spontaneous Brugada-type ECG. Family members of patients with Brugada syndrome were excluded from the study. Results: Twenty-nine of 30 patients (96.7%) remained symptom-free for at least 3 years. One patient (case 1) with a family history of sudden death died suddenly during sleep. Ventricular fibrillation was induced by programmed electrical stimulation in 14 of 18 subjects (78%), but none of these 18 subjects developed spontaneous ventricular arrhythmias. Genetic screening failed to identify SCN5A mutations in most cases but demonstrated a novel double missense mutation (K1527R and A1569P) located on the same allele in another asymptomatic subject (case 2). Heterologously expressed mutant Na channels exhibited a negative shift of steady-state inactivation (9.2 mV) and enhanced slow inactivation, suggesting this individual harbors a subclinical channel dysfunction compatible with symptomatic Brugada syndrome. Conclusions: Asymptomatic individuals with a Brugada-type ECG generally have a better prognosis than their symptomatic counterparts, but a subgroup of these individuals may have a poor prognosis. Severe Na channel dysfunction as a result of SCN5A mutations may not be sufficient to cause symptoms or arrhythmias in patients with Brugada syndrome, suggesting unknown factors or modifier genes influence arrhythmogenesis