Overexpression of thioredoxin in islets transduced by a lentiviral vector prolongs graft survival in autoimmune diabetic NOD mice

<p>Abstract</p> <p>Pancreatic islet transplantation is considered an appropriate treatment to achieve insulin independence in type I diabetic patients. However, islet isolation and transplantation-induced oxidative stress and autoimmune-mediated destruction are still the major obstacles to the long-term survival of graft islets in this potential therapy. To protect islet grafts from inflammatory damage and prolong their survival, we transduced islets with an antioxidative gene <it>thioredoxin (TRX) </it>using a lentiviral vector before transplantation. We hypothesized that the overexpression of TRX in islets would prolong islet graft survival when transplanted into diabetic non-obese diabetic (NOD) mice.</p> <p>Methods</p> <p>Islets were isolated from NOD mice and transduced with lentivirus carrying <it>TRX </it>(Lt-<it>TRX</it>) or enhanced green fluorescence protein (Lt-e<it>GFP</it>), respectively. Transduced islets were transplanted under the left kidney capsule of female diabetic NOD mice, and blood glucose concentration was monitored daily after transplantation. The histology of the islet graft was assessed at the end of the study. The protective effect of TRX on islets was investigated.</p> <p>Results</p> <p>The lentiviral vector effectively transduced islets without altering the glucose-stimulating insulin-secretory function of islets. Overexpression of TRX in islets reduced hydrogen peroxide-induced cytotoxicity <it>in vitro</it>. After transplantation into diabetic NOD mice, euglycemia was maintained for significantly longer in Lt-TRX-transduced islets than in Lt-eGFP-transduced islets; the mean graft survival was 18 vs. 6.5 days (n = 9 and 10, respectively, p < 0.05).</p> <p>Conclusion</p> <p>We successfully transduced the <it>TRX </it>gene into islets and demonstrated that these genetically modified grafts are resistant to inflammatory insult and survived longer in diabetic recipients. Our results further support the concept that the reactive oxygen species (ROS) scavenger and antiapoptotic functions of TRX are critical to islet survival after transplantation.</p

Genetically Engineered Islets and Alternative Sources of Insulin-Producing Cells for Treating Autoimmune Diabetes: Quo Vadis?

Islet transplantation is a promising therapy for patients with type 1 diabetes that can provide moment-to-moment metabolic control of glucose and allow them to achieve insulin independence. However, two major problems need to be overcome: (1) detrimental immune responses, including inflammation induced by the islet isolation/transplantation procedure, recurrence autoimmunity, and allorejection, can cause graft loss and (2) inadequate numbers of organ donors. Several gene therapy approaches and pharmaceutical treatments have been demonstrated to prolong the survival of pancreatic islet grafts in animal models; however, the clinical applications need to be investigated further. In addition, for an alternative source of pancreatic β-cell replacement therapy, the ex vivo generation of insulin-secreting cells from diverse origins of stem/progenitor cells has become an attractive option in regenerative medicine. This paper focuses on the genetic manipulation of islets during transplantation therapy and summarizes current strategies to obtain functional insulin-secreting cells from stem/progenitor cells

Generalized radio resource management for overlapping MBS zones

Multicast and broadcast service (MBS) is a point-to-multipoint service where data packets are transmitted simultaneously from a single source to multiple destinations. In MBS, some base stations (BSs) may form an MBS zone and transmit identical MBS contents simultaneously using the same modulation and coding scheme. Hence, the network has to coordinate the transmission of BSs such that BSs belonging to multiple MBS zones may utilize non-conflict resources to transmit different MBS contents. This paper extends the work in [10] for accommodating MBS zones with different service presence probabilities and various bandwidth requirements. A continuous allocation algorithm and a non-continuous allocation algorithm are presented to allocate resource units for overlapping MBS zones. Simulations were conducted to verify the effectiveness of the proposed algorithms

Factors Predicting Emotional Cue-Responding Behaviors of Nurses in Taiwan: An Observational Study

Objective Responding to emotional cues is an essential element of therapeutic communication. The purpose of this study is to examine nurses' competence of responding to emotional cues (CRE) and related factors while interacting with standardized patients with cancer. Methods This is an exploratory and predictive correlational study. A convenience sample of registered nurses who have passed the probationary period in southern Taiwan was recruited to participate in 15-minute videotaped interviews with standardized patients. The Medical Interview Aural Rating Scale was used to describe standardized patients' emotional cues and to measure nurses' CRE. The State-Trait Anxiety Inventory was used to evaluate nurses' anxiety level before the conversation. We used descriptive statistics to describe the data and stepwise regression to examine the predictors of nurses' CRE. Results A total of 110 nurses participated in the study. Regardless of the emotional cue level, participants predominately responded to cues with inappropriate distancing strategies. Prior formal communication training, practice unit, length of nursing practice, and educational level together explain 36.3% variances of the nurses' CRE. Conclusions This study is the first to explore factors related to Taiwanese nurses' CRE. Compared to nurses in other countries, Taiwanese nurses tended to respond to patients' emotional cues with more inappropriate strategies. We also identified significant predictors of CRE that show the importance of communication training. Future research and education programs are needed to enhance nurses' CRE and to advocate for emotion-focused communication

Alternative Sources of Insulin-Producing Cells for Treating Autoimmune Diabetes: Quo Vadis?

Islet transplantation is a promising therapy for patients with type 1 diabetes that can provide moment-to-moment metabolic control of glucose and allow them to achieve insulin independence. However, two major problems need to be overcome: (1) detrimental immune responses, including inflammation induced by the islet isolation/transplantation procedure, recurrence autoimmunity, and allorejection, can cause graft loss and (2) inadequate numbers of organ donors. Several gene therapy approaches and pharmaceutical treatments have been demonstrated to prolong the survival of pancreatic islet grafts in animal models; however, the clinical applications need to be investigated further. In addition, for an alternative source of pancreatic β-cell replacement therapy, the ex vivo generation of insulin-secreting cells from diverse origins of stem/progenitor cells has become an attractive option in regenerative medicine. This paper focuses on the genetic manipulation of islets during transplantation therapy and summarizes current strategies to obtain functional insulin-secreting cells from stem/progenitor cells

Social skills deficits and their association with Internet addiction and activities in adolescents with attention-deficit/hyperactivity disorder

The aims of this study were to examine the association between social skills deficits and Internet addiction and activities in adolescents with attention-deficit/hyperactivity disorder (ADHD) as well as the moderators for this association. Methods A total of 300 adolescents, aged between 11 and 18 years, who had been diagnosed with ADHD participated in this study. Their Internet addiction levels, social skills deficits, ADHD, parental characteristics, and comorbidities were assessed. The various Internet activities that the participants engaged in were also examined. Results The associations between social skills deficits and Internet addiction and activities and the moderators of these associations were examined using logistic regression analyses. Social skills deficits were significantly associated with an increased risk of Internet addiction after adjustment for the effects of other factors [odds ratio (OR) = 1.049, 95% confidence interval (CI) = 1.030–1.070]. Social skills deficits were also significantly associated with Internet gaming and watching movies. The maternal occupational socioeconomic levels of the participants moderated the association between social skills deficits and Internet addiction. Conclusions Social skills deficits should be considered targets in prevention and intervention programs for treating Internet addiction among adolescents with ADHD

Cdc42 Regulates Extracellular Matrix Remodeling in Three Dimensions*

Extracellular matrix (ECM) actively participates in normal cell regulation and in the process of tumor progression. The Rho GTPase Cdc42 has been shown to regulate cell-ECM interaction in conventional two-dimensional culture conditions by using dominant mutants of Cdc42 in immortalized cell lines that may introduce nonspecific effects. Here, we employ three-dimensional culture systems for conditional gene targeted primary mouse embryonic fibroblasts that better simulate the reciprocal and adaptive interactions between cells and surrounding matrix to define the role of Cdc42 signaling pathways in ECM organization. Cdc42 deficiency leads to a defect in global cell-matrix interactions reflected by a decrease in collagen gel contraction. The defect is associated with an altered cell-matrix interaction that is evident by morphologic changes and reduced focal adhesion complex formation. The matrix defect is also associated with a reduction in synthesis and activation of matrix metalloproteinase 9 (MMP9) and altered fibronectin deposition patterning. A Cdc42 mutant rescue experiment found that downstream of Cdc42, p21-activated kinase (PAK), but not Par6 or WASP, may be involved in regulating collagen gel contraction and fibronectin organization. Thus, in addition to the previously implicated roles in intracellular regulation of actin organization, proliferation, and vesicle trafficking, Cdc42 is essential in ECM remodeling in three dimensions

Carbon Dioxide Angiography in Lower Limbs: A Prospective Comparative Study With Selective Iodinated Contrast Angiography

This was a prospective comparison of the accuracy and image quality of carbon dioxide digital subtraction angiography (CO2 DSA) and iodinated contrast digital subtraction angiography (ICDSA) in evaluating lower extremity arteries and patient tolerance of the procedures. Selective DSA was performed in 14 Taiwanese patients who were diagnosed with peripheral artery occlusive disease (PAOD). Both contrast materials were administered through mechanical injectors. Post-processing of the image used pixel shifting. Images of vessels were divided into 22 anatomic segments and evaluated by two experienced radiologists. A four-point scale was used to classify diseased vessels. Two interpreters rated the CO2 DSA image against the ICDSA image on a three-point scale. Patient tolerance was assessed from verbal descriptions. Cohen's kappa was used to determine interobserver agreement and descriptive statistics were used to summarize patient experience. Interobserver agreement ranged from fair to excellent, with most being good or excellent. Three patients (21.4%) could not tolerate the whole procedure and nine patients (64.3%) reported discomfort during the CO2 DSA procedure. CO2 DSA image quality was better for the thigh than the distal runoff and pelvic regions. Our results showed that selective CO2 DSA cannot replace ICDSA as a routine diagnostic tool for PAOD because it does not give images of comparative quality