Compositional analysis and biological characterization of Cornus officinalis on human 1.1B4 pancreatic ß cells.

Type 1 diabetes (T1D) is an autoimmune disease resulting from the loss of pancreatic ß cells and subsequent insulin production. Novel interventional therapies are urgently needed that can protect existing ß cells from cytokine-induced death and enhance their function before symptomatic onset. Our initial evidence is suggesting that bioactive ingredients within Cornus officinalis (CO) may be able to serve in this function. CO has been extensively used in Traditional Chinese Medicine (TCM) and reported to possess both anti-inflammatory and pro-metabolic effects. We hypothesize that CO treatment may provide a future potential candidate for interventional therapy for early stage T1D prior to significant ß cell loss. Our data demonstrated that CO can inhibit cytokine-mediated ß cell death, increase cell viability and oxidative capacity, and increase expression of NFATC2 (Nuclear Factor of Activated T Cells, Cytoplasmic 2). We have also profiled the bioactive components in CO from multiple sources by HPLC/MS (High Performance Liquid Chromatography/Mass Spectrometry) analysis. Altogether, CO significantly increases the energy metabolism of ß cells while inducing the NFAT pathway to signal for increased proliferation and endocrine function.

Cationic gadolinium chelate for magnetic resonance imaging of cartilaginous defects.

The ability to detect meniscus defects by magnetic resonance arthrography (MRA) can be highly variable. To improve the delineation of fine tears, we synthesized a cationic gadolinium complex, (Gd-DOTA-AM4 )(2+) , that can electrostatically interact with Glycosaminoglycans (GAGs). The complex has a longitudinal relaxivity (r1) of 4.2 mM(-1) s(-1) and is highly stable in serum. Its efficacy in highlighting soft tissue tears was evaluated in comparison to a clinically employed contrast agent (Magnevist) using explants obtained from adult bovine menisci. In all cases, Gd-DOTA-AM4 appeared to improve the ability to detect the soft tissue defect by providing increased signal intensity along the length of the tear. Magnevist shows a strong signal near the liquid-meniscus interface, but much less contrast is observed within the defect at greater depths. This provides initial evidence that cationic contrast agents can be used to improve the diagnostic accuracy of MRA. Copyright © 2016 John Wiley & Sons, Ltd.

Large Hill-Sachs Lesion: a Comparative Study of Patients Treated with Arthroscopic Bankart Repair with or without Remplissage.

BACKGROUND: There is little comparative long-term clinical data comparing Bankart repair alone to the addition of remplissage. QUESTIONS/PURPOSES: Our purpose was to compare results of patients with significant humeral head lesions and who underwent either isolated arthroscopic Bankart repair or remplissage. METHODS: This is a retrospective cohort study of 14 isolated arthroscopic Bankart and 10 remplissage repairs all with large engaging Hill-Sachs (HS) lesions. Average follow-up was 40.72 months (26.3-51.1) in the Bankart group and 31.55 months (24.1-39.9) in the remplissage group. Surgical failure was defined as a dislocation or subluxation. Groups were matched on handedness, age within 3 years, and HS lesion size. Glenoid bone loss and HS size were measured on MRI. Additionally, WOSI and DASH scores were obtained. RESULTS: The average age at surgery was 26.0 years (17.8-41.1) of the isolated Bankart patient and 24.4 years (16.4-38.3) in the remplissage group. The average HS lesion volume was 310.22 mm(3) in the Bankart group and 283.79 mm(3) in the remplissage group. The failure rate for the Bankart group was 8 out of 14 patients (57.14%). For the remplissage group, the failure rate was 2 out of 10 patients (20.0%). Average WOSI scores were 73.72 in the Bankart group and 79.54 in the remplissage group. For DASH scores, the average Disability/Symptoms Scores were 16.23 for the Bankart group and 12.05 for the remplissage patients. CONCLUSIONS: In comparison to isolated Bankart repair, remplissage was a superior option for recurrent instability patients with large Hill-Sachs lesions as seen by diminished failure rates and improved outcome scores.

Genetically reprogrammed, liver-derived insulin-producing cells are glucose-responsive, but susceptible to autoimmune destruction in settings of murine model of type 1 diabetes.

Many previous studies demonstrate that hepatocytes can be reprogrammed into insulin-producing cells (IPCs) utilizing viral vector-mediated delivery of pancreatic transcription factors (PTFs). However, whether these liver-derived IPCs are susceptible to autoimmune attack in animal models of type 1 diabetes remains unclear, in part due to the immunogenicity of the viral vectors used to introduce PTF genes. Adeno-associated virus serotype 2 vector-expressing Pdx1-VP16 (Pdx1) and Ngn3 were prepared and injected into the portal vein of streptozotocin (Stz)/diabetic NOD/SCID mice. The presence of glucose-responsive liver-IPCs and their susceptibility to anti-beta cell autoimmunity were assessed by blood glucose levels, insulin content, IPC cell distribution, and intraperitoneal glucose tolerance test following subtotal pancreatectomy (Px) and passive transfer of diabetogenic splenocytes isolated from diabetic female NOD mice. A combination of two PTF genes (Pdx1/Ngn3) effectively reprogrammed liver cells into glucose-responsive IPCs. These IPCs corrected hyperglycemia in Stz/diabetic NOD/SCID mice and maintained normoglycemia following subtotal Px, indicating that liver-derived IPCs could maintain glucose homeostasis. Importantly, we also demonstrated that the glucose-responsive liver-derived IPCs were susceptible to autoimmune destruction by diabetogenic splenocytes, as indicated by progressive elevation in blood glucose levels as well as mixed T-, and B-lymphocytic infiltrates surrounding liver-IPCs 2~3 weeks following transferring of diabetogenic splenocytes into NOD/SCID mice, and confirmed by immunohistochemical studies. In conclusion, genetically reprogrammed liver-IPCs, like pancreatic islet beta-cells, are susceptible to autoimmune attack, suggesting that for cell-replacement therapy of treating type 1 diabetes, beta-cell surrogates may require concomitant immunotherapy to avoid autoimmune destruction.

Iron chelator-based amplification strategy for improved targeting of transferrin receptor with SPIO.

A major obstacle faced by magnetic resonance (MR) as a platform for molecular imaging is the low sensitivity for detecting receptor-targeted MR contrast agents. The versatility of MR imaging, however, could be improved if there existed a strategy to upregulate the receptor of interest prior to administration of the targeted contrast agent. Here, we describe an amplification strategy that uses iron chelators to upregulate the transferrin receptor (TfR) prior to administration of TfR-targeted superparamagnetic iron oxide nanoparticles (SPIO). When K562 human leukemic cells were incubated with the iron chelator desferrioxamine (DFO), followed by administration of anti-TfR SPIO, there was a 57% improvement in the T2 relaxation time compared with cells not treated with DFO and an 82% improvement compared with cells not targeted with SPIO. The effects of incubation time, temperature, SPIO concentration and targeting molecule on contrast enhancement were also examined. The results reported here suggest that iron chelators have the potential to significantly improve the sensitivity of TfR-mediated cancer detection, providing a new paradigm for MR signal amplification.