Aravind Arepally

Magnetic resonance–guided, real-time targeted delivery and imaging of magnetocapsules immunoprotecting pancreatic islet cells

In type I diabetes mellitus, islet transplantation provides a moment-to-moment fine regulation of insulin. Success rates vary widely, however, necessitating suitable methods to monitor islet delivery, engraftment and survival. Here magnetic resonance–trackable magnetocapsules have been used simultaneously to immunoprotect pancreatic β-cells and to monitor, non-invasively in real-time, hepatic delivery and engraftment by magnetic resonance imaging (MRI). Magnetocapsules were detected as single capsules with an altered magnetic resonance appearance on capsule rupture. Magnetocapsules were functional in vivo because mouse β-cells restored normal glycemia in streptozotocin-induced diabetic mice and human islets induced sustained C-peptide levels in swine. In this large-animal model, magnetocapsules could be precisely targeted for infusion by using magnetic resonance fluoroscopy, whereas MRI facilitated monitoring of liver engraftment over time. These findings are directly applicable to ongoing improvements in islet cell transplantation for human diabetes, particularly because our magnetocapsules comprise clinically applicable materials.

Pelvic Congestion Syndrome (Pelvic Venous Incompetence): Impact of Ovarian and Internal Iliac Vein Embolotherapy on Menstrual Cycle and Chronic Pelvic Pain

PURPOSE The purpose of this study was to analyze the impact of transcatheter embolotherapy on pain perception and menstrual cycle in women with chronic pelvic pain caused by the presence of ovarian and pelvic varices (ie, women with pelvic congestion syndrome or pelvic venous incompetence). MATERIALS AND METHODS From July 1998 to August 2000, 56 patients (mean age, 32.3 y) were treated for chronic pelvic pain. Diagnostic venography of the ovarian veins was followed by transcatheter embolotherapy with a sclerosing agent and coils. A second session was completed to embolize the internal iliac veins in 43 of 56 patients. Visual analog scales (VAS) used to measure pain were administered before embolization and at 3-, 6-, and 12-month follow-up. Questionnaires regarding menstrual history were used as part of the postprocedural analysis. RESULTS Percutaneous transcatheter embolotherapy of ovarian and pelvic varices was technically successful in 56 of 56 patients (100%); three patients developed recurrent varices, two of whom were treated with repeat transcatheter embolotherapy. Two patients, early in the experience, had complications in which coils placed in the internal iliac veins embolized to the pulmonary circulation; the coils were snared without clinical sequelae. On the VAS, the mean baseline pain level was 7.8 (range, 3.2-9.8; n = 56); at 3-month follow-up, it was 4.2 (range, 0.0-7.2; n = 56); at 6 months, 3.8 (range, 0.0-6.7; n = 41); and at 12 months, 2.7 (range, 0.0-6.9; n = 32). Differences were significant (P <.001) between baseline pain levels and those at all follow-up intervals (ie, 3, 6, and 12 months). The mean decrease in VAS was 5.1 (65% decrease). The clinical follow-up in this series ranged between 6 and 38 months; the mean was 22.1 months. Regarding the impact of embolization on menstruation, all 24 patients responding to questionnaires indicated no change in menstrual cycle. CONCLUSION For patients with ovarian/internal iliac varices, transcatheter embolotherapy provides a nonsurgical treatment option. There is a significant decrease in pain based on VAS without any notable impact on menstrual cycle.

Trimodal Gadolinium-Gold Microcapsules Containing Pancreatic Islet Cells Restore Normoglycemia in Diabetic Mice and Can Be Tracked by Using US, CT, and Positive-Contrast MR Imaging

PURPOSE To develop microcapsules that immunoprotect pancreatic islet cells for treatment of type I diabetes and enable multimodal cellular imaging of transplanted islet cells. MATERIALS AND METHODS All animal experiments were approved by the institutional animal care and use committee. Gold nanoparticles functionalized with DTDTPA (dithiolated diethylenetriaminepentaacetic acid):gadolinium chelates (GG) were coencapsulated with pancreatic islet cells by using protamine sulfate as a clinical-grade alginate cross linker. Conventional poly-l-lysine-cross-linked microcapsules and unencapsulated islets were included as controls. The viability and glucose responsiveness of islet cells were assessed in vitro, and in vivo insulin (C-peptide) secretion was monitored for 6 weeks in (streptozotocin-induced) diabetic mice with (n = 7) or without (n = 8) intraabdominally engrafted islet cells. Five nondiabetic mice were included as controls. Differences between samples were calculated by using a nonparametric Wilcoxon Mann-Whitney method. To adjust for multiple comparisons, a significance level of P < .01 was chosen. Generalized estimating equations were used to model cell function over time. Three mice with engrafted capsules were imaged in vivo with high-field-strength (9.4-T) magnetic resonance (MR) imaging, micro-computed tomography (CT), and 40-MHz ultrasonography (US). RESULTS Encapsulated human pancreatic islets were functional in vitro for at least 2 weeks after encapsulation. Blood glucose levels in the diabetic mice transplanted with GG-labeled encapsulated mouse βTC6 insulinoma cells returned to normal within 1 week after transplantation, and normoglycemia was sustained for at least 6 weeks without the use of immunosuppressive drugs. GG microcapsules could be readily visualized with positive-contrast high-field-strength MR imaging, micro-CT, and US both in vitro and in vivo. CONCLUSION Cell encapsulation with GG provides a means of trimodal noninvasive tracking of engrafted cells.

Transhepatic Catheter-directed Thrombectomy and Thrombolysis of Acute Superior Mesenteric Venous Thrombosis

PURPOSE To evaluate clinical outcomes after percutaneous treatment of superior mesenteric vein (SMV) thrombosis. MATERIALS AND METHODS A retrospective chart review was conducted of all patients with SMV thrombosis treated with percutaneous catheter-directed thrombectomy/thrombolysis. The demographics of the study population, potential causative factors contributing to SMV thrombosis, and morbidity and mortality associated with therapy were assessed. RESULTS Eleven patients (mean age, 44.3 years +/- 12.8) with SMV thrombosis were treated with percutaneous transhepatic catheter-directed thrombectomy/thrombolysis. Potential causative factors included recent major abdominal surgery, thrombophilic conditions, pancreatitis, and repetitive abdominal trauma. The mean duration between the onset of symptoms and percutaneous treatment was 8.6 days +/- 6.5. Computed tomography confirmed the clinical diagnosis in nine patients (81.8%). One patient (9.1%) had a bleeding complication, which was treated by chest tube drainage without long-term sequelae. One patient (9.1%) with refractory SMV thrombosis died of sepsis and multiple organ failure. No recurrent episode of SMV thrombosis or mortality was documented during a mean follow-up of 42 months +/- 22.5. CONCLUSIONS Percutaneous transhepatic catheter-directed thrombectomy/thrombolysis for SMV thrombosis is associated with a rapid improvement in symptoms and low incidences of long-term morbidity and mortality. Percutaneous thrombectomy and thrombolysis should be considered in all patients with acute SMV thrombosis without evidence of bowel necrosis.

Fluorocapsules for improved function, immunoprotection, and visualization of cellular therapeutics with MR, US, and CT imaging

PURPOSE To develop novel immunoprotective alginate microcapsule formulations containing perfluorocarbons (PFCs) that may increase cell function, provide immunoprotection for xenografted cells, and simultaneously enable multimodality imaging. MATERIALS AND METHODS All animal experiments were approved by an Institutional Animal Care and Use Committee. Cadaveric human islet cells were encapsulated with alginate, poly-l-lysine, and perfluorooctyl bromide (PFOB) or perfluoropolyether (PFPE). In vitro viability and the glucose-stimulation index for insulin were determined over the course of 2 weeks and analyzed by using a cross-sectional time series regression model. The sensitivity of multimodality (computed tomography [CT], ultrasonography [US], and fluorine 19 [(19)F] magnetic resonance [MR] imaging) detection was determined for fluorocapsules embedded in gel phantoms. C57BL/6 mice intraperitoneally receiving 6000 PFOB-labeled (n = 6) or 6000 PFPE-labeled (n = 6) islet-containing fluorocapsules and control mice intraperitoneally receiving 6000 PFOB-labeled (n = 6) or 6000 PFPE-labeled (n = 6) fluorocapsules without islets were monitored for human C-peptide (insulin) secretion during a period of 55 days. Mice underwent (19)F MR imaging at 9.4 T and micro-CT. Swine (n = 2) receiving 9000 PFOB capsules through renal artery catheterization were imaged with a clinical multidetector CT scanner. Signal intensity was evaluated by using a paired t test. RESULTS Compared with nonfluorinated alginate microcapsules, PFOB fluorocapsules increased insulin secretion of encapsulated human islets, with values up to 18.5% (3.78 vs 3.19) at 8-mmol/L glucose concentration after 7 days in culture (P < .001). After placement of the immunoprotected encapsulated cells into mice, a sustained insulin release was achieved with human C-peptide levels of 19.1 pmol/L ± 0.9 (standard deviation) and 33.0 pmol/L ± 1.0 for PFPE and PFOB capsules, respectively. Fluorocapsules were readily visualized with (19)F MR imaging, US imaging, and CT with research- and clinical-grade imagers for all modalities. CONCLUSION Fluorocapsules enhance glucose responsiveness and insulin secretion in vitro, enable long-term insulin secretion by xenografted islet cells in vivo, and represent a novel contrast agent platform for multimodality imaging.

Multifunctional capsule-in-capsules for immunoprotection and trimodal imaging.

Type I diabetes mellitus (T1DM) is a T-cell-mediated autoimmune disease that results in destruction of insulin-producing β cells and subsequent hyperglycemia.[1,2] The current way of treating T1DM is insulin replacement therapy through repetitive injections of recombinant insulin. In more serious cases, a cadaveric pancreas[3] or purified pancreatic islets[4,5] can be transplanted to restore proper glucose regulation. However, the risks of surgery and the accompanying life-long immunosuppression outweigh the disadvantages of continued administration of insulin. The immunoisolation of islets by alginate microencapsulation is an emerging and promising solution to circumvent immune rejection and so overcome this limitation.[6] While the semipermeable alginate membrane blocks penetration of immune cells and antibodies, it allows the unhindered passage of nutrients, metabolites, and insulin that are produced by encapsulated islet cells.[7] Intraperitoneal administration of microencapsulated islets in monkeys and humans has showed considerable promise for the treatment of T1DM.[8,9]

Treatment of Splenic Artery Aneurysm with Use of a Stent-Graft

The authors present a case of a 63-year-old woman with portal hypertension discovered incidentally to have a 2.5-cm splenic artery aneurysm. Mainly because of concern about rupture, the aneurysm was successfully excluded with use of a Wallgraft. This article will discuss the surgical and endovascular management of patients with splenic artery aneurysms.

Use of perfluorocarbon nanoparticles for non-invasive multimodal cell tracking of human pancreatic islets

In vivo imaging of engraftment and immunorejection of transplanted islets is critical for further clinical development, with (1)H MR imaging of superparamagnetic iron oxide-labeled cells being the current premier modality. Using perfluorocarbon nanoparticles, we present here a strategy for non-invasive imaging of cells using other modalities. To this end, human cadaveric islets were labeled with rhodamine-perfluorooctylbromide (PFOB) nanoparticles, rhodamine-perfluoropolyether (PFPE) nanoparticles or Feridex as control and tested in vitro for cell viability and c-peptide secretion for 1 week. (19)F MRI, computed tomography (CT) and ultrasound (US) imaging was performed on labeled cell phantoms and on cells following transplantation beneath the kidney capsule of mice and rabbits. PFOB and PFPE-labeling did not reduce human islet viability or glucose responsiveness as compared with unlabeled cells or SPIO-labeled cells. PFOB- and PFPE-labeled islets were effectively fluorinated for visualization by (19)F MRI. PFOB-labeled islets were acoustically reflective for detection by US imaging and became sufficiently brominated to become radiopaque allowing visualization with CT. Thus, perfluorocarbon nanoparticles are multimodal cellular contrast agents that may find applications in real-time targeted delivery and imaging of transplanted human islets or other cells in a clinically applicable manner using MRI, US or CT imaging.

Magnetic resonance image-guided trans-septal puncture in a swine heart

To test the feasibility of performing magnetic resonance (MR)‐guided trans‐septal punctures in the swine heart.

A Randomized Controlled Trial of β-Blockers Versus Endoscopic Band Ligation for Primary Prophylaxis: A Large Sample Size is Required to Show a Difference in Bleeding Rates

Primary prophylaxis with nonselective β-blockers in high-risk subjects has been shown to be effective in reducing both esophageal variceal bleeding and mortality. Recently it has been suggested that band ligation may be a better option for primary prophylaxis. We compared nonselective β-blockers with band ligation in patients with large varices (F2, F3) and elevated hepatic venous wedge pressure gradient (HVWPG, ≥12 mm Hg). All patients were prospectively followed for variceal bleeding, mortality, and treatment-related complications. Based on previous published studies, we estimated that 90 patients in each arm would be required to show a difference in bleeding rate. The study was prematurely terminated when we realized that our estimated sample size was inadequate to show a difference based on the observed bleeding rate. At the time of termination, 31 patients (Child A, 11; B, 14; C, 6), with a mean HVWPG of 19 ± 9.1 mm Hg, were randomized to either band ligation (group A; n = 16) or β-blockers (group B; n = 15). Baseline demographics of both groups were similar and the mean follow-up period was 27.4 ± 12.9 months. During the follow-up, two patients in group A and one patient in group B had bleeding. Nine patients (29%; group A, six; group B, three; P = ns) died due to non-bleeding-related causes and five (16%) patients (group A, three; group B, two) underwent liver transplantation. Treatment-related complication were minimal in both groups. Despite the selection of high-risk patients, the observed bleeding rate was much lower than anticipated. Based on our observed bleeding rates, 424 patients would be required in each arm to show a difference between band ligation and β-blocker therapy.