Optimisation of Negative Fixed Charge Based Edge Termination for Vertical GaN Schottky Devices.

This study focuses on the impact of negative fixed charge, achieved through fluorine (F) implantation, on breakdown voltage (BV) enhancement in vertical GaN Schottky diodes. Several device and implant-related parameters are examined using Synopsys Sentaurus TCAD simulations in order to determine the optimum fixed negative charge concentration required to achieve the highest BV. The simulated structure consisted of a Schottky diode with a box consisting of negative fixed charges to achieve the edge termination of the Schottky device. An empirical equation is proposed to determine the optimum fixed charge concentration for the highest BV based on depth. The simulation also considered implantation profiles derived from SIMS data from an actual device implanted with multi-energy and multi-dose F. It is demonstrated that the BV has a similar dependence on the key parameters like in the box profile. In summary, this work provides valuable insights into optimizing edge termination techniques using negative fixed charge for improved BV in vertical GaN power devices.

Novel enantiopure cyclopentadienyl Ti(IV) oximato compounds as potential anticancer agents.

The synthesis and characterization of new enantiopure cyclopentadienyl titanium oximato compounds (S,R)-[(η(5)-C5H5)Ti{к(2)NO,(R)NH·HCl}Cl2] (R=Ph (phenyl) 1a·HCl, Bn (benzyl) 1b·HCl, 2-pic (2-picolyl) 1c·HCl), (S,R)-[(η(5)-C5H5)TiCl2{к(2)NO,(Ph)NH}] (1a) and (S,R)-[(η(5)-C5H5)2TiCl{к(2)NO,(R)NH}] (R=Ph 2a, Bn 2b, 2-pic 2c), along with studies on their behavior in D2O at different pD values are reported. The structure of previously described ammonium-oxime (2S,5R)-{NOH,(Bn)NH·HCl} (b·HCl) and novel titanium derivative 1a have been determined by single crystal X-ray crystallography. The effect of the compounds on cytotoxicity, cell adhesion and migration of the androgen-independent prostate cancer PC-3 cells has been assessed. Compounds 2b and 2c are more cytotoxic than additive doses of titanocene dichloride and free oxime proligand, probing the synergistic effect of these novel compounds. The cytotoxicity of 2b and 2c has been further evaluated against human renal Caki-1, colon DLD-1 and triple negative breast MDA-MB-231 cancer cell lines. The activity found for 2c on PC-3 and Caki-1 is higher than that of highly active Titanocene Y (bis-[(p-methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride), while showing selectivity against renal cancer when compared to a non-tumorigenic human renal (HEK-293T) cell line. Compounds 2b and especially 2c are apoptotic in Caki-1 cancer cell lines. Cell adhesion and wound-healing assays confirmed that derivatives 1c·HCl, 2b and 2c affect the adhesion and migration patterns of the PC-3 cell line. Interactions of the novel compounds with plasmid (pBR322) DNA have also been studied, showing that the oximato Ti(IV) derivatives have a weak or no interaction with DNA at physiological pH.

Hydrogen bonding and anticancer properties of water-soluble chiral p-cymene Ru(II) compounds with amino-oxime ligands.

The investigation of the hydrogen-bonding effect on the aggregation tendency of ruthenium compounds [(η6-p-cymene)Ru(κNHR,κNOH)Cl]Cl (R = Ph (1a), Bn (1b)) and [(η6-p-cymene)Ru(κ2NH(2-pic),κNOH)][PF6]2 (1c), [(η6-p-cymene)Ru(κNHBn,κNO)Cl] (2b) and [(η6-p-cymene)Ru(κNBn,κ2NO)] (3b), has been performed by means of concentration dependence 1H NMR chemical shifts and DOSY experiments. The synthesis and full characterization of new compounds 1c, [(η6-p-cymene)Ru(κNPh,κ2NO)] (3a) and 3b are also reported. The effect of the water soluble ruthenium complexes 1a-1c on cytotoxicity, cell adhesion and cell migration of the androgen-independent prostate cancer PC3 cells have been assessed by MTT, adhesion to type-I-collagen and recovery of monolayer wounds assays, respectively. Interactions of 1a-1c with DNA and human serum albumin have also been studied. Altogether, the properties reported herein suggest that ruthenium compounds 1a-1c have considerable potential as anticancer agents against advanced prostate cancer.

Searching for the second best graft for coronary artery bypass surgery: a network meta-analysis of randomized controlled trials†.

OBJECTIVES: There is a lack of unequivocal evidence basis for selecting the best second conduit in coronary artery bypass grafting (CABG). We thus aimed to perform head-to-head relative effect estimate on angiographic outcomes for second conduits, including the right internal mammary artery (RIMA), radial artery (RA), right gastroepiploic artery (RGEA) and saphenous vein graft (SVG) by means of network meta-analysis of randomized controlled trials (RCTs). METHODS: Databases were searched for RCTs comparing angiographic outcomes (≥4 weeks) of second conduits in CABG. Odds ratios (95% confidence intervals) were computed with Markov Chain Monte Carlo simulation. RESULTS: A total of nine RCTs were identified, including 2780 patients and 1620 angiographic results available for analysis to compare RIMA (n=145) versus RA (n=871) versus RGEA (n=92) versus SVG (n=845). The mean time to angiographic follow-up ranged from 1 to 7.7 years. An SVG was significantly associated with a 4-fold (1.67-16.00) and 3-fold (0.78-22.20) increased risk of late (≥4 years) functional graft occlusion when compared with the RIMA and RA, respectively. A RIMA was associated with a non-significant 27% absolute risk reduction for functional graft occlusion when compared with the RA. CONCLUSIONS: The present network meta-analysis consistently demonstrated an angiographic superiority of RIMA and RA over SVG. The RIMA is expected to achieve a better patency rate than the RA, but further studies are needed.

Mitral commissurotomy through the left ventricle apical orifice with Heart Ware left ventricular assist device implantation.

Diseased, replaced or repaired mitral valve can lead to restricted blood flow to left ventricle and inadequate flow in left ventricular assist device (LVAD). A middle age woman with 'burnt out' hypertrophic cardiomyopathy had mitral valve repair for mitral regurgitation. She needed LVAD to support severe decompensating heart failure. Repaired mitral valve posed a risk of restricted flow through the device. Mitral commissurotomy was performed on beating heart through the left ventricular apical hole created for insertion of inflow cannula of LVAD.

Expansion of memory-type CD8+ T cells correlates with the failure of early immunosuppression withdrawal after cadaver liver transplantation using high-dose ATG induction and rapamycin.

BACKGROUND: We report on a pilot study investigating the feasibility of early immunosuppression withdrawal after liver transplantation (LT) using antithymocyte globulin (ATG) induction and rapamycin. METHODS: LT recipients received 3.75 mg/kg per day ATG from days 0 to 5 followed by rapamycin-based immunosuppression. In the absence of acute rejection (AR), rapamycin was withdrawn after month 4. Immunomonitoring included analysis of peripheral T-cell phenotypes and clonality, cytokine production in mixed lymphocyte reaction, and characterization of intragraft infiltrating cells. RESULTS: Ten patients were enrolled between October 2009 and July 2010. In the first three patients, complete withdrawal of immunosuppression after month 4 led to AR. No further withdrawals of immunosuppressive were attempted. Two AR occurred in the remaining seven patients. ATG induced profound T-cell depletion followed by CD8(+) T-cell reexpansion exhibiting memory/effector-like phenotype associated with progressive oligoclonal T-cell expansion (Vß/HPRT ratio) and gradually enhanced anti-cytomegalovirus and anti-Epstein-Barr virus T-cell frequencies. Patients developing AR were characterized by decreased TCAIM expression. AR were associated with increased donor-specific production of interferon (IFN)-γ and interleukin (IL)-17, increased intragraft expression of IFN-γ mRNA, and significant CD8(+) T-cell infiltrates colocalizing with IL-17(+) cells. CONCLUSION: High-dose ATG followed by short-term rapamycin treatment failed to promote early operational tolerance to LT. AR correlates with expansion of memory-type CD8(+) T cells and increased levels of IFN-γ and IL-17 in mixed lymphocyte reaction and in the graft. This suggests that resistance and preferential expansion of effector memory T-cell in lymphopenic environment could represent the major barrier for establishment of tolerance to LT in approaches using T-cell-depleting induction.

Reversal of severe heart failure with a continuous-flow left ventricular assist device and pharmacological therapy: a prospective study.

BACKGROUND: We have previously shown that a specific combination of drug therapy and left ventricular assist device unloading results in significant myocardial recovery, sufficient to allow pump removal, in two thirds of patients with dilated cardiomyopathy receiving a Heartmate I pulsatile device. However, this protocol has not been used with nonpulsatile devices. METHODS AND RESULTS: We report the results of a prospective study of 20 patients who received a combination of angiotensin-converting enzymes, ß-blockers, angiotensin II inhibitors, and aldosterone antagonists followed by the ß2-agonist clenbuterol and were regularly tested (echocardiograms, exercise tests, catheterizations) with the pump at low speed. Before left ventricular assist device insertion, patient age was 35.2 ± 12.6 years (16 male patients), patients were on 2.0 ± 0.9 inotropes, 7 (35) had an intra-aortic balloon pump, 2 were hemofiltered, 2 were ventilated, 3 had a prior Levitronix device, and 1 had extracorporeal membrane oxygenation. Cardiac index was 1.39 ± 0.43 L · min⁻¹ · m⁻², pulmonary capillary wedge pressure was 31.5 ± 5.7 mm Hg, and heart failure history was 3.4 ± 3.5 years. One patient was lost to follow-up and died after 240 days of support. Of the remaining 19 patients, 12 (63.2) were explanted after 286 ± 97 days. Eight had symptomatic heart failure for ≤6 months and 4 for >6 months (48 to 132 months). Before explantation, at low flow for 15 minutes, ejection fraction was 70 ± 7, left ventricular end-diastolic diameter was 48.6 ± 5.7 mm, left ventricular end-systolic diameter was 32.3 ± 5.7 mm, mV(O2) was 21.6 ± 4 mL · kg⁻¹ · min⁻¹, pulmonary capillary wedge pressure was 5.9 ± 4.6 mm Hg, and cardiac index was 3.6 ± 0.6 L · min⁻¹ · m⁻². Estimated survival without heart failure recurrence was 83.3 at 1 and 3 years. After a 430.7 ± 337.1-day follow-up, surviving explants had an ejection fraction of 58.1 ± 13.8, left ventricular end-diastolic diameter of 59.0 ± 9.3 mm, left ventricular end-systolic diameter of 42.0 ± 10.7 mm, and mV(O2) of 22.6 ± 5.3 mL · kg⁻¹ · min⁻¹. CONCLUSIONS: Reversal of end-stage heart failure secondary to nonischemic cardiomyopathy can be achieved in a substantial proportion of patients with nonpulsatile flow through the use of a combination of mechanical and pharmacological therapy.

Bridging patients after salvage from bridge to decision directly to transplant by means of prolonged support with the CentriMag short-term centrifugal pump.

OBJECTIVE: Optimum strategy for salvage in patients with acutely decompensated end-stage heart failure and severe multiorgan dysfunction is complex. We present our experience with prolonged CentriMag (Levitronix, Waltham, Mass) support for transitioning patients after successful salvage from bridge to decision directly to transplant. METHODS: Records of patients who underwent salvage with a CentriMag as bridge to decision and later to transplant were reviewed. Between June 2003 and June 2008, 4 patients in cardiogenic shock from acute decompensated end-stage heart failure and multiorgan dysfunction underwent salvage with biventricular CentriMag as bridge to decision. Three were male. Mean age was 39.3 years (range 24-52 years). Three had dilated cardiomyopathy; 1 had ischemic cardiomyopathy. All had preoperative mechanical ventilation, large doses of multiple inotropes, and intra-aortic balloon support. All also had acute liver and renal failure and metabolic acidosis. RESULTS: After mean postimplant period of 43 days (range 7-70 days), patients had reversal of end-organ dysfunction; after mean waiting time of 31 days (range 21-67 days), all were transplant listed. Mean mechanical circulatory support was 87.7 days (range 26-105 days). No thromboembolic or neurologic events or mechanical failures occurred. Posttransplant mean ventilation and intensive care unit stay were 2 and 4 days (ranges 1-4 and 3-7 days), respectively. All patients were discharged home and remain alive and well. CONCLUSION: CentriMag use as long as 3 months appears to be safe and cost-effective for bridging selected patients directly to transplant after salvage. Further clinical experience is still needed.

Acute liver transplant rejection upon immunosuppression withdrawal in a tolerance induction trial: potential role of IFN-gamma-secreting CD8+ T cells.

We designed a pilot trial in cadaveric liver transplantation to determine whether induction with antithymocyte globulins (ATG) and sirolimus would allow immunosuppression withdrawal. Patients received ATG 3.75 mg/kg per day from day 1 to 5 after transplantation followed by sirolimus for 4 to 6 months. We monitored interleukin (IL)-7 serum levels, interferon (IFN)-gamma, and IL-2 mRNA accumulation in mixed leukocyte reaction and intragraft IFN-gamma mRNA expression. In the first three patients, immunosuppression discontinuation was followed by reversible acute rejection occurring on days 280, 246, and 163 posttransplantation, corresponding to days 140, 40, and 39 after drug withdrawal, respectively. At the time of rejection, blood CD8+ T-cells counts had returned to or above pretransplant levels in two of three patients, whereas CD4+ T-cell count remained low. IL-7 serum levels rose in all three patients in the first months after transplantation and IFN-gamma mRNA accumulated in mixed leukocyte reaction between recipient T cells and donor spleen cells at the time of rejection. High levels of IFN-gamma mRNA were consistently detected in liver biopsy performed at the time of rejection. In conclusion, lymphopenia-induced IL-7 production after induction with ATG and sirolimus might lead to emergence of IFN-gamma-secreting CD8+ T-cells responsible for acute rejection after immunosuppression withdrawal.

Intrathoracic organ transplantation from donors with meningitis: a single-center 20-year experience.

BACKGROUND: Availability of cadaveric organs continues to be the key factor limiting the number of transplants performed. Donor with bacterial meningitis is often considered to be controversial for organ retrieval. The purpose of this retrospective study was to review the long-term outcome of orthotopic heart and lung transplantation at our institution, from donors who died as a result of meningitis. METHODS: Between July 1986 and July 2006, 39 adult patients who underwent heart and lung transplantation performed with organs from cadaveric donors with bacterial meningitis were retrospectively studied. Donors and recipients were identified by a prospectively kept database. Bacterial meningitis was identified either with positive blood or cerebrospinal fluid culture and positive signs and symptoms. All patients had one or more of these criteria. There were 15 heart, 12 lung (4 bilateral), and 12 heart-lung transplants. RESULTS: All donors had identified pathogens: Neisseria meningitidis (n = 21; 53.8%), Streptococcus pneumoniae (n = 16; 41%), and Haemophilus influenzae (n = 2; 5.2%). Adequate antimicrobial therapy before organ retrieval and after transplant was administered. The hospital mortality was 10.2% (n = 4). There were no infectious complications caused by meningeal pathogens. Other causes of hospital mortality were rejection (n = 2), intracranial bleeding (n = 1), and staphylococcus sepsis (n = 1). The mean posttransplant follow-up was 5.35 +/- 5.54 years (range, 1 month to 18.9 years). CONCLUSIONS: Intrathoracic organ transplantation using donors with bacterial meningitis is an acceptable strategy. No organism (Neisseria meningitides, Streptococcus pneumoniae, and Haemophilus influenzae) could be identified as contraindication because no recipient died of infectious-related diseases.

Bridge to decision using the Levitronix CentriMag short-term ventricular assist device.

BACKGROUND: Ventricular assist devices are effective in severe end-stage cardiac failure but outcomes remain poor in critically ill patients. Cheaper and less invasive short-term devices have been used in this setting. We report our experience with the Levitronix CentriMag short-term ventricular assist device as a potential bridge prior to deciding whether a more expensive device should be used or whether transplantation should be undertaken. METHODS: Since August 2003, 16 moribund patients (14 males; age 32.7 +/- 14.9 [range 16 to 62] years) have been supported with the CentriMag device as a "bridge to decision." Twelve patients had an intra-aortic balloon pump pre-operatively, 13 had multi-organ failure, 11 had septic shock, and in 5 patients the neurologic status was uncertain at the time of insertion of the device. RESULTS: Operative mortality was 18.7% (3 patients). Seven patients (43.7%) were reoperated for bleeding. The mean support duration was 46.9 +/- 32.3 (range 6 to 111) days. There were 2 late deaths during Levitronix utilization. Follow-up was 12.8 +/- 12.5 (range 0.6 to 43) months. Eleven patients (68.7%) are currently alive and well: 2 patients recovered and had the Levitronix device explanted; 6 patients were upgraded to a long-term device; and 3 patients were bridged directly to transplantation. The actuarial survival at 1, 6 and 12 months was 85.7%, 64.9% and 64.9%, respectively. There were no instances of device failure. CONCLUSIONS: The Levitronix device is effective in rescuing critically ill "moribund" patients and can provide an opportunity for low-cost support and optimization of their condition prior to deciding whether a more expensive device should be placed or if transplantation should be undertaken. Better candidate selection for further procedures can then be allowed.

Midterm experience with the Jarvik 2000 axial flow left ventricular assist device.

OBJECTIVE: Rotary axial flow pumps have several potential advantages and disadvantages over pulsatile pumps. The Jarvik 2000 is distinctive in being intracardiac. We report our experience in 22 patients. METHODS: The Jarvik 2000 was implanted in 15 men and 7 women. Mean age was 38.8 (range 23-59) years, preoperative diagnosis was dilated cardiomyopathy in 16, postpartum cardiomyopathy in 3, ischemic heart disease in 2, and chronic allograft failure in 1. Twenty-one patients were in New York Heart Association class IV, and 1 patient was in class III. Nineteen patients were on inotropic support, 6 were supported with an intra-aortic balloon pump, and 2 patients had been salvaged with a Centrimag (Levitronix) ventricular assist device. The median pulmonary vascular resistance was 3 Wood units; median pulmonary capillary wedge pressure was 26.6 mm Hg; and mean Cardiac Index was 1.5 L/min/m2. RESULTS: There were 2 early deaths and 6 late deaths. The average postoperative ventilation time and Intensive Treatment Unit stay was 2.2 and 10 days, respectively. One patient required a right ventricular assist device for short-term support and another for medium-term support. Seven patients were bridged to transplant, 3 had myocardial recovery, and 4 are ongoing. Mean and total duration of support was 280.5 and 6172 days, respectively. Driveline failures were noted in 3, but there were no pump infections or failure. CONCLUSION: The Jarvik 2000 provides satisfactory intermediate-term results as a bridge to transplant or recovery. It appears to be associated with a low rate of serious driveline or pump infections and technical failure. However, bleeding complications due to the required anticoagulation treatment frequently occurred.

C-type natriuretic peptide relaxes human coronary artery bypass grafts preconstricted by endothelin-1.

BACKGROUND: Endothelin is implicated in graft spasm after coronary artery bypass grafting. We assessed reversal by the endothelium-derived vasodilator C-type natriuretic peptide of prior contraction of radial artery and other vessels commonly used for coronary artery bypass surgery. METHODS: Segments of human radial artery, saphenous vein, and internal mammary artery were mounted in organ baths after removal from patients undergoing cardiac surgery (n = 34; 64 +/- 2 years). Effects of increasing concentrations of C-type natriuretic peptide (with or without aprotinin, 1,000 U/mL) on endothelin-induced contraction were compared with acetylcholine, sodium nitroprusside, and papaverine. RESULTS: C-type natriuretic peptide relaxed endothelin precontraction in all vessels (F = 17.8, 36.3, and 48.4, respectively; p < 0.001), with maximum relaxations of 44%, 54%, and 66% in saphenous vein, internal mammary artery, and radial artery, respectively. Aprotinin did not affect relaxation to C-type natriuretic peptide. Acetylcholine relaxed the saphenous vein weakly, with maximal relaxation of 9% at 10(-6) M. However, the radial artery and internal mammary artery relaxed strongly to acetylcholine. The highest concentration of papaverine completely relaxed all vessels, but responses were less sensitive than to sodium nitroprusside or acetylcholine. CONCLUSIONS: C-type natriuretic peptide reverses endothelin-induced constriction in arterial and venous conduits used for coronary artery bypass, particularly the radial artery. Proteolytic breakdown of C-type natriuretic peptide by local vascular enzymes appears of little importance in vitro. This signals the therapeutic potential of using C-type natriuretic peptide as an antagonist of graft vasospasm after coronary artery bypass surgery.

Functional renal outcome in on-pump and off-pump coronary revascularization: a propensity-based analysis.

BACKGROUND: Since the advent of off-pump coronary artery bypass grafting (OPCAB), comparisons have been made between it and on-pump coronary artery bypass grafting. Some observe a lesser incidence of acute renal failure requiring renal replacement therapy with OPCAB whereas others do not. The objective was to compare the occurrence of renal adverse outcome between on-pump coronary artery bypass grafting and OPCAB. Renal adverse outcome was defined as minor (20% increase in serum creatinine from preoperative) or major (composite end point of postoperative serum creatinine >200 mumol/L or postoperative mechanical renal support). METHODS: The study was based on 2,041 patients with no known preoperative renal disease having first-time isolated coronary artery bypass grafting of multiple coronary arteries between January 2001 and November 2003, at St. Mary's Hospital, Harefield Hospital, and Hammersmith Hospital, in West London; 1,224 patients had on-pump coronary artery bypass grafting and 817 patients had OPCAB. Selection bias for surgical technique was addressed by calculating the propensity score for each patient and using it as an independent variable for adjustment in the multivariate analysis. Univariate and multivariate ordered logistic regressions were used to identify factors associated with renal adverse outcome ordered as none, minor, and major. RESULTS: The number of grafts was 3.22 +/- 0.82 for the on-pump coronary artery bypass grafting group and 3.35 +/- 0.95 for the OPCAB group. On-pump coronary artery bypass grafting and increasing age were found to be the strongest independent predictors (p < 0.001) of renal adverse outcome. Other independent predictors included hypertension (p = 0.005), diabetes (p = 0.032), and preoperative serum creatinine (p = 0.001). A left ventricular ejection fraction of 0.30 to 0.49 (p = 0.099) and an ejection fraction of 0.50 or greater (p < 0.001) were associated with decreased risk compared with patients with an ejection fraction of less than 0.30. Interestingly, the use of non-left internal mammary arterial conduits significantly decreased the likelihood of renal adverse outcome (p = 0.034). CONCLUSIONS: The results of this propensity-based study show that the OPCAB technique may reduce the risk for minor and major renal adverse outcome after coronary artery bypass grafting.

Familial cluster headache: a series of 186 index patients.

OBJECTIVE: To investigate the familial occurrence of cluster headache in a series of French patients fulfilling the International Headache Society diagnosis criteria. METHODS: One hundred eighty-six index patients and 624 first-degree relatives were surveyed. RESULTS: A positive family history of cluster headache was found in 20 index patients (10.75%) with 22 affected first-degree relatives (3.4%). In multiplex families 6 of the 68 second-degree relatives that were contacted had cluster headache. CONCLUSION: No precise mode of inheritance could be drawn from the observed repartition of cases within multiplex families.