Seismic velocities of CaSiO3 perovskite can explain LLSVPs in Earth's lower mantle.

Seismology records the presence of various heterogeneities throughout the lower mantle1,2, but the origins of these signals-whether thermal or chemical-remain uncertain, and therefore much of the information that they hold about the nature of the deep Earth is obscured. Accurate interpretation of observed seismic velocities requires knowledge of the seismic properties of all of Earth's possible mineral components. Calcium silicate (CaSiO3) perovskite is believed to be the third most abundant mineral throughout the lower mantle. Here we simultaneously measure the crystal structure and the shear-wave and compressional-wave velocities of samples of CaSiO3 perovskite, and provide direct constraints on the adiabatic bulk and shear moduli of this material. We observe that incorporation of titanium into CaSiO3 perovskite stabilizes the tetragonal structure at higher temperatures, and that the material's shear modulus is substantially lower than is predicted by computations3-5 or thermodynamic datasets6. When combined with literature data and extrapolated, our results suggest that subducted oceanic crust will be visible as low-seismic-velocity anomalies throughout the lower mantle. In particular, we show that large low-shear-velocity provinces (LLSVPs) are consistent with moderate enrichment of recycled oceanic crust, and mid-mantle discontinuities can be explained by a tetragonal-cubic phase transition in Ti-bearing CaSiO3 perovskite.

The iTreAD project: a study protocol for a randomised controlled clinical trial of online treatment and social networking for binge drinking and depression in young people.

BACKGROUND: Depression and binge drinking behaviours are common clinical problems, which cause substantial functional, economic and health impacts. These conditions peak in young adulthood, and commonly co-occur. Comorbid depression and binge drinking are undertreated in young people, who are reluctant to seek help via traditional pathways to care. The iTreAD project (internet Treatment for Alcohol and Depression) aims to provide and evaluate internet-delivered monitoring and treatment programs for young people with depression and binge drinking concerns. METHODS: Three hundred sixty nine participants will be recruited to the trial, and will be aged 18-30 years will be eligible for the study if they report current symptoms of depression (score 5 or more on the depression subscale of the Depression Anxiety Stress Scale) and concurrent binge drinking practices (5 or more standard drinks at least twice in the prior month). Following screening and online baseline assessment, participants are randomised to: (a) online monthly self-assessments, (b) online monthly self-assessments + 12-months of access to a 4 week online automated cognitive behaviour therapy program for binge drinking and depression (DEAL); or (c) online monthly assessment + DEAL + 12-months of access to a social networking site (Breathing Space). Independent, blind follow-up assessments occur at 26, 39, 52 and 64-weeks post-baseline. DISCUSSION: The iTreAD project is the first randomised controlled trial combining online cognitive behaviour therapy, social networking and online monitoring for young people reporting concerns with depression and binge drinking. These treatments represent low-cost, wide-reach youth-appropriate treatment, which will have significantly public health implications for service design, delivery and health policy for this important age group. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12614000310662. Date registered 24 March 2014.

Granulocyte colony-stimulating factor therapy is associated with a reduced incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients.

BACKGROUND: We evaluated the potential effects of granulocyte colony-simulating factor (G- CSF) on the incidence of rejection and allograft vasculopathy in heart transplant recipients. METHODS: Of 247 patients undergoing heart transplantation from 2000 to 2007, 52 (21%) developed leukopenia (white blood cell [WBC] <2.5 × 10(9) cells/L) in the absence of active infection, rejection, or malignancy. In 24 (46%) patients a clinical decision was made to treat the leukopenia with G-CSF (G-CSF group), and 28 (54%) Patients received no G-CSF (non-GCSF group). Patients followed up for 1 year after the period of leukopenia were assessed for allograft vasculopathy and acute rejection incidence. RESULTS: At baseline, the G-CSF group and the non-GCSF group did not differ in age, gender, race, heart failure etiology, creatinine, left ventricular ejection fraction (LVEF) or immunosupressive regimen. During 1-year follow-up there were no deaths in the G-CSF group, and 1 death in the non-GCSF group (P = .34). The incidence of rejection or progressive allograft vasculopathy was lower in the G-CSF group when compared with the non-GCSF group (2 [8%] vs 15 [53%]; P < .01). Multivariate analysis identified both prior rejection episodes and G-CSF therapy as factors associated with the combined end-point of rejection or progressive allograft vasculopathy (odds ratio [OR] = 7.89 [1.67-37.2] and OR = 0.09 [0.02-0.52], respectively). CONCLUSIONS: G-CSF therapy appears to be associated with a decreased incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients, suggesting a potential immunomodulatory effect of G-CSF.

Outcome in cardiac recipients of donor hearts with increased left ventricular wall thickness.

The ongoing shortage of donors for cardiac transplantation has led to a trend toward acceptance of donor hearts with some structural abnormalities including left ventricular hypertrophy. To evaluate the outcome in recipients of donor hearts with increased left ventricular wall thickness (LVWT), we retrospectively analyzed data for 157 cardiac donors and respective recipients from January 2001 to December 2004. There were 47 recipients of donor heart with increased LVWT >or=1.2 cm, which constituted the study group and 110 recipients of a donor heart with normal LVWT < 1.2 cm that formed the control group. At 3 +/- 1.5 years, recipient survival was lower (50% vs. 82%, p = 0.0053) and incidence of allograft vasculopathy was higher (50% vs. 22%, p = 0.05) in recipients of donor heart with LVWT > 1.4 cm as compared to LVWT 1.4 cm (p = 0.003), recipient preoperative ventricular assist device (VAD) support (p = 0.04) and bypass time > 150 min (p = 0.05) were predictors of reduced survival. Our results suggest careful consideration of donor hearts with echocardiographic evidence of increased LVWT in the absence of hypovolemia, because they may be associated with poorer outcomes; such hearts should potentially be reserved only for the most desperately ill recipients.

Wound healing complications with de novo sirolimus versus mycophenolate mofetil-based regimen in cardiac transplant recipients.

Sirolimus was introduced in de novo immunosuppression at Stanford University in view of its favorable effects on reduced rejection and cardiac allograft vasculopathy. After an apparent increase in the incidence of post-surgical wound complications as well as symptomatic pleural and pericardial effusions, we reverted to a mycophenolate mofetil (MMF)-based regimen. This retrospective study compared the outcome in heart transplant recipients on sirolimus (48 patients) with those on MMF (46 patients) in de novo immunosuppressive regimen. The incidence of any post-surgical wound complication (52% vs. 28%, p=0.019) and deep surgical wound complication (35% vs. 13%, p=0.012) was significantly higher in patients on sirolimus than on MMF. More patients on sirolimus also had symptomatic pleural (p=0.035) and large pericardial effusions (p=0.033) requiring intervention. Logistic regression analysis showed sirolimus (p=0.027) and longer cardiac bypass time (OR=1.011; p=0.048) as risk factors for any wound complication. Sirolimus in de novo immunosuppression after cardiac transplantation was associated with a significant increase in the incidence of post-surgical wound healing complications as well as symptomatic pleural and pericardial effusions.

Mild hyperhomocysteinemia is not associated with cardiac allograft coronary disease.

BACKGROUND: Hyperhomocysteinemia is an independent risk factor for coronary disease and elevated plasma homocysteine levels have been documented in heart transplant recipients. The aim of this study was to test the hypothesis that homocysteine levels are associated with presence or absence of transplant coronary artery disease. METHODS: Forty-three non-smoking adults were recruited, all of whom had received a heart transplant between 2 and 7 yr previously. All 43 had blood drawn for fasting homocysteine level on the day of presentation. All patients had undergone diagnostic coronary angiography within the past 6 months. RESULTS: For all patients, the average fasting plasma homocysteine level was 17.0+/-SD 6.6 micromol/L with a range from 6.0 to 36.9 micromol/L. Twenty-six patients (60%) had fasting plasma homocysteine levels above 15.0 micromol/L. On the basis of arteriography, patients were categorized as those with angiographically normal (n=22) or abnormal (n=21) coronary arteries. There was no difference in the mean plasma homocysteine level comparing patients with angiographically normal (17.2+/-SD 7.0 micromol/L) to those with abnormal (16.8+/-SD 6.2 micromol/L) coronary arteries. Plasma homocysteine levels increased with increasing plasma creatinine levels (r=0.63, p<0.0001) and with decreasing vitamin B6 levels (r=-0.56, p<0.0001). CONCLUSIONS: Mild hyperhomocysteinemia is a consistent finding among heart transplant recipients. This finding was not associated with transplant coronary artery disease in our patients. The combination of renal dysfunction and vitamin B6 deficiency may explain the unusual prevalence of hyperhomocysteinemia in heart transplant recipients.

Severe tricuspid regurgitation after heart transplantation.

BACKGROUND: Tricuspid regurgitation (TR) is common after heart transplantation. However, the incidence of severe TR and the incidence of symptoms after echocardiographic diagnosis of severe TR have not been documented. The purpose of this study is to determine the incidence of severe TR and its clinical significance in the heart transplant population. METHODS: We reviewed echocardiograms (echo) of all heart transplant patients coming for regular echocardiographic follow-up between 1990 and 1995. We reviewed the charts of all patients who had echo diagnosis of severe TR. RESULTS: A total of 336 patients had echo follow-up during this time period. The number of months post-heart transplant to last echo was 54 +/- 50 (range, 1 to 265 months). Ninety patients had moderate TR and 23 patients had severe TR. Mean time from heart transplantation to diagnosis of severe TR was 43 +/- 38 months (range, 1 to 132). Using Cutler-Ederer analysis, at 5 years, 92.2% of surviving patients were free from severe TR. At 10 years, 85.8% of surviving patients were free from severe TR. Of the 23 patients with severe TR, 17 had charts available for review. The mean number of prior endomyocardial biopsies was 28 +/- 21 (range, 3 to 88). These patients were followed for 35 +/- 18 months after diagnosis. During this period, they developed significant heart failure and peripheral edema. Six patients eventually underwent tricuspid valve replacement. CONCLUSIONS: Moderate to severe TR commonly occurs following heart transplantation. Severe TR is associated with significant morbidity.

Who and when to consider for heart transplantation.

The number of patients who are potentially eligible for heart transplantation is increasing steadily in the face of a plateaued or stable donor supply. Therefore, development of fair, sensible, and consistently and widely applied criteria for transplant recipient selection is a crucial medical and societal issue. This article examines the evolution of these criteria and advocates a flexible approach to their continued evolution.

New technique for treatment of unstable distal femur fractures by locked double-plating: case report and biomechanical evaluation.

BACKGROUND: A comminuted, intra-articular distal femur fracture was surgically treated by the authors with a locked, double-plating technique because fixation stability could not be initially achieved by using a standard double-plating technique. The purpose of this study was to determine biomechanically whether a locked double-plate construct would enhance fixation stability compared with a nonlocked double-plate construct. METHODS: Six matched pairs of mildly osteopenic femurs were selected and all had a reproducible intra-articular fracture pattern created. Each pair underwent fixation with either a double-plating construct or a locked, double-plating construct that was randomly assigned. The instrumented femurs were then mechanically tested in several loading modes to determine fixation stability. After initial testing, specimens were cyclically loaded and retested for stability. RESULTS: The locked, double-plating construct provided significantly greater fixation stability than the standard double-plating construct in precycling and postcycling biomechanical testing. CONCLUSION: The technique described is particularly applicable for severely comminuted fractures of the distal femur and fractures in osteopenic bone with poor screw purchase. It offers a simple alternative for enhancing fixation stability, which avoids the potential complications of methylmethacrylate-enhanced screw fixation.

New immunosuppressive agents in clinical use: mycophenolate mofetil and tacrolimus.

Since the early 1980s, a 3-drug regimen that includes cyclosporine, azathioprine, and usually corticosteroids has been the mainstay of immunosuppression for patients undergoing cardiac transplantation. This regimen, however, has a variety of inherent toxicities and is not associated with any lesser incidence of graft coronary artery disease than the earlier regimen. For these reasons, there has been a widely perceived need for the introduction of improved immunosuppressive agents. Two such agents have thus far been introduced into clinical organ transplantation: mycophenolate mofetil and tacrolimus. Mycophenolate mofetil is used as a substitute for azathioprine and has been shown to result in significantly lower mortality rates and freedom from rejection in heart transplant recipients. Tacrolimus can be used as a substitute for cyclosporine but (at least in the short-term) seems to offer no important advantage in terms of survival or rejection. The combination of these 2 new agents seems to have no short-term disadvantage and longer-term follow-up is pending.

Neoplasia after heart transplantation.

Transplant recipients have a higher incidence of cancer compared with the general population. This increased risk is related to the intensity and chronicity of immunosuppression that these patients receive. The common types and presentations of posttransplant tumors are reviewed and discussed. Regular surveillance is of paramount importance in detecting such tumors. Treatment invariably includes attempts to reduce immunosuppression.

Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis: a post hoc analysis of a randomized, placebo-controlled study.

BACKGROUND: Coronary artery disease occurs in an accelerated fashion in the donor heart after heart transplantation (TxCAD), but the cause is poorly understood. The risk of developing TxCAD is increased by cytomegalovirus (CMV) infection and decreased by use of calcium blockers. Our group observed that prophylactic administration of ganciclovir early after heart transplantation inhibited CMV illness, and we now propose to determine whether this therapy also prevents TxCAD. METHODS AND RESULTS: One hundred forty-nine consecutive patients (131 men and 18 women aged 48+/-13 years) were randomized to receive either ganciclovir or placebo during the initial 28 days after heart transplantation. Immunosuppression consisted of muromonab-CD3 (OKT-3) prophylaxis and maintenance with cyclosporine, prednisone, and azathioprine. Mean follow-up time was 4.7+/-1.3 years. In a post hoc analysis of this trial designed to assess efficacy of ganciclovir for prevention of CMV disease, we compared the actuarial incidence of TxCAD, defined by annual angiography as the presence of any stenosis. Because calcium blockers have been shown to prevent TxCAD, we analyzed the results by stratifying patients according to use of calcium blockers. TxCAD could not be evaluated in 28 patients because of early death or limited follow-up. Among the evaluable patients, actuarial incidence of TxCAD at follow-up (mean, 4.7 years) in ganciclovir-treated patients (n=62) compared with placebo (n=59) was 43+/-8% versus 60+/-10% (P<0.1). By Cox multivariate analysis, independent predictors of TxCAD were donor age >40 years (relative risk, 2.7; CI, 1.3 to 5.5; P<0.01) and no ganciclovir (relative risk, 2.1; CI, 1.1 to 5.3; P=0.04). Stratification on the basis of calcium blocker use revealed differences in TxCAD incidence when ganciclovir and placebo were compared: no calcium blockers (n=53), 32+/-11% (n=28) for ganciclovir versus 62+/-16% (n=25) for placebo (P<0.03); calcium blockers (n=68), 50+/-14% (n=33) for ganciclovir versus 45+/-12% (n=35) for placebo (P=NS). CONCLUSIONS: TxCAD incidence appears to be lower in patients treated with ganciclovir who are not treated with calcium blockers. Given the limitations imposed by post hoc analysis, a randomized clinical trial is required to address this issue.

Thirty years of cardiac transplantation at Stanford university.

BACKGROUND: The experience with 30 years of cardiac transplantation at Stanford University Medical Center was reviewed. A total of 954 transplants were performed in 885 patients. Patients were divided into 3 groups based on immunosuppression received: group I, no cyclosporine (INN: ciclosporin) (n = 201) (January 1968-November 1980); group II, cyclosporine (n = 248) (December 1980-June 1987); and group III, cyclosporine + OKT3 (n = 436) (July 1987-March 1998). RESULTS: The 1-, 5-, and 10-year actuarial survivals were 68%, 41%, and 24% (group I); 80%, 57%, and 37% (group II); and 85%, 68%, and 46% (group III) (I vs II, P <.01; I vs III, P <.005; and II vs III, P <.005). The 1-, 5-, and 10-year actuarial death rates from rejection were 8%, 12%, and 14% (group I); 5%, 7%, and 7% (group II); and 2%, 5%, and 5% (group III) (I vs II, P = not significant; I vs III, P <.005; and II vs III, P <.005). The 1-, 5-, and 10-year actuarial death rates from infection were 25%, 43%, and 50% (group I); 8%, 17%, and 29% (group II); and 6%, 11%, and 16% (group III) (I vs II, P <.005; I vs III, P <.005; and II vs III, P <.05). The 1-, 5-, and 10-year actuarial death rates from graft coronary artery disease were 0%, 5%, and 13% (group I); 0%, 12%, and 19% (group II); and 1%, 6%, and 9% (group III) (I vs II, P <.01; I vs III, P <.005; and II vs III, P = not significant). There have been 69 retransplants in 67 patients with 1-, 5-, and 10-year actuarial survivals of 49%, 27%, and 15%, respectively. CONCLUSIONS: The evolution of 3 decades of experience with cardiac transplantation has resulted in improved overall survival. The incidence of rejection and of death from infection and graft coronary artery disease have decreased over time, primarily as a result of improvements in immunosuppression and in the prevention and treatment of infection. Continued advances in perioperative management and the development of more specific, less toxic immunosuppressive agents could further refine this initial experience and improve the survival and quality of life of patients after cardiac transplantation.

Current status of cardiac transplantation.

Cardiac transplantation, first introduced 30 years ago, has become a widely used and increasingly important procedure for treatment of truly end-stage heart disease. Current use is limited strictly by donor supply, making selection of appropriate recipients an important ethical and societal issue. Survival rates after transplantation rose in the 1980s with the use of cyclosporine and have remained relatively consistent since then, although recipients older than 65 years or younger than 1 year have lower survival rates than recipients of other ages. Although immunosuppressive drugs have helped establish cardiac transplantation as a successful procedure, risks of opportunistic infection and rejection, as well as coronary arteriopathy, have led to development of new immunosuppressive agents currently under study. Future alternatives to the current technology of cardiac allotransplantation may include xenotransplantation and/or nonbiological replacement of the heart with mechanical devices.