Calcified plaque: measurement of area at thin-section flat-panel CT and 64-section multidetector CT and comparison with histopathologic findings

The purpose of this study was to assess the blooming artifacts in ex vivo coronary arteries at multidetector computed tomography (CT) and flat-panel-volume CT by comparing measured areas of calcified plaque with respect to the reference standard of histopathologic findings. Three ex vivo hearts were scanned with multidetector CT and flat-panel-volume CT after institutional review board approval. The area of calcified plaque was measured at histopathologic examination, multidetector CT, and flat-panel-volume CT. The plaque area was overestimated at multidetector CT by 400% (4.61/1.15) on average, and the predicted difference between the measurements was significant (3.46 mm(2), P = .018). The average overestimation of plaque area at flat-panel-volume CT was twofold (214% [2.18/1.02]), and the predicted difference was smaller (1.16 mm(2), P = .08). The extent of the blooming artifact in visualizing calcified coronary plaque is reduced by using flat-panel-volume CT.     

An MHC class II disparity raises the threshold for tolerance induction in pulmonary allografts in miniature swine

OBJECTIVES: The mechanisms and treatment of chronic rejection in pulmonary allotransplantation remain elusive. We have induced robust tolerance to class I-disparate lung allografts in miniature swine using an intensive 12-day course of tacrolimus. Here, we tested whether a tolerant state can be induced in swine receiving fully mismatched lung allografts. METHODS: Orthotopic left lung allografts were performed using MHC class I-disparate (group 1: n = 3) or fully disparate (group 2: n = 6) donors. The recipients received a 12-day postoperative course of tacrolimus (continuous intravenous infusion; target level = 35-50 ng/mL) as their only immunosuppression. RESULTS: All swine in group 1 maintained their grafts long term without developing any lesions of chronic rejection (>497, >432, >451 days). These recipients exhibited donor-specific hyporesponsiveness in cell-mediated lymphocytotoxity (CML) and mixed lymphocyte reaction (MLR) assays. In group 2, five of the six recipients maintained their grafts long term (sacrificed on postoperative days 515, 389, 429, 481, and 438 with viable grafts). Isolated lesions of obliterative bronchiolitis were occasionally seen on biopsy, and donor-specific hyporesponsiveness on assays was consistently observed. The remaining recipient rejected its graft on day 103 with histologic findings of obliterative bronchiolitis. CONCLUSIONS: We report long-term graft acceptance without chronic immunosuppression in five of six recipients across a full MHC disparity, albeit with some evidence of obliterative bronchiolitis. These data suggest that the class II disparity inherent in a fully mismatched transplant increases the requirement for tolerance induction.     

Barriers to effective symptom management in hospice

The barriers to effective symptom management in hospice are not well described. We surveyed nurses of hospices affiliated with the Population-based Palliative Care Research Network (PoPCRN) to identify barriers to the effective management of common symptoms in terminally ill patients. 867/1710 (51%) nurses from 67 hospices in 25 U.S. States returned surveys. Of 32 symptoms, nurses reported agitation (45%), pain (40%), and dyspnea (34%) as the 'most difficult to manage.' The most common perceived barriers to effective symptom management were inability of family care providers to implement or maintain recommended treatments (38%), patients or families not wanting recommended treatments (38%), and competing demands from other distressing symptoms (37%). Patterns of barriers varied by symptom. These nurses endorsed multiple barriers contributing to unrelieved symptom distress in patients receiving hospice care. Interventions to improve symptom management in hospice may need to account for these differing barrier patterns.     

Potential of aspirin to inhibit thrombotic microangiopathy in alpha1,3-galactosyltransferase gene-knockout pig hearts after transplantation in baboons

Hearts from alpha1,3-Galactosyltransferase gene-knockout (GaIT-KO) pigs were transplanted heterotopically into 8 baboons that received an anti-CD154 monoclonal antibody (mAb)-based immunosuppressive regimen and heparin. Three baboons died or were euthanized with beating grafts on 16, 23, and 56 days, respectively, and the remaining 5 grafts functioned for 59-179 days. Hyperacute rejection did not occur, and classical features of acute humoral xenograft or acute cellular rejection were rare. However, thrombotic microangiopathy (TM) developed in all cases; its onset was delayed in 2 baboons that received aspirin. Function of a pig organ in a baboon for a period approaching 6 months has not been reported previously and lends encouragement that the barriers to xenotransplantation will be overcome, but TM requires investigation.     

Combination treatment with donor-specific transfusions and cyclosporine a induces long-term survival of cardiac allografts in miniature Swine

BACKGROUND: To evaluate whether pretransplant donor-specific transfusions (DST) can induce tolerance to cardiac allografts in large animals, heterotopic cardiac transplants were performed across a class I MHC barrier in inbred miniature swine. METHODS: Experimental animals received two DSTs, each containing 1.4x10 viable peripheral blood mononuclear cells, 14 and 7 days prior to transplantation together with a 12-day course of cyclosporine (CyA) (13 mg/kg IV) starting on postoperative day (POD) 0. RESULTS: Untreated (n=2) and DST-only (n=2) treated control animals rejected between POD 6 and 8. Animals treated with CyA alone (n=3) exhibited graft survival to 53, 52 and 59 days. In contrast, the combination of DST and CyA (n=3) led to stable graft function for >200 days. Long-term survivors maintained peripheral CML response against donor antigen. Following DSTs, the donor-specific proliferative response of CD8+ recipient T cells was significantly increased (P=0.011), and a significant number of CD8+ T cells underwent apoptosis (10.1% on POD 0; 5.2% on POD -14; P=0.04). None of the DST-treated animals developed donor-specific antibodies. CONCLUSIONS: These results are the first to demonstrate the ability of DST to induce operational tolerance to cardiac allografts in large animals, and they suggest that peripheral mechanisms of tolerance mediate this effect.     

Long-term acceptance of porcine pulmonary allografts without chronic rejection

OBJECTIVES: The mechanisms and treatment of chronic rejection in pulmonary allotransplantation remain elusive. Using a strategy to induce tolerance across strong allogeneic barriers, we have employed a brief, intensive course of immunosuppression to determine whether the induction of donor-specific hyporesponsiveness would prevent allograft rejection in a preclinical model of lung transplantation using MHC-inbred miniature swine. METHODS: Orthotopic left lung allografts were performed using MHC class I-disparate donors. The recipients received a 12-day postoperative course of cyclosporine (n = 6) or a 12-day postoperative course of high-dose tacrolimus (n = 3) as their only immunosuppression. Control animals received no immunosuppression (n = 3). RESULTS: Cyclosporine-treated recipients exhibited graft survival ranging from 67 to >605 days. All six animals developed acute cellular rejection between postoperative days (PODs) 27 and 108. Two animals lost their grafts on PODs 67 and 69, before developing obliterative bronchiolitis (OB). The other four recipients developed OB between PODs 119 and 238. In contrast, all tacrolimus-treated recipients maintained their grafts long term, without developing chronic rejection (>339, >308, and >231). These recipients also exhibited donor-specific hyporesponsiveness in assays of cell-mediated lymphocytotoxity. All untreated control animals lost their grafts to acute rejection by POD 11. CONCLUSIONS: This study demonstrates the ability of a brief course of high-dose tacrolimus to induce long-term graft acceptance with donor-specific hyporesponsiveness in a class I-disparate preclinical lung transplant model.     

Is depressed myocyte contractility centrally involved in heart failure?

This review examines the evidence for and against the hypothesis that abnormalities in cardiac contractility initiate the heart failure syndrome and drive its progression. There is substantial evidence that the contractility of failing human hearts is depressed and that abnormalities of basal Ca2+ regulation and adrenergic regulation of Ca2+ signaling are responsible. The cellular and molecular defects that cause depressed myocyte contractility are not well established but seem to culminate in abnormal sarcoplasmic reticulum uptake, storage, and release. There are also strong links between Ca2+ regulation, Ca2+ signaling pathways, hypertrophy, and heart failure that need to be more clearly delineated. There is not substantial direct evidence for a causative role for depressed contractility in the initiation and progression of human heart failure, and some studies show that heart failure can occur without depressed myocyte contractility. Stronger support for a causal role for depressed contractility in the initiation of heart failure comes from animal studies where maintaining or improving contractility can prevent heart failure. Recent clinical studies in humans also support the idea that beneficial heart failure treatments, such as beta-adrenergic antagonists, involve improved contractility. Current or previously used heart failure treatments that increase contractility, primarily by increasing cAMP, have generally increased mortality. Novel heart failure therapies that increase or maintain contractility or adrenergic signaling by selectively modulating specific molecules have produced promising results in animal experiments. How to reliably implement these potentially beneficial inotropic therapies in humans without introducing negative side effects is the major unanswered question in this field.     

Hormonal changes associated with the transition between nursing and natural fasting in northern elephant seals (Mirounga angustirostris)

To better interpret previously described hormonal changes observed during the natural postweaning fast (2-3 months) endured by pups of the northern elephant seal (Mirounga angustirostris), we compared plasma cortisol, thyroid hormones, and leptin in pups (n=5) measured during nursing and fasting periods. Blood samples were taken at four times; early (9 days postpartum) and late (18-22 days postpartum) nursing, and early (second week postweaning) and late (eighth week postweaning) fasting. Plasma cortisol increased 39% between early and late nursing and almost 4-fold by late fasting. After the early nursing period, cortisol and body mass were negatively correlated (y=28.3-0.19 x; R=0.569; p=0.027). Total thyroxine (tT(4)), free T(4) (fT(4)), total triiodothyronine (tT3) and reverse T(3) (rT(3)) were greatest at early nursing and reduced by late nursing and remained so throughout the fast, with the exception of tT(4), which increased between late nursing (17.7+/-2.1 ng mL(-1)) and late fasting (30.1+/-2.8 ng mL(-1)) periods. Leptin remained unaltered among the four sampling periods and was not correlated with body mass. Pups appear to exhibit a shift in the relationship between cortisol and body mass suggesting a potential role for cortisol in the regulation of body fat. The higher concentrations of tT(3) and tT(4) during early nursing may reflect enhanced growth and development during this period, however the increase late in fasting is likely physiologically insignificant and an artifact of reduced metabolic clearance of these hormones. Transition of the pups from nursing to fasting states is characterized by a striking lack of change in cortisol, thyroid hormones, and leptin suggesting that any metabolic alterations associated with this transition may occur independent of these hormones.     

Defining and understanding healthy lifestyles choices for adolescents.

PURPOSE: To: (a) establish criteria for defining positive health behaviors and lifestyle; and (b) identify characteristics of adolescents who practice a healthy lifestyle. METHODS: Responses from a 1998 survey via questionnaire, of 1487 students, from a public high school, Cambridge, Massachusetts, were used to assess correlates of healthy lifestyle choices. Strict and broad assessments of healthy behaviors were defined for students: use of alcohol, tobacco, and illegal drugs; sexual behavior; attempted suicide. Whereas the "strict" criteria included only those adolescents who did not practice any of the behaviors in question, the broad criteria reflected experimentation and moderate risk-taking. The prevalence of positive behaviors was assessed by demographic and student characteristics. In addition, logistic regression models were created to predict determinants of teenagers' healthy lifestyles using both strict and broad definitions. RESULTS: Using strict criteria of healthy lifestyle, significant predictors were being female, born outside the United States, higher academic performance, and fewer stressful life events. Using a broad definition of a healthy lifestyle, significant predictors were being non-Caucasian, in the lower grade levels at the school, higher academic performance, and fewer stressful life events. In both models, peers' approval of risky behaviors negatively influenced teens' lifestyles, whereas parents' disapproval of risky behaviors was a positive influence. CONCLUSIONS: These results reinforce the importance of school, peer, and parent support of positive behaviors. It is important for public health workers and families to understand and define healthy lifestyles choices for adolescents.     

A deterministic iterative least-squares algorithm for beam weight optimization in conformal radiotherapy

Currently, inverse treatment planning in conformal radiotherapy is, in part, a trial-and-error process due to the interplay of many competing criteria for obtaining a clinically acceptable dose distribution. A new method is developed for beam weight optimization that incorporates clinically relevant nonlinear and linear constraints. The process is driven by a nonlinear, quasi-quadratic objective function and the solution space is defined by a set of linear constraints. At each step of iteration, the optimization problem is linearized by a self-consistent approximation that is local to the existing dose distribution. The dose distribution is then improved by solving a series of constrained least-squares problems using an established method until all prescribed constraints are satisfied. This differs from the current approaches in that it does not rely on the search for the global minimum of a specific objective function. Essentially, our proposed objective function can be construed as a functional that comprises a class of dose-based quadratic objective functions. Empirical adjustment for appropriate model parameters in the construction of objective function is minimized, since these parameters are in effect adaptively adjusted during optimization. The method is robust in solving difficult clinical cases using either aperture or pencil beam based planning techniques for intensity-modulated radiation therapy.