Longitudinal analysis of fibroblast growth factor expression after transplantation and association with severity of cardiac allograft vasculopathy.

BACKGROUND: Vascular smooth muscle cell growth factors are postulated to contribute to cardiac allograft vasculopathy (CAV). Few data quantitatively address the timing, location, or stimuli for growth factor expression and relationship to CAV. METHODS AND RESULTS: Acidic fibroblast growth factor (aFGF) mRNA expression was determined in serial endomyocardial biopsies during the first year after transplantation. Patients with high levels of aFGF mRNA and elevations after the early posttransplant period had significantly more severe CAV than patients with low aFGF and no late elevations. CONCLUSIONS: Parenchymal aFGF expression varies between patients and in the same patient over time and correlates with development of CAV.

Relationship between exertional symptoms and functional capacity in patients with heart failure.

OBJECTIVES: The present study was undertaken to investigate the relationship over time between exertional symptoms in heart failure and functional capacity. BACKGROUND: Most clinicians rely on exertional symptoms rather than on exercise testing to assess functional capacity in heart failure. However, it remains uncertain whether the subjective symptoms reported by patients provide a reliable index of functional capacity. METHODS: Fifty patients with heart failure underwent serial cardiopulmonary exercise testing and evaluation of exertional fatigue and dyspnea over a period of one to four years. Exercise testing was performed using the Naughton treadmill protocol and a MedGraphics metabolic cart. Fatigue and dyspnea were each scored from 0 to 3 (p = none, 1 = mild, 2 = moderate, 3 = severe). A composite symptom score was determined by adding together the fatigue and dyspnea scores. RESULTS: Patients underwent a total of 185 tests at an average interval of 4.3 months (average tests/patient = 3.7). Composite symptom scores noted at the time of exercise testing correlated significantly with peak exercise minute oxygen consumption (VO2) (r = 0.47, p < 0.01). In addition, the change in symptoms scores and change in peak VO2 noted between the baseline and final exercise test correlated significantly (r = 0.50, p < 0.01). However, patients reported few or no symptoms (symptom score < or =2) 45% of the time when peak VO2 was <14 ml/min/kg, consistent with a severe functional disability, and 72% of the time when peak VO2 was 14 to 18 ml/min/kg, consistent with moderate functional disability. CONCLUSIONS: Exertional symptoms reported by patients with heart failure generally correlate with maximal exercise capacity. However, exertional symptoms frequently underestimate the severity of functional disability. Cardiopulmonary exercise testing rather than symptoms should be used to assess functional capacity in heart failure.

Safety, tolerability and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil based formulation of cyclosporine--results at six months after transplantation.

BACKGROUND: The introduction of cyclosporine has resulted in significant improvement in the survival of cardiac allograft recipients due to decreased mortality from infection and rejection. The original oil-based cyclosporine formulation exhibits variable and unpredictable bioavailability that correlates with an increased incidence of acute and chronic rejection in those patients in whom this is most pronounced. The primary objectives of this prospective, multicenter, randomized, double-blind study in cardiac transplant patients were: to compare the efficacy of cyclosporine microemulsion (CsA-NL) with oil-based cyclosporine (CsA-SM) as measured by cardiac allograft and recipient survival and the incidence and severity of acute rejection episodes; and to assess the safety and tolerability of CsA-NL compared with CsA-SM in this population. This report represents the analysis of results 6 months after transplantation. METHODS: A total of 380 patients undergoing their first cardiac transplant at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial examining the safety and efficacy of CsA-NL versus CsA-SM. Rejection was diagnosed using endomyocardial biopsy and were graded according to standardized criteria of the International Society of Heart and Lung Transplantation (ISHLT). Clinical parameters were monitored during the study. Survival and freedom from were used for analysis as was Fisher's exact test for comparisons between groups. RESULTS: At 6 months after transplantation, allograft and patient survival were the same for both groups. The frequency of ISHLT grade 3A or greater episodes in the two groups was identical. Fewer CsA-NL patients (5.9%) required antilymphocyte antibody (ATG or OKT-3) therapy for rejection compared with the CsA-SM-treated patients (14.1%, P=0.01). Females with ISHLT rejection grade > or = 3A treated with CsA-NL had a 46% lower incidence of rejection compared with the CsA-SM-treated group (31.3% vs. 57.6%, P=0.032). Fewer infections were seen in the CsA-NL. With the exception of baseline and 1 week posttransplant creatinines which were higher in the CsA-NL group, the overall creatinine was not significantly different between the two groups. CONCLUSIONS: This multicenter, randomized study of cardiac transplant recipients documented less severe rejection (in particular those requiring antibody therapy) and a lower incidence of infection in CsA-NL-treated patients. Results from the female subgroup analysis suggest that the improved bioavailability of CsA-NL might reduce the frequency of rejection episodes in female patients. The use of CsA-NL was not associated with an increased risk of adverse events.

Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine--results at 24 months after transplantation.

BACKGROUND: The widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary end. points of the present, prospective, randomized multicenter, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade > or =3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation. METHODS: A total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fisher's exact test were used for comparisons between groups. RESULTS: After 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%, P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the CsA-SM group (18; 9.4%, P=0.037). The average corticosteroid dose was lower in the CsA-NL group (0.37 mg/kg/day) compared with the CsA-SM group (0.48 mg/kg/day, P=0.034) over the 24-month study period. Overall, there was no difference in blood pressure or creatinine between the two study groups. CONCLUSIONS: The final results of this multi-center, randomized study of two forms of cyclosporine confirmed that there were fewer episodes of rejection requiring antilymphocyte antibodies and fewer study discontinuations for treatment failures in CsA-NL-treated patients compared to those treated with CsA-SM. The use of CsA-NL did not predispose these patients to a higher risk of adverse events.

Selective enhancement of excitatory synaptic activity in the rat nucleus tractus solitarius by hypocretin 2.

Hypocretin 2 (orexin B) is a hypothalamic neuropeptide thought to be involved in regulating energy homeostasis, autonomic function, arousal, and sensory processing. Neural circuits in the caudal nucleus tractus solitarius (NTS) integrate viscerosensory inputs, and are therefore implicated in aspects of all these functions. We tested the hypothesis that hypocretin 2 modulates fast synaptic activity in caudal NTS areas that are generally associated with visceral sensation from cardiorespiratory and gastrointestinal systems. Hypocretin 2-immunoreactive fibers were observed throughout the caudal NTS. In whole-cell recordings from neurons in acute slices, hypocretin 2 depolarized 48% and hyperpolarized 10% of caudal NTS neurons, effects that were not observed when Cs(+) was used as the primary cation carrier. Hypocretin 2 also increased the amplitude of tractus solitarius-evoked excitatory postsynaptic currents (EPSCs) in 36% of neurons and significantly enhanced the frequency of spontaneous EPSCs in most (59%) neurons. Spontaneous inhibitory postsynaptic currents (IPSCs) were relatively unaffected by the peptide. The increase in EPSC frequency persisted in the presence of tetrodotoxin, suggesting a role for the peptide in regulating glutamate release in the NTS by acting at presynaptic terminals. These data suggest that hypocretin 2 modulates excitatory, but not inhibitory, synapses in caudal NTS neurons, including viscerosensory inputs. The selective nature of the effect supports the hypothesis that hypocretin 2 plays a role in modulating autonomic sensory signaling in the NTS.

Magnetic resonance coronary angiography in heart transplant recipients.

BACKGROUND: Annual coronary angiography is routinely performed to evaluate cardiac allografts. Recently, magnetic resonance coronary angiography has been used to imagine native coronary arteries, but its use in transplant recipients, with rapid heart rates, metallic sternal sutures, and altered cardiac orientation, has not been described. Our goal was to describe the feasibility of noninvasive magnetic resonance coronary angiography in cardiac allograft recipients, detect flow-limiting focal stenoses, and quantify the altered coronary artery orientation. METHODS AND RESULTS: We performed magnetic resonance coronary angiography is 18 adult heart transplant recipients (15 men and 3 women) with use of a breath-hold ECG-gated segmented k-space technique. Multiple transverse and oblique images were obtained in each subject. A control population of 16 adult patients without transplant and without angiographic evidence of coronary disease provided a reference for the coronary artery length visualized by magnetic resonance coronary angiography. This technique identified the left main coronary artery in 15 of 15 transplant recipients with normal coronary anatomy. Magnetic resonance coronary angiography demonstrated a +25-degree anterior (clockwise) right coronary artery ostial rotation in transplant recipients (p = 0.0001 versus control group) with corresponding realignment of the left main ostium. By magnetic resonance coronary angiography, the mean contiguous length of coronary artery visualized in the transplant recipients was similar to that in the control subjects for all major vessels (p = not significant). Five transplant recipients had nine discrete stenoses (50% or greater luminal diameter) identified by contrast angiography, of which seven stenoses were identified as signal voids by magnetic resonance coronary angiography. coronary stenoses not seen by this technique were located in the distal one third of the artery. CONCLUSIONS: These data confirm and for the first time quantify the previously observed anterior rotation of the coronary ostia, which may be used to guide coronary engagement for subsequent interventions. In addition, these data demonstrate the potential of magnetic resonance coronary angiography to image noninvasively the coronary arteries and identify focal stenoses in cardiac allograft recipients.

The effects of chronic lead exposure on reactivity to frustrative nonreward in rats.

Prior to straight runway training two groups of rats received lead exposure (500 ppm via the drinking water) for 106 days. Two additional groups of animals received access to plain tap water. An 80-trial runway acquisition phase followed an initial 60-day fluid exposure phase. During acquisition one lead-exposed group and one water-exposed group received 50% partial reinforcement training, while the remaining animals received continuous reinforcement training. An 80-trial extinction phase immediately followed acquisition. Acquisition results were characterized by superior performance by the continuous reinforcement animals. The partial reinforcement animals took significantly longer to extinguish the alleyway response than did the continuous reinforcement animals. Moreover, the lead-exposed, partial reinforcement animals took longer to extinguish in the goal section of the runway than did the water-exposed, partial reinforcement animals. Conversely, the lead-exposed, continuously reinforced animals displayed significantly more rapid goal-measure extinction than did the water-exposed, continuously reinforced animals. When interpreted by the classic frustration theory [1,2], these latter two findings are supportive of a heightened emotional reaction being promulgated by lead exposure.

Pulmonary artery catheterization: the right heart should not be left out--a case report.

Tricuspid valve stenosis in the setting of endocarditis is associated with a high morbidity. Diagnostic approaches incorporate a high clinical index of suspicion, echocardiographic evidence, and inferences about hemodynamic data derived from pulmonary artery catheterization. As demonstrated by the case presented herein, inadequate initial evaluation of right-sided pressures delayed the diagnosis and treatment of prosthetic tricuspid valve stenosis.

Left internal mammary artery graft retransplantation from the recipient to the donor heart: a case report.

A case of heart transplantation with concomitant coronary artery bypass graft is reported. The patient was an alternate transplant list candidate with a history of bilateral below-knee amputation and 2 previous myocardial revascularization procedures. The previously used and patent left internal mammary artery graft was successfully removed and retransplanted from the recipient to the donor heart.

Conditioning and retention of defensive burying as a function of the injection of a central cholinergic stimulant.

Two groups of rats received defensive-burying testing under the effects of saline or physostigmine injection. Saline-injected animals buried more during the first (drug-state) session than did the physostigmine-injected animals. Twenty-four hours later all Ss received a retention test under the nondrug condition. Ss originally tested under the physostigmine state buried more than the saline-injected animals did.

Utilization of odor cues as a function of reward-magnitude contrast and delay of reinforcement.

An experiment manipulating both reward-magnitude contrast and delay of reinforcement is reported. The results indicated that odor cues are produced under conditions of delayed large-reward versus nonreward contrast but not under large- versus small-reward contrast. Additional magnitude and delay manipulations that resulted in the elimination of odor-based double-alternation patterning in the straight runway are presented.

The interrelationships of ego strength, self-esteem, death anxiety, and gender in undergraduate college students.

The interrelationships of ego strength (Barron Ego Strength Scale), death anxiety (Death Anxiety Scale), and self-esteem (Texas Social Behavior Inventory) were studied in undergraduate university males (n = 20) and females (n = 59). Significant negative relationships between death anxiety and self-esteem and ego strength, and a significant positive relationship between self-esteem and ego strength were shown by both males and females. Moreover, males showed significantly higher self-esteem and ego strength scores, and significantly lower death anxiety scores than did females.

Shock-elicited aggression as a function of acute and chronic ethanol challenges.

In a test of competing hypotheses regarding the effects of alcohol on shock-elicited aggression, animals maintained on a food restricted regimen were administered either chronic or acute ethanol challenges. Chronic Ss showed a significantly higher rate of target-directed aggression and spent significantly more time in aggressive activity than did acute or saline control animals. Results support the proposed interactive effect of food restriction and extended periods of alcohol intake leading to increased aggression.

Taste preference of the adult rat as a function of prenatal exposure to ethanol.

Two groups of pregnant rats (n = 10) received exposure to either 10% ethanol or water. All male offspring (n = 43) received a six-day preference test (ethanol vs water) at 90 days of age. Fluid consumption scores indicated a significant preference for water by all Ss. However, those animals receiving prenatal ethanol exposure consumed significantly more ethanol during preference testing than did the animals receiving prenatal water exposure.

Shock-elicited aggression as a function of early ethanol exposure.

Upon reaching maturity the offspring (N = 88) of animals exposed during pregnancy to ethanol and plain water, respectively, served as Ss in a shock-elicited aggression test. Significantly higher levels of aggression were shown by those animals that had received prenatal ethanol exposure. Several ethanol-related birth effects were also noted.

Analyzing aversiveness of denatonium saccharide and quinine in rats.

Denatonium saccharide is reported to be the most bitter substance currently known. Two experiments comparing the suppressive capabilities of this compound and the more common bitter, quinine, are presented. Analysis indicated that rats preferred to consume denatonium rather than quinine when afforded a choice between the two. Exp. 2 also indicated that the pairing of quinine with vanilla and almond flavors resulted in subsequent refusal of these flavors. Pairing flavors with denatonium did not produce comparable refusals. Caution is expressed with regard to the use of denatonium saccharide as a rodent repellent.