Resistance exercise prevents glucocorticoid-induced myopathy in heart transplant recipients

During the winter 1991-92, 42 reindeer hinds of the Kaamanen Experimental Reindeer Herd in Finnish Lapland, naturally infected with various parasites, were allocated to 3 groups. One group was an untreated control group and the other 2 groups received either moxidectin or ivermectin at a dose of 200 micrograms kg-1 subcutaneously. The efficacy of treatment was followed with monthly faecal examinations for nematode eggs and counting of warbles, Hypoderma tarandi larvae, and throat bots, Cephenemyia trompe larvae, from live animals in spring. The efficacy of moxidectin against warbles (92.8%) and throat bots (70.8%) did not match that of ivermectin, which was 100% against both species. Both moxidectin and ivermectin were effective against gastrointestinal trichostrongylid egg production over the December to May trial period indicating good efficacy against adult and inhibited trichostrongylids. Only non-significant differences were seen in weight development and calf birth weights between the groups. Because of its only moderate insecticidal efficacy, moxidectin cannot be recommended as an endectocide in reindeer.     

Enhanced brain natriuretic peptide response to peak exercise in heart transplant recipients

We investigated the atrial (ANP) and brain natriuretic peptides (BNP), catecholamines, heart rate, and blood pressure responses to graded upright maximal cycling exercise of eight matched healthy subjects and cardiac-denervated heart transplant recipients (HTR). Baseline heart rate and diastolic blood pressure, together with ANP (15.2 +/- 3.7 vs. 4.4 +/- 0.8 pmol/l; P < 0.01) and BNP (14.3 +/- 2. 6 vs. 7.4 +/- 0.6 pmol/l; P < 0.01), were elevated in HTR, but catecholamine levels were similar in both groups. Peak exercise O2 uptake and heart rate were lower in HTR. Exercise-induced maximal ANP increase was similar in both groups (167 +/- 34 vs. 216 +/- 47%). Enhanced BNP increase was significant only in HTR (37 +/- 8 vs. 16 +/- 8%; P < 0.05). Similar norepinephrine but lower peak epinephrine levels were observed in HTR. ANP and heart rate changes from rest to 75% peak exercise were negatively correlated (r = -0.76, P < 0.05), and BNP increase was correlated with left ventricular mass index (r = 0.83, P < 0.01) after heart transplantation. Although ANP increase was not exaggerated, these data support the idea that the chronotropic limitation secondary to sinus node denervation might stimulate ANP release during early exercise in HTR. Furthermore, the BNP response to maximal exercise, which is related to the left ventricular mass index of HTR, is enhanced after heart transplantation.     

Chronotropic response to exercise. Improved performance of ST-segment depression criteria after adjustment for heart rate reserve

BACKGROUND: Heart rate (HR) response to exercise plays an important role in the diagnosis of coronary artery disease (CAD). Adjustment of ST-segment depression for the change in HR with exercise increases the accuracy of the exercise ECG in the detection of CAD. In addition, an attenuated HR response to exercise, a manifestation of chronotropic incompetence, may have independent diagnostic value for CAD. METHODS AND RESULTS: The diagnostic value of adjusting the magnitude of ST-segment depression, the ST-segment (ST)/HR index, and the ST/HR slope for chronotropic response to exercise was assessed in 283 control subjects and 337 patients with CAD by dividing each ST measurement by the fraction of HR reserve achieved. At a matched specificity of 96%, ST-segment depression of > 160 microV identified CAD with a sensitivity of 52%, an ST/HR index of > 1.69 microV/bpm identified CAD with a sensitivity of 90%, and an ST/HR slope of > 2.96 microV/bpm identified CAD with a sensitivity of 88%. Adjustment for HR reserve improved the sensitivity of each method: adjusted ST-segment depression of > 176 had a sensitivity of 87% (P < .0001), an adjusted ST/HR index of > 2.14 had a sensitivity of 94% (P = .005), and an adjusted ST/HR slope of > 3.47 had a sensitivity of 93% (P = .0001). In addition, the 94% and 93% sensitivities of the adjusted ST/HR index and ST/HR slope were significantly greater than the 87% sensitivity of adjusted ST-segment depression (P < .0001). CONCLUSIONS: Correction for an attenuated HR response to exercise improves performance of the simple and HR-adjusted ST-segment depression criteria for the identification of CAD. These findings support assessment of the degree of chronotropic reserve in routine evaluation of the exercise ECG.     

Cardiac function during graded bicycle exercise: Doppler-echocardiographic findings in normal subjects and heart transplant recipients

Orthotopic heart transplantation results in altered atrial anatomy and denervation of the donor heart. To assess the impact of these sequelae on left ventricular filling and systolic performance, 16 heart transplant recipients and 10 normal controls were evaluated by Doppler echocardiography at rest and during graded bicycle exercise. Global and regional systolic ventricular allograft function was normal at rest and during exercise. Resting Doppler profiles demonstrated diminished atrial contribution to ventricular filling in transplant recipients. The response to dynamic exercise was different in both groups; controls increased heart rate, while mitral time-velocity integral was unchanged. Heart transplant recipients, in contrast, showed a blunted heart rate response and increased time-velocity integral. Atrial contribution to ventricular filling was not augmented during exercise as in normal controls. Alterations in transmitral flow profiles in heart transplant recipients do not necessarily reflect ventricular myocardial damage, but may be related to impaired atrial function.     

The acute reversal of a diet-induced metabolic acidosis does not restore endurance capacity during high-intensity exercise in man

The present experiment was designed to investigate whether a diet-induced metabolic acidosis was a major factor in the earlier onset of fatigue during high-intensity exercise. Six healthy males cycled to exhaustion at a workload equivalent to 95 percent of maximum oxygen uptake on four separate occasions. Exercise tests were performed after an overnight fast and each test was preceded by one of four experimental conditions. Two experimental diets were designed, either to replicate each subject's own normal diet [N diet, mean (SD) daily energy intake (E) = 13 (0.7) MJ, 14.5 (0.8) percent protein (Pro), 37.5 (2.2) percent fat (Fat) and 47.5 (2.1) percent carbohydrate (CHO)], or a low-carbohydrate diet [E = 12.6 (0.8) MJ, 33.6 (1.3) percent Pro, 64.4 (1.5) percent Fat and 2.2 (0.4) percent CHO]. These diets were prepared and consumed within the department over a 3-day period. Over a 3-period prior to the exercise trial subjects ingested either NaHCO(3) or CaCO(3) (3.6 and 3.0 mmol*kg body mass), thus giving four experimental conditions: N diet and treatment, N diet and placebo, low-CHO diet and treatment and low-CHO diet and placebo. Treatments were assigned using a randomised protocol. Arterialised venous blood samples were taken for the determination of acid-base status and metabolite concentrations at rest prior to exercise and at intervals for 30 min following exhaustion. Consumption of the low-CHO diet induced a mild metabolic acidosis which was reversed by the ingestion of NaHCO(3). Blood pH, bicarbonate (HCO-(3)) and base excess (BE) were higher following NaHCO(3) ingestion after the normal diet than all of the other experimental conditions (P <0.01). Exercise time following the low-CHO diet was less than on the normal diet conditions (P <0.05): bicarbonate ingestion had no effect on exercise time on either of the diet conditions. Post-exercise blood pH, HCO-(3); and BE were higher following the ingestion of NaHCO(3) irrespective of the pre-exercise diet (P <0.05). Blood lactate concentration was higher 2 min after exercise following the N diet with NaHCO(3) when compared to the low-CHO diets with either NaHCO(3) or placebo (P <0.05). Plasma ammonia accumulation was not significantly different between experimental conditions. These data confirm previous data showing that the ingestion of a low-CHO diet reduces the capacity to perform high-intensity exercise, but it appears that the metabolic acidosis induced by the low-CHO diet is not the cause of the reduced exercise capacity observed during high-intensity exercise under these conditions.     

Metabolic myopathy as a cause of the exercise limitation in lung transplant recipients

BACKGROUND: Cardiopulmonary exercise (CPEx) studies of lung transplant (LTx) recipients have found low maximum oxygen consumptions because of an as yet unexplained mechanism. Although it is likely that a significant problem resides within the mitochondria, this study determines whether a defect in oxygen uptake or utilization is present. METHODS: Six LTx recipients and six age- and sex-matched, healthy control subjects were studied to assess the possibility of a mitochondrial myopathy in LTx recipients. We used standard CPEx testing in conjunction with near-infrared spectroscopy (NIRS), a noninvasive optical technique to assess peripheral oxygen uptake in exercising muscle. NIRS analyzes the absorption spectra of hemoglobin and myoglobin at 760 and 850 nm to determine the relative oxygen saturation of these compounds during exercise with respect to baseline values. Relative changes in oxygen saturation are determined from the application of Beers law to changes in absorbance to compute changes in optical density (deltaOD). The LTx recipients and control subjects performed maximal noninvasive CPEx studies with NIRS analysis of the vastus lateralis muscle. RESULTS: All subjects had a circulatory limitation to exercise. The LTx group had a significantly lower percent predicted maximum oxygen consumption than the control group (45.3%+/-14% vs 100.8%+/-15.6%, [mean +/- SD] P < .001) and earlier onset of the anaerobic threshold (30.3%+/-7.6% vs 60.3%+/-8.0% of predicted VO2max, P < .0001) The LTx recipients demonstrated a significantly smaller deltaOD at maximum exercise as determined by NIRS analysis (0.024+/-0.005 deltaOD vs 0.054+/-0.03 deltaOD, P < .05). CONCLUSIONS: LTx recipients have an impaired maximal exercise capacity because of a disorder of peripheral oxygen utilization. This may be caused by a cyclosporine-induced mitochondrial myopathy.     

Invasive electrophysiologic evaluation in octogenarians: is age a limiting factor?

To assess the indications, diagnostic yield, and incidence of complications of electrophysiologic testing in the elderly we reviewed our experience with 60 procedures in 45 patients aged > or = 80 years (range 80 to 92 years, mean age 83) undergoing full electrophysiologic evaluation in our laboratory over the past 7 years. The yield of inducible ventricular tachycardia (31%), supraventricular tachycardia (4%), and previously unsuspected conduction abnormalities significant enough to warrant permanent pacemaker implantation (9%), together with the low incidence of complications (1 patient had a deep venous thrombosis and femoral artery pseudoaneurysm, representing an incidence of 2.2% of patients undergoing studies or 3.3% incidence of complications per procedure), suggest that invasive electrophysiologic procedures in the elderly can provide useful information at a complication rate comparable with that of younger patients.     

Chlamydia pneumoniae infection is frequent but not associated with coronary arteriosclerosis in cardiac transplant recipients

We sought to explore the relation between Chlamydia pneumoniae, cytomegalovirus (CMV), and cardiac transplant-associated arteriosclerosis. Serologic evidence of past Chlamydia pneumoniae infection was investigated in 3 patient groups at the time of cardiac catheterization: cardiac transplant recipients (n=49), patients having coronary artery bypass grafting (CABG) (n=39), and a control group free of angiographic coronary artery disease (n=21). High Chlamydia pneumoniae immunoglobulin G titers (> or =1:160) were more frequently observed in cardiac transplant recipients (odds ratio[OR] 13.7; 95% confidence intervals [CI] 1.6 to 117.4, p <0.05) and CABG patients (OR 21.7; 95% CI 1.6 to 287.0, p <0.05) than in controls. However, high Chlamydia pneumoniae titers did not distinguish between cardiac transplant recipients with or without angiographic transplant-associated arteriosclerosis or CABG patients with or without bypass vein graft disease. Furthermore, there was no significant relation between elevated Chlamydia pneumoniae titers and the presence or progression of transplant-associated arteriosclerosis in the subgroup of patients who were also CMV positive. Yet, analysis of the same angiograms demonstrated an association between CMV infection and the recent progression of transplant-associated arteriosclerosis. Thus, patients with cardiac transplantation have evidence of past Chlamydia pneumoniae and CMV infection but Chlamydia pneumoniae does not appear to have an independent role or synergistic relation to CMV in the development of transplant-associated arteriosclerosis.     

CD4 lymphocytopenia as a risk factor for skin cancers in renal transplant recipients

BACKGROUND: Renal transplant recipients are at increased risk of developing skin cancer. It remains difficult to establish the actual influence of overimmunosuppression in the development of skin cancers. We investigated whether lymphocyte subset count may predict the risk of developing skin cancer in long-term renal transplant recipients. METHODS: One hundred fifty long-term renal transplant recipients were followed for a mean period of 26 months. Each patient was examined at least annually by a dermatologist. Lymphocyte subsets were measured annually. RESULTS: Fifteen patients exhibited skin cancers. Patients with and without skin cancer did not differ in age, gender, transplant duration, hemodialysis duration before transplantation, immunosuppressive regimen, and serum creatinine concentration. CD4 cell counts were significantly lower in patients with skin cancers (330+/-179/mm3 vs. 503+/-338/mm3; P<0.01), whereas total lymphocyte and CD8 and CD19 cell counts were similar between the two groups. CONCLUSIONS: CD4 cell depletion is associated with skin cancer in long-term renal transplant recipients.     

Effect of endurance exercise training on heart rate variability at rest in healthy young and older men

Heart rate variability (HRV) (SD of the RR interval), an index of parasympathetic tone, was measured at rest and during exercise in 13 healthy older men (age 60 to 82 years) and 11 healthy young men (age 24 to 32 years) before and after 6 months of aerobic exercise training. Before exercise training, the older subjects had a 47% lower HRV at rest compared with the young subjects (31 +/- 5 ms vs 58 +/- 4 ms, p = 0.0002). During peak exercise, the older subjects had less parasympathetic withdrawal than the young subjects (-45% vs -84%, p = 0.0001). Six months of intensive aerobic exercise training increased maximum oxygen consumption by 21% in the older group and 17% in the young group (analysis of variance: overall training effect, p = 0.0001; training effect in young vs old, p = NS). Training decreased the heart rate at rest in both the older (-9 beats/min) and the young groups (-5 beats/min, before vs after, p = 0.0001). Exercise training increased HRV at rest (p = 0.009) by 68% in the older subjects (31 +/- 5 ms to 52 +/- 8 ms) and by 17% in the young subjects (58 +/- 4 ms to 68 +/- 6 ms). Exercise training increases parasympathetic tone at rest in both the healthy older and young men, which may contribute to the reduction in mortality associated with regular exercise.     

ECG anomalies and axis deviations in heart transplant recipients: MRI studies]

Side effects of morphine are common when given in titrated doses to control severe pain in advanced cancer. We report a case series of acutely ill cancer patients suffering from pain, complications of advanced disease, and opioid side effects. They were treated with intravenous (i.v.) ketorolac along with i.v. morphine using repeated dosing. Excellent pain relief with improvement in the opioid bowel syndrome was achieved. We found it possible to switch from IV ketorolac to oral ketorolac along with oral morphine for long-term pain control. Ketorolac can be well tolerated in high-dose, long-term use even in this frail patient population. An algorithm is presented for the suggested use of ketorolac as a morphine sparing agent. Potential methods for studying ketorolac further in this role are discussed.     

Mitral inflow and pulmonary venous Doppler measurements do not predict pulmonary capillary wedge pressure in heart transplant recipients

We examined the spectrum of p53 mutations found in 40 UV-induced skin tumors of xeroderma pigmentosum group A gene (XPA)-deficient mice. p53 mutations were detected in 48% of the tumors. Nearly all of the mutations were induced at dipyrimidine sites. Ninety-three % of the mutations were G.C-->A.T transitions at dipyrimidine sites, including tandem transitions (CC-->TT), which are the hallmark of the UVB-induced mutation. Seventy-two % of the mutations at dipyrimidine sites could be ascribed to damage on the transcribed strand. In addition, no evident mutational hot spots were detected. This is in contrast to the UVB-induced skin tumors of normal mice, in which 92% of p53 mutations occurred as a result of DNA damage on the nontranscribed strand, and clear hot spots were observed. Thus, XPA-deficient mice showed significant mutation features that might be characteristic of the absence of nucleotide excision repair and may provide a good animal model for the analysis of the high incidence of skin cancer in xeroderma pigmentosum group A patients.     

Influence of heart rate, respiration and recipient atrial contraction on pulsed wave transmitral Doppler flow indices in orthotopic heart transplant recipients

Conformational features of charged dibucaine in [2H6]DMSO were elucidated by measuring 13C and 1H spin-lattice relaxation rates and 1H-(1H) and 13C-(1H) nuclear Overhauser effects. The reorientational correlation time of the aromatic moiety was evaluated at 0.16 ns at room temperature and side chains were observed to display segmental motion. Relevant distances were calculated by isolating dipolar interaction terms of 1H-1H or 13C-1H pairs. The 'preferred' conformation in solution was shown to present several analogies, but also some differences, with the structures obtained by solid state experiments, energy calculations and LIS data.     

Pneumocystis carinii infection in heart transplant recipients. Efficacy of a weekend prophylaxis schedule

The inhibitory effects of beta-carotene or vitamin A on preneoplastic lesions induced in rats were compared, when specifically administered during early promotion of hepatocarcinogenesis. Initiation was performed by diethylnitrosamine. During the selection/promotion period 2-acetylaminofluorene was administered, and a partial hepatectomy was performed. Afterwards, the rats were divided into 3 groups. To two groups, beta-carotene or vitamin A were given for five weeks. Another group served as control and received corn oil. At the end of the study, beta-carotene reduced the incidence and total number of hepatocyte nodules. Vitamin A rats exhibited a lower number of nodules, but the incidence was 100%. Moreover, beta-carotene reduced the total number of gamma GT-positive preneoplastic lesions, as well as the morphometric parameters of persistent gamma GT-positive lesions. In contrast, morphometric parameters of persistent lesions remained almost unaffected in vitamin A animals. Furthermore, beta-carotene significantly increased the number of remodeling gamma GT-positive preneoplastic lesions. Vitamin A administration, however, resulted only in a small increase in the number of remodeling lesions. These results suggest that the inhibitory effects of beta-carotene during early promotion of hepatocarcinogenesis can be attributed not only to an inhibitory effect on persistent lesions, but also to a striking stimulatory activity on remodeling gamma GT-positive lesions.     

FGF is a prospective competence factor for early activin-type signals in Xenopus mesoderm induction

Normal pattern formation during embryonic development requires the regulation of cellular competence to respond to inductive signals. In the Xenopus blastula, vegetal cells release mesoderm-inducing factors but themselves become endoderm, suggesting that vegetal cells may be prevented from expressing mesodermal genes in response to the signals that they secrete. We show here that addition of low levels of basic fibroblast growth factor (bFGF) induces the ectopic expression of the mesodermal markers Xbra, MyoD and muscle actin in vegetal explants, even though vegetal cells express low levels of the FGF receptor. Activin, a potent mesoderm-inducing agent in explanted ectoderm (animal explants), does not induce ectopic expression of these markers in vegetal explants. However, activin-type signaling is present in vegetal cells, since the vegetal expression of Mix.1 and goosecoid is inhibited by the truncated activin receptor. These results, together with the observation that FGF is required for mesoderm induction by activin, support our proposal that a maternal FGF acts at the equator as a competence factor, permitting equatorial cells to express mesoderm in response to an activin-type signal. The overlap of FGF and activin-type signaling is proposed to restrict mesoderm to the equatorial region.