Transamidase site-targeted agents alter the conformation of the transglutaminase cancer stem cell survival protein to reduce GTP binding activity and cancer stem cell survival.

Type 2 transglutaminase (TG2) is an important cancer stem cell survival protein that exists in open and closed conformations. The major intracellular form is the closed conformation that functions as a GTP-binding GTPase and is required for cancer stem cell survival. However, at a finite rate, TG2 transitions to an open conformation that exposes the transamidase catalytic site involved in protein-protein crosslinking. The activities are mutually exclusive, as the closed conformation has GTP binding/GTPase activity, and the open conformation transamidase activity. We recently showed that GTP binding, but not transamidase activity, is required for TG2-dependent cancer stem cell invasion, migration and tumour formation. However, we were surprised that transamidase site-specific inhibitors reduce cancer stem cell survival. We now show that compounds NC9, VA4 and VA5, which react exclusively at the TG2 transamidase site, inhibit both transamidase and GTP-binding activities. Transamidase activity is inhibited by direct inhibitor binding at the transamidase site, and GTP binding is blocked because inhibitor interaction at the transamidase site locks the protein in the extended/open conformation to disorganize/inactivate the GTP binding/GTPase site. These findings suggest that transamidase site-specific inhibitors can inhibit GTP binding/signalling by driving a conformation change that disorganizes the TG2 GTP binding to reduce TG2-dependent signalling, and that drugs designed to target this site may be potent anti-cancer agents.

The effect of coenzyme Q10 in patients with congestive heart failure.

BACKGROUND: Coenzyme Q10 is commonly used to treat congestive heart failure on the basis of data from several unblinded, subjective studies. Few randomized, blinded, controlled studies have evaluated objective measures of cardiac performance. OBJECTIVE: To determine the effect of coenzyme Q10 on peak oxygen consumption, exercise duration, and ejection fraction. DESIGN: Randomized, double-blind, controlled trial. SETTING: University and Veterans Affairs hospitals. PATIENTS: 55 patients who had congestive heart failure with New York Heart Association class III and IV symptoms, ejection fraction less than 40%, and peak oxygen consumption less than 17.0 mL/kg per minute (or <50% of predicted) during standard therapy were randomly assigned. Forty-six patients completed the study. INTERVENTION: Coenzyme Q10, 200 mg/d, or placebo. MEASUREMENTS: Left ventricular ejection fraction (measured by radionuclide ventriculography) and peak oxygen consumption and exercise duration (measured by a graded exercise evaluation using the Naughton protocol) with continuous metabolic monitoring. RESULTS: Although the mean (+/-SD) serum concentration of coenzyme Q10 increased from 0.95+/-0.62 microg/mL to 2.2+/-1.2 microg/mL in patients who received active treatment, ejection fraction, peak oxygen consumption, and exercise duration remained unchanged in both the coenzyme Q10 and placebo groups. CONCLUSION: Coenzyme Q10 does not affect ejection fraction, peak oxygen consumption, or exercise duration in patients with congestive heart failure receiving standard medical therapy.

Effects of BG9719 (CVT-124), an A1-adenosine receptor antagonist, and furosemide on glomerular filtration rate and natriuresis in patients with congestive heart failure.

OBJECTIVES: To determine the effects of furosemide and the selective A1 adenosine receptor BG9719 on renal function in patients with congestive heart failure (CHF). BACKGROUND: Studies suggest that adenosine may affect renal function by various mechanisms, but the effects of blockade of this system in humans is unknown. In addition, the effects of a therapeutic dose of furosemide on glomerular filtration rate (GFR) and renal plasma flow (RPF) in heart failure patients are controversial. METHODS: On different days, 12 patients received placebo, BG9719 and furosemide. Glomerular filtration rate, RPF and sodium and water excretion were assessed immediately following drug administration. RESULTS: Glomerular filtration rate was 84 +/- 23 ml/min/1.73m2 after receiving placebo, 82 +/- 24 following BG9719 administration and a decreased (p < 0.005) 63 +/- 18 following furosemide. Renal plasma flow was unchanged at 293 +/- 124 ml/min/1.73m2 on placebo, 334 +/- 155 after receiving BG9719 and 374 +/- 231 after receiving furosemide. Sodium excretion increased from 8 +/- 8 mEq following placebo administration to 37 +/- 26 mEq following BG9719 administration. In the six patients in whom it was measured, sodium excretion was 104 +/- 78 mEq following furosemide administration. CONCLUSIONS: Natriuresis is effectively induced by both furosemide and the adenosine A1 antagonist BG9719 in patients with CHF. Doses of the two drugs used in this study did not cause equivalent sodium and water excretion but only furosemide decreased GFR. These data suggest that adenosine is an important determinant of renal function in patients with heart failure.

Effects of exercise training on peak performance and quality of life in congestive heart failure patients.

BACKGROUND: Exercise programs for patients with heart failure have often enrolled and evaluated relatively healthy, young patients. They also have not measured the impact of exercise performance on daily activities and quality of life. METHODS AND RESULTS: We investigated the impact of a 6-month supervised and graded exercise program in 33 elderly patients with moderate to severe heart failure randomized to usual care or an exercise program. Six of 17 patients did not tolerate the exercise program. Of those who did, peak oxygen consumption increased by 2.4 +/- 2.8 mL/kg/min (P < .05) and 6-minute walk increased by 194 ft (P < .05). However, outpatient energy expenditure did not increase, as measured by either the doubly labeled water technique or Caltrac accelerometer. Perceived quality of life also did not improve, as measured by the Medical Outcomes Study, Functional Status Assessment, or Minnesota Living With Heart Failure questionnaires. CONCLUSION: Elderly patients with severe heart failure can safely exercise, with an improvement in peak exercise tolerance. However, not all patients will benefit, and daily energy expenditure and quality of life do not improve to the same extent as peak exercise.

A four-part regimen for clinical heart failure.

Combination therapy with a diuretic, digoxin, ACE inhibitor, and beta-blocker can help patients with heart failure caused by severe systolic dysfunction feel better and live longer. Especially with ACE inhibitors and beta-blockers, the key to success is starting at low doses and titrating carefully to proven target doses. The demanding complexity of the four-drug regimen is well worth the results.

Costing nursing education programs. It's as easy as 1-2-3.

Staff development departments are pressured to reveal the costs of their educational programs and to compete with outside vendors for programming. The process of implementing a spreadsheet template for costing out staff development programs is described. The template is easy to use and supports "what if" analysis. This model allows educators to evaluate cost implications of curricular decisions and to better negotiate with internal and external customers.

The effects of diuresis on the pharmacokinetics of the loop diuretics furosemide and torsemide in patients with heart failure.

PURPOSE: To evaluate the pharmacokinetics of furosemide and torsemide before and after diuresis in patients presenting with marked fluid overload. SUBJECTS AND METHODS: We studied 44 patients with New York Heart Association class III or IV heart failure, ejection fraction < or =40%, and an estimated excess fluid body weight > or =6.8 kg. Oral furosemide or torsemide was administered before and after diuresis. Pharmacokinetic parameters were assessed before and after diuresis. RESULTS: Following diuresis, maximum plasma concentration increased from 11.0+/-5.0 microg/mL to 13.9+/-6.8 with torsemide (P <0.05) and from 3.1< or =1.5 to 3.9+/-1.9 with furosemide (P=0.16). Maximum concentration increased by more than 30% in only one third of the patients. Total absorption (by area under the curve method) increased 6% among patients on torsemide (P=0.38) and 7% among patients on furosemide (P=0.63) and increased >30% in only 1 torsemide and 2 furosemide patients. The time to maximum concentration decreased from 1.40+/-.82 h to 0.81+/-0.36 with torsemide (P <0.01). There were no differences between furosemide and torsemide in the effects of edema on absorption. CONCLUSION: Marked diuresis altered the pharmacokinetics of both furosemide and torsemide in only a small percentage of patients. The use of adequate doses of oral diuretics in edematous patients may be successful, thereby permitting home treatment with oral diuretics and avoiding the cost of hospitalizations or home intravenous administration services.

Daily energy requirements in heart failure patients.

Diminished body cell mass in heart failure patients contributes to poor prognosis and decreased quality of life. The level of daily energy intake needed to maintain body cell mass and optimal physiological function in heart failure patients is unknown. Thus, we examined daily energy expenditure in free-living heart failure patients to estimate daily energy requirements. Daily energy expenditure (doubly labeled water) and its components (resting and physical activity energy expenditures) were measured in 26 heart failure patients (25 men and one woman aged 69 +/- 7 years) and 50 healthy controls (48 men and two women aged 69 +/- 6 years). Resting energy expenditure was measured by indirect calorimetry; physical activity energy expenditure from the difference between daily and resting energy expenditure; body composition by dual-energy x-ray absorptiometry; leisure time physical activity from a questionnaire; and peak oxygen consumption ([peak VO2] n = 16 heart failure patients) from a treadmill test to exhaustion. Plasma markers of nutritional status were also considered. Daily energy expenditure was 17% lower (2,110 +/- 500 v 2,543 +/- 449 kcal/d) and physical activity energy expenditure 54% lower (333 +/- 345 v 728 +/- 374 kcal/d) in heart failure patients compared with healthy controls. Daily energy expenditure was related to physical activity energy expenditure (r = .79, P < .01), resting energy expenditure (r = .63, P < .01), leisure time physical activity (r = .63, P < .01), and peak VO2 (r = .58, P < .01) in heart failure patients. Stepwise regression analysis showed that daily energy requirements in heart failure patients were best estimated by a combination of resting energy expenditure and reported leisure time physical activity (total R2 = 61%; standard error of the estimate, +/- 333 kcal/d). Daily energy requirements predicted from equations derived in healthy elderly were inaccurate when applied to heart failure patients, deviating -10% to +30% from measured daily energy expenditure. We conclude that despite low levels of activity, markers of physical activity predicted daily energy needs in heart failure patients. We provide a new equation to estimate energy needs in free-living heart failure patients based on measurements of daily energy expenditure.

Skeletal muscle atrophy and peak oxygen consumption in heart failure.

We measured skeletal muscle mass and peak oxygen consumption (VO2) in 13 cachectic heart failure patients, 14 noncachectic patients, and in 52 healthy controls to examine skeletal muscle atrophy and its relation to low peak VO2 in heart failure patients. Our results show that skeletal muscle atrophy is associated with prior weight loss and is related to low peak VO2 in heart failure patients.

Plasma leptin concentrations and energy expenditure in heart failure patients.

Leptin, the protein encoded by the obese gene, is a newly described hormone implicated in the regulation of energy balance. To examine the possible role of leptin in the energy dysregulation that frequently accompanies chronic heart failure, we examined plasma leptin concentrations and energy expenditure in 18 heart failure patients (aged 71 +/- 6 years) and 46 healthy elderly controls (66 +/- 6 years). Plasma leptin concentrations were measured by radioimmunoassay, daily energy expenditure by doubly labeled water, and body composition by dual-energy x-ray absorptiometry. Fat mass was lower (P < .01) in heart failure patients compared with healthy controls, whereas fat-free mass did not differ between groups. Plasma leptin concentrations were not different between heart failure patients and healthy controls (5.1 +/- 4.2 v 6.8 +/- 4.4 pg/mL) and remained similar after statistical control for fat mass (6.0 +/- 3.1 v 7.1 +/- 3.2 pg/mL). Plasma leptin was related to fat mass in heart failure patients (r = .92, P < .01) and healthy controls (r = .69, P < .01). Free-living daily and physical-activity energy expenditures were lower (P < .01) in heart failure patients compared with healthy controls. Plasma leptin concentrations were related to both daily (r = .67, P < .01) and resting (r = .67, P < .01) energy expenditure in heart failure patients, but not in healthy controls (r = .09 and r = .33, respectively). In conclusion, we found an association between plasma leptin concentrations and energy expenditure in heart failure patients, but not in healthy controls. Thus, leptin may participate in the regulation of energy expenditure and body energy stores in heart failure patients.

Daily energy expenditure in free-living heart failure patients.

We examined the hypothesis that weight loss in heart failure patients is associated with elevated daily energy expenditure. Twelve cachectic patients [age = 73 +/- 6 yr; weight loss = 15 +/- 6 kg; body mass index (BMI) = 21 +/- 5 kg/m2], 13 noncachectic patients (age = 67 +/- 5 yr; BMI = 27 +/- 5 kg/m2), and 50 healthy elderly controls (age = 69 +/- 6 yr; BMI = 26 +/- 4 kg/m2) were studied. Daily energy expenditure and it components were measured using doubly labeled water and indirect calorimetry and body composition by dual-energy X-ray absorptiometry. Fat mass and fat-free mass were lower (P < 0.05) in cachectic patients compared with noncachectic patients and healthy controls. Daily energy expenditure was lower (P < 0.05) in cachectic patients (1,870 +/- 347 kcal/day) compared with noncachectic patients (2,349 +/- 545 kcal/day) and healthy controls (2,543 +/- 449 kcal/day). Differences in daily energy expenditure were primarily due to lower (P < 0.05) physical activity energy expenditure in cachectic (269 +/- 307 kcal/day) and noncachectic patients (416 +/- 361 kcal/day) compared with healthy controls (728 +/- 374 kcal/day). A lower (P < 0.05) resting energy expenditure was also noted in cachectic patients (1,414 +/- 210 kcal/day) compared with noncachectic patients (1,698 +/- 252 kcal/day) and healthy controls (1,561 +/- 223 kcal/day). These findings show that daily energy expenditure is not higher, but significantly lower, in cachectic heart failure patients due to lower physical activity and resting energy expenditure. These results argue against the hypothesis that an abnormally elevated daily energy expenditure is associated with weight loss in heart failure.

The acute hemodynamic effects of right ventricular septal pacing in patients with congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

To assess the hemodynamic effects of right ventricular septal pacing in patients with severe chronic heart failure, we studied 13 patients during intrinsic rhythm and with pacing in the VDD mode at atrioventricular delays of 100 to 200 ms. There was no improvement of any hemodynamic parameter measured with pacing, even in the subgroup of patients with prolonged PR intervals.

Therapeutic options in advanced heart failure.

Treatment of advanced heart failure is usually a challenge. The successful use of beta-blockers to alleviate mild to moderate symptoms of cardiac dysfunction suggests that even severe cases of heart failure may be reversible. Transplantation remains the only sure way to obtain a fully functional heart, but new medications, mechanical devices, and surgical procedures could eventually prove to be alternatives.

Energy expenditure and symptom severity in men with heart failure.

Our results demonstrate a graded increase in resting metabolic rate based on symptom severity as reflected in the New York Heart Association classification. This finding supports the hypothesis that clinical severity of illness corresponds to the magnitude of the increase in resting energy demands.

The impact of parental presence on parental anxiety and satisfaction.

Researchers used an experimental research design to vary the amount of parental presence during their children's anesthesia induction and recovery and measured the effect of parental presence on parental anxiety and satisfaction with care. The State-Trait Anxiety Inventory was used to assess parental anxiety. The researchers measured parents' blood pressures and pulse rates as a second measure of anxiety. They found no significant differences in parental anxiety between study groups (i.e., the parents attending during their children's anesthesia induction and recovery, the parents not attending) but observed significant differences between mothers and fathers. Overall satisfaction scores were high, with little variability and no significant differences between study groups. Parents and physicians and nursing staff members supported the practice of parental presence during children's anesthesia induction and immediate postoperative recovery period.

Inheritance of resistance to potyviruses in Phaseolus vulgaris L. IV. Inheritance, linkage relations, and environmental effects on systemic resistance to four potyviruses.

We have examined the genetics of systemic resistance in Phaseolus vulgaris to azuki bean mosaic virus (AzMV) and cowpea aphid-borne mosaic virus (CABMV) and the relationship of this resistance to a phenotypically similar resistance to watermelon mosaic virus (WMV) and soybean mosaic virus (SMV). In P. vulgaris cv 'Great Northern 1140' (GN1140), resistance to SMV and WMV has been attributed to the genes Smv and Wmv, respectively, which have been shown to segregate as a unit. Systemic resistance to AzMV is conferred by two incompletely dominant alleles, Azm1 and Azm2, at unlinked loci. At least three resistance alleles must be present at these two loci for systemic resistance to be expressed in the plant. Systemic resistance to CABMV in GN 1140 is conditioned by a dominant allele that has been designated Cam2. Under some environmental conditions, a recessive allele at an unlinked locus, cam3, also controls a resistant response to CABMV. Resistance to AzMV and CABMV does not assort independently from Wmv/Smv, but also does not consistently cosegregate, suggesting that perhaps in each case one of the factors involved in resistance is associated with Smv/Wmv.