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Can serum NT-proBNP detect changes of functional capacity in patients with chronic heart failure?

Recently, in a cross-sectional study, a correlation of moderate degree was documented between serum BNP (brain natriuretic peptide) and exercise capacity in patients with chronic heart failure (CHF). However, it remains unknown if BNP, which increases in response to high myocardial wall stress, is sufficiently sensitive for changes in exercise capacity during clinical follow-up. To elucidate this, 42 CHF patients were recruited and randomized into a training (T; 58 +/- 10 years; n = 14 NYHA II; n = 5 NYHA III) and a control group (CO; 54 +/- 9, n = 17 NYHA II; n = 6 NYHA III). T carried out 12 weeks of endurance training on a cycle ergometer (4 sessions per week, 45 min duration). Venous blood sampling and cycle ergometry with simultaneous gas exchange measurements were carried out prior to and after the experimental phase. Due to its superior stability during laboratory procedures, NTproBNP was determined instead of BNP. Both proteins are secreted in equimolar amounts and share an identical diagnostic meaning. In both groups, NT-proBNP decreased slightly (T: from 1092 +/- 980 to 805 +/- 724 pg x ml(-1); CO: from 1075 +/- 1068 to 857 +/- 1138 pg x ml(-1); T vs CO: p = 0.65). Anaerobic threshold (AT) as a measure of exercise capacity went up in T (from 0.96 +/- 0.17 to 1.10 +/- 0.22 l x min(-1)) but remained almost constant in CO (pre: 1.02 +/- 0.27; post: 1.00 +/- 0.27 l x min(-1); T vs CO: p < 0.001). The correlation between changes in NT-proBNP and changes in AT remained insignificant (r = 0.02, p = 0.89)-even if only T was considered (r = 0.09, p = 0.72). Improved exercise capacity in CHF patients due to 3 months of endurance training is not reflected in the course of NT-proBNP. These findings are inconsistent with a sufficient sensitivity of this parameter to detect changes in exercise capacity during clinical follow-up. Changes in NT-proBNP beyond its spontaneous variability are more likely to be detected following therapeutical interventions which aim more clearly at the myocardium. In determining alterations of functional capacity ergometric testing cannot be replaced by serial determinations of NT-proBNP.

Aged↗

Backward and forward walking use different patterns of phase-dependent modulation of cutaneous reflexes in humans.

1. The phase-dependent modulation of medium-latency (P2) (70-80 ms) responses in semitendinosus (ST), biceps femoris (BF), rectus femoris (RF), and tibialis anterior (TA) was studied with the use of low-intensity stimulation (2 times perception threshold) of the sural nerve. The shocks were given in a random order at 16 phases of the step cycle in 10 normal subjects during forward walking (FW) or backward walking (BW) on a treadmill. 2. All subjects exhibited P2 responses in all muscles studied both during BW and FW. The amplitude of the facilitatory P2 responses showed phase-dependent changes that could not have been predicted on the basis of the variations in background activity throughout the step cycle. 3. During FW, the P2 facilitatory responses in BF were large (with respect to the background activity) throughout the whole step cycle except for a short period near the end of the swing phase. In ST the responses were smaller and appeared primarily at the end of the stance phase and during the first part of the swing phase. During the second half of swing the P2 responses were basically suppressive. A modulation pattern similar to the one in ST was found in RF and TA, except that there was no reversal to suppressive responses in the swing phase in RF. Instead, a reduction in the amplitude of the facilitatory P2 responses occurred. 4. During BW, the modulation pattern recorded in the same subjects was different from the one seen during FW. Large facilitatory P2 responses were present in all muscles in middle and late swing. In the first half of stance the responses were most prominently seen in BF and RF. At the end of stance and/or at the onset of swing the facilitatory responses decreased in amplitude (BF and RF) or reversed to P2 suppressions (ST and TA). 5. We conclude that there are both facilitatory and suppressive pathways from the sural nerve to the leg muscles studied and that the balance of activity in these paths is phase dependent during both FW and BW. It is suggested that the phase-dependent modulation of P2 responses could largely rely on a central motor program. During BW the same motor program is used as during FW, but possibly running in reverse, thereby causing a shift both in the timing of the reflex reversal and in the periods of reflex suppression.

Adult↗

Interval training program optimization in highly trained endurance cyclists.

PURPOSE: The purpose of this study was to examine the influence of three different high-intensity interval training (HIT) regimens on endurance performance in highly trained endurance athletes. METHODS: Before, and after 2 and 4 wk of training, 38 cyclists and triathletes (mean +/- SD; age = 25 +/- 6 yr; mass = 75 +/- 7 kg; VO(2peak) = 64.5 +/- 5.2 mL x kg(-1) min(-1)) performed: 1) a progressive cycle test to measure peak oxygen consumption (VO(2peak)) and peak aerobic power output (PPO), 2) a time to exhaustion test (T(max)) at their VO(2peak) power output (P(max)), as well as 3) a 40-km time-trial (TT(40)). Subjects were matched and assigned to one of four training groups (G(2), N = 8, 8 x 60% T(max) at P(max), 1:2 work:recovery ratio; G(2), N = 9, 8 x 60% T(max) at P(max), recovery at 65% HR(max); G(3), N = 10, 12 x 30 s at 175% PPO, 4.5-min recovery; G(CON), N = 11). In addition to G(1), G(2), and G(3) performing HIT twice per week, all athletes maintained their regular low-intensity training throughout the experimental period. RESULTS: All HIT groups improved TT(40) performance (+4.4 to +5.8%) and PPO (+3.0 to +6.2%) significantly more than G(CON) (-0.9 to +1.1%; P < 0.05). Furthermore, G(1) (+5.4%) and G(2) (+8.1%) improved their VO(2peak) significantly more than G(CON) (+1.0%; P < 0.05). CONCLUSION: The present study has shown that when HIT incorporates P(max) as the interval intensity and 60% of T(max) as the interval duration, already highly trained cyclists can significantly improve their 40-km time trial performance. Moreover, the present data confirm prior research, in that repeated supramaximal HIT can significantly improve 40-km time trial performance.

Adult↗

Influence of test duration and event specificity on maximal accumulated oxygen deficit of high performance track cyclists.

This study examined the relationship between the time required to fully utilise the maximal accumulated oxygen deficit (MAOD) and event specificity of track cyclists. Twelve track endurance and 6 sprint high performance track cyclists performed four treatments of 70 s, 120 s, 300 s and 115% VO2max of maximal cycling on an air-braked ergometer. Peak blood lactate was measured immediately after each test with VO2 kinetics being assessed during the 115% VO2max time to exhaustion test. When the two cycling groups were combined there was no significant difference in the MAOD when assessed under the four different exercise durations. However, when the groups were analysed separately the following results were apparent: (1) the sprint cyclists achieved a significantly greater MAOD (66.9 +/- 2.2 ml.kg-1) compared to the track endurance cyclists (57.6 +/- 6.7 ml.kg-1) when a 70 s test duration was employed (2) even though the track endurance cyclists achieved their greatest MAOD during the 300 s test protocol (62.1 +/- 11.0 ml.kg-1), it was not significantly different to the MAOD's measured during the three other test durations and (3) the sprint cyclists recorded their greatest MAOD during the 70 s supramaximal test protocol (66.9 +/- 2.2 ml.kg-1). This was not significantly different to the 120 s test MAOD, but it was significantly higher than the MAOD values recorded during the 115% VO2max and 300 s test durations. There was no significant difference between the two groups in the peak post-exercise blood lactate concentrations for any of the tests and only the 70 s test produced a significant correlation between peak blood lactate and the MAOD. The VO2 kinetics (VO2 t1/2) of the sprinters was significantly slower than that of the track endurance cyclists (26.3 +/- 2.3 vs 23.9 +/- 2.8 s.). The findings of this study demonstrate that sprint cyclists can fully express their anaerobic capacity within an event specific 70 s all-out test and that these cyclists progressively decrease their anaerobic capacity during a 120 s, 115% VO2max (mean time = 210 s) or 300 s test, despite giving all-out efforts. Conversely, track endurance cyclists achieve their highest mean score during an event specific 300 s test and their lowest during a 70 s test. These findings have important implications when testing high performance cyclists for determination of MAOD, with the implication that it is necessary to assess MAOD under exercise conditions (i.e., duration, pacing) specific to the cyclist's chosen event.

Adolescent↗

Effect of blood haemoglobin concentration on V(O2,max) and cardiovascular function in lowlanders acclimatised to 5260 m.

The principal aim of this investigation was to determine the influence of blood haemoglobin concentration ([Hb]) on maximal exercise capacity and maximal O(2) consumption (V(O(2),max)) in healthy subjects acclimatised to high altitude. Secondarily, we examined the effects of [Hb] on the regulation of cardiac output (CO), blood pressure and muscular blood flow (LBF) during exercise. Eight Danish lowlanders (three females and five males; 24 +/- 0.6 years, mean +/- S.E.M.) performed submaximal and maximal exercise on a cycle ergometer after 9 weeks at an altitude of 5260 m (Mt Chacaltaya, Bolivia). This was done first with the high [Hb] resulting from acclimatisation and again 2-4 days later, 1 h after isovolaemic haemodilution with Dextran 70 to near sea level [Hb]. After measurements at maximal exercise while breathing air at each [Hb], subjects were switched to hyperoxia (55 % O(2) in N(2)) and the measurements were repeated, increasing the work rate as tolerated. Hyperoxia increased maximal power output and leg V(O(2),max), showing that breathing ambient air at 5260 m, V(O(2),max) is limited by the availability of O(2) rather than by muscular oxidative capacity. Altitude increased [Hb] by 36 % from 136 +/- 5 to 185 +/- 5 g l(-1) (P < 0.001), while haemodilution (replacing 1 l of blood with 1 l of 6 % Dextran) lowered [Hb] by 24 % to 142 +/- 6 g l(-1) (P < 0.001). Haemodilution had no effect on maximal pulmonary or leg V(O(2),max), or power output. Despite higher LBF, leg O(2) delivery was reduced and maximal V(O(2)) was thus maintained by higher O(2) extraction. While CO increased linearly with work rate irrespective of [Hb] or inspired oxygen fraction (F(I,O(2))), both LBF and leg vascular conductance were systematically higher when [Hb] was low. Close and significant relationships were seen between LBF (and CO) and both plasma noradrenaline and K(+) concentrations, independently of [Hb] and F(I,O(2)). In summary, under conditions where O(2) supply limits maximal exercise, the increase in [Hb] with altitude acclimatisation does not improve maximal exercise capacity or V(O(2),max), and does not alter peak CO. However, LBF and vascular conductance are higher at altitude when [Hb] is lowered to sea level values, with both relating closely to catecholamine and potassium concentrations. This suggests that the lack of effect of [Hb] on V(O(2),max) may involve reciprocal changes in LBF via local metabolic control of the muscle vasculature.

Acclimatization↗

Power output and muscle metabolism during and following recovery from 10 and 20 s of maximal sprint exercise in humans.

On two separate days eight male subjects performed a 10- or 20-s cycle ergometer sprint (randomized order) followed, after 2 min of recovery, by a 30-s sprint. Muscle biopsies were obtained from the vastus lateralis at rest, immediately after the first sprint and after the 2 min of recovery on both occasions. The anaerobic ATP turnover during the initial 10 s of sprint 1 was 129 +/- 12 mmol kg dry weight-1 and decreased to 63 +/- 10 mmol kg dry weight-1 between the 10th and 20th s of sprint 1. This was a result of a 300% decrease in the rate of phosphocreatine breakdown and a 35% decrease in the glycolytic rate. Despite this 51% reduction in anaerobic ATP turnover, the mean power between 10 and 20 s of sprint 1 was reduced by only 28%. During the same period, oxygen uptake increased from 1.30 +/- 0.15 to 2.40 +/- 0.23 L min-1, which partially compensated for the decreased anaerobic metabolism. Muscle pH decreased from 7.06 +/- 0.02 at rest to 6.94 +/- 0.02 after 10 s and 6.82 +/- 0.03 after 20 s of sprinting (for all changes P < 0.01). Muscle pH did not change following a 2-min recovery period after both the 10- and 20-s sprints, but phosphocreatine was resynthesized to 86 +/- 3 and 76 +/- 3% of the resting value, respectively (n.s. 10- vs. 20-s sprint). Following 2 min of recovery after the 10-s sprint subjects were able to reproduce peak but not mean power. Restoration of both mean and peak power following the 20-s sprint was 88% of sprint 1, and was lower compared with that after the 10-s sprint (P < 0.01). Total work during the second 30-s sprint after the 10- and the 20-s sprint was 19.3 +/- 0.6 and 17.8 +/- 0.5 kJ, respectively (P < 0.01). As oxygen uptake was the same during the 30-s sprints (2.95 +/- 0.15 and 3.02 +/- 0.16 L min-1), and (Phosphocreatine) before the sprint was similar, the lower work may be related to a reduced glycolytic ATP regeneration as a result of the higher muscle acidosis.

Acid-Base Equilibrium↗

Exercise gas transport determinants in elderly normotensive and hypertensive humans.

This study examined the effect of the phenylalkylamine calcium channel blocker verapamil, on resting left ventricular (LV) function and O2 uptake rate (VO2) during exercise at maximal and submaximal work rates. Nine older hypertensive (71 years; OH), 10 older sedentary normotensive (69 years; OS), 10 older active (71 years; OA) and 10 young (24 years; Y) individuals volunteered. Studies were completed in the control condition and 4-6 h following 240 mg verapamil SR per os. Resting LV systolic (fractional shortening; FS) and diastolic (early: late (E/A) flow velocity ratio and isovolumic relaxation time (IVRT) were measured by Doppler echocardiography. Maximal oxygen uptake (VO2,max) and, on subsequent test days, four transitions to and from a 6 min square wave exercise perturbation at a sub-anaerobic threshold intensity of 40 W (OH, OS, OA) or 100 W (Y) for determination of VO2 kinetics were performed on a cycle ergometer. Breath-by-breath VO2 transients were fitted with a monoexponential equation, starting at phase 2 of the response, while heart rate (HR) was fitted from phase 1, for the determination of the time constant of VO2 (tau VO2) and HR (tau HR). Baseline left ventricular FS was significantly greater in the OS (32%), OA (34%) and Y (34%) than in the OH (23%) groups, while E/A was significantly greater in the OA (1.16) and Y (2.34) than in the OH (0.9) and OS (0.82) groups (P < 0.05). Baseline VO2,max was higher and tau VO2 faster in the young (41.4 ml kg-1 min-1; 25.2 s) than in the older groups and in the OA (28.8 ml kg-1 min-1; 44.3 s) than in both OH (20.8 ml kg-1 min-1; 71.3 s) and OS (22.0 ml kg-1 min-1; 59.5 s) groups (P < 0.05). Heart rate kinetics showed similar differences to VO2 kinetics among the groups. After verapamil, no significant changes in FS, E/A or IVRT were observed in the OA and Y groups. In the OH group, FS (32%) and E/A (1.15) increased while IVRT decreased significantly (from 0.103 to 0.07; P < 0.05). In the OS group, only E/A increased significantly (0.82 to 1.0; P < 0.05). None of the exercise variables (VO2,max, tau VO2 or tau HR) were altered for the OA or Y groups. VO2,max increased (from 20.8 to 22.8 ml kg-1 min-1) in the OH and (from 22.0 to 24.1 ml kg-1 min-1) in the OS (P < 0.05). tau VO2 was accelerated from 71.3 to 49.2 s in the OH group and from 59.5 to 48.2 s in the OS group (P < 0.05). These results suggest that VO2 responses at maximal and submaximal work rates may be dependent upon the initial cardiac pump function of the study population.

Adult↗

Resistance and aerobic exercise have similar effects on 24-h nutrient oxidation.

BACKGROUND: Whether resistance exercise is as effective as aerobic exercise for body-weight management is debated. PURPOSE: To compare 24-h energy expenditure (EE) and macronutrient oxidation elicited by comparable bouts of stationary cycling (BK) and weightlifting (WTS). METHODS: 24-h EE and macronutrient oxidation were measured in 10 nonobese male subjects on three occasions using whole-room indirect calorimetry. BK and WTS days were compared with a nonexercise control day (Con). RESULTS: During BK, subjects exercised for 49 +/- 7 min (mean +/- SEM) at 70% of OV(2max) and expended 546 +/- 16 kcal. During WTS, subjects performed a 70-min circuit consisting of four sets of 10 different exercises at 70% of exercise-specific 1-repetition maximum and expended 448 +/- 21 kcal (P < 0.001 vs BK). 24-h EE on BK and WTS days (2,787 +/- 76 kcal x d(-1), 2,730 +/- 106 kcal x d(-1), respectively, P > 0.05) was elevated compared with Con (2,260 +/- 96 kcal x d(-1), P < 0.001), but 24-h respiratory exchange ratio (RER) was not different. 24-h carbohydrate oxidation was significantly elevated on the exercise days (BK = 370 +/- 18 g x d(-1), WTS = 349 +/- 23 g x d(-1), P > 0.05) compared with Con (249 +/- 29 g x d(-1), P = 0.04). 24-h fat and protein oxidation were the same on BK, WTS, and Con days. EE and macronutrient oxidation in the periods after exercise also did not differ across conditions. CONCLUSION: In men, resistance exercise has a similar effect on 24-h EE and macronutrient oxidation as a comparable bout of aerobic exercise. Neither exercise produced an increase in 24-h fat oxidation above that observed on a nonexercise control day.

Adult↗

Oxygenation trends in vastus lateralis muscle during incremental and intense anaerobic cycle exercise in young men and women.

The purposes of this study were to compare the acute cardiorespiratory responses and muscle oxygenation trends during incremental cycle exercise to exhaustion with those observed during 30 s and 45 s Wingate tests in healthy men and women, and to examine the relationships between selected variables among these tests. Seventeen healthy junior badminton players, nine men [mean age, height, body mass and maximal oxygen uptake (VO2max) were 15.8 (SD 0.8) years, 1.73 (SD 0.08) m, 65.6 (SD 6.3) kg and 50.6 (SD 6.9) ml x kg(-1) x min(-1) respectively] and eight women [mean age, height, body mass and VO2max were 16.6 (SD 1.0) years, 1.65 (SD 0.03) m, 62.7 (SD 4.5) kg and 42.0 (SD 5.0) ml x kg(-1) x min(-1) respectively] completed a stepwise incremental exercise test to voluntary exhaustion and two Wingate tests lasting 30 s and 45 s in three separate sessions in random order. Cardiorespiratory responses were monitored breath-by-breath using a metabolic cart interfaced with an electrocardiogram. Tissue absorbancy trends were continuously recorded from the right vastus lateralis muscle using dual wavelength near infrared spectroscopy. Oxygen uptake and heart rate were significantly higher during the incremental test when compared to the two Wingate tests in the men and women. However, the oxygen pulse (oxygen utilization per heart beat, i.e., the product of stroke volume and arterio-venous oxygen difference) was not significantly different among the three tests in both sexes. The minimal tissue absorbancy, an index of muscle deoxygenation, was also not significantly different among the three tests in both sexes. Significant relationships were observed for the oxygen uptake (r2=0.72) and oxygen pulse (r2=0.60) between the incremental and 45 s Wingate tests in the sample for both sexes combined. The minimal tissue absorbancy, however, was not significantly related between the two tests. It was concluded that the significantly higher oxygen uptake during the incremental test was due to the higher heart rate because: firstly, oxygen pulse was not significantly different among the three tests, and secondly, peripheral factors, as indicated by the changes in muscle oxygenation, were not significantly different among the three test conditions. Although the peak values of the oxygen pulse during the incremental and 45 s Wingate tests were significantly correlated, the common variance of the minimal tissue absorbancy measurements between these two tests was quite low, suggesting considerable variation in the peripheral contribution during these two tests.

Adolescent↗

Across-channel masking and comodulation masking release.

These experiments on across-channel masking (ACM) and comodulation masking release (CMR) were designed to extend the work of Grose and Hall [J. Acoust. Soc. Am. 85, 1276-1284 (1989)] on CMR. They investigated the effect of the temporal position of a brief 700-Hz signal relative to the modulation cycle of a 700-Hz masker 100% sinusoidally amplitude modulated (SAM) at a 10-Hz rate, which was either presented alone (reference masker) or formed part of a masker consisting of the 3rd to 11th harmonics of a 100-Hz fundamental. In the harmonic maskers, each harmonic was either SAM with the same 10-Hz modulator phase (comodulated masker) or with a shift in modulator phase of 90 degrees for each successive harmonic (phase-incoherent masker). When the signal was presented at the dips of the envelope of the 700-Hz component, the comodulated masker gave lower thresholds than the reference masker, while the phase-incoherent masker gave higher thresholds, i.e., a CMR was observed. No CMR was found when the signal was presented at the peaks of the envelope. In experiment 1, we replicated the experiment of Grose and Hall, but with an additional condition in which the 600- and 800-Hz components were removed from the masker, in order to investigate the role of within-channel masking effects. The results were similar to those of Grose and Hall. In experiment 2, the signal was added at the peaks of the envelope of the 700-Hz component, but in antiphase to the carrier of that component and at a level chosen to transform the peaks into dips. No CMR was found. Rather, performance was worse for both the comodulated and phase-incoherent maskers than for the reference masker. This was true even when the flanking components in the maskers were all remote in frequency from 700 Hz. In experiment 3, the masker components were all 50% SAM and the signal was added in antiphase at a dip of the envelope of the 700-Hz component, thus making the dip deeper. Performance was worse for the phase-incoherent than for the reference masker and was worse still for the comodulated masker. The results of all three experiments indicate strong ACM effects. CMR was found only when the signal was placed in the dips of the masker envelope and when it produced an increase in level relative to that in adjacent bands.

Adult↗

Chronoastrobiology: proposal, nine conferences, heliogeomagnetics, transyears, near-weeks, near-decades, phylogenetic and ontogenetic memories.

"Chronoastrobiology: are we at the threshold of a new science? Is there a critical mass for scientific research?" A simple photograph of the planet earth from outer space was one of the greatest contributions of space exploration. It drove home in a glance that human survival depends upon the wobbly dynamics in a thin and fragile skin of water and gas that covers a small globe in a mostly cold and vast universe. This image raised the stakes in understanding our place in that universe, in finding out where we came from and in choosing a path for survival. Since that landmark photograph was taken, new astronomical and biomedical information and growing computer power have been revealing that organic life, including human life, is and has been connected to invisible (non-photic) forces, in that vast universe in some surprising ways. Every cell in our body is bathed in an external and internal environment of fluctuating magnetism. It is becoming clear that the fluctuations are primarily caused by an intimate and systematic interplay between forces within the bowels of the earth--which the great physician and father of magnetism William Gilbert called a 'small magnet'--and the thermonuclear turbulence within the sun, an enormously larger magnet than the earth, acting upon organisms, which are minuscule magnets. It follows and is also increasingly apparent that these external fluctuations in magnetic fields can affect virtually every circuit in the biological machinery to a lesser or greater degree, depending both on the particular biological system and on the particular properties of the magnetic fluctuations. The development of high technology instruments and computer power, already used to visualize the human heart and brain, is furthermore making it obvious that there is a statistically predictable time structure to the fluctuations in the sun's thermonuclear turbulence and thus to its magnetic interactions with the earth's own magnetic field and hence a time structure to the magnetic fields in organisms. Likewise in humans, and in at least those other species that have been studied, computer power has enabled us to discover statistically defined endogenous physiological rhythms and further direct effects that are associated with these invisible geo- and heliomagnetic cycles. Thus, what once might have been dismissed as noise in both magnetic and physiological data does in fact have structure. And we may be at the threshold of understanding the biological and medical meaning and consequences of these patterns and biological-astronomical linkages as well. Structures in time are called chronomes; their mapping in us and around us is called chronomics. The scientific study of chronomes is chronobiology. And the scientific study of all aspects of biology related to the cosmos has been called astrobiology. Hence we may dub the new study of time structures in biology with regard to influences from cosmo- helio- and geomagnetic rhythms chronoastrobiology. It has, of course, been understood for centuries that the movements of the earth in relation to the sun produce seasonal and daily cycles in light energy and that these have had profound effects on the evolution of life. It is now emerging that rhythmic events generated from within the sun itself, as a large turbulent magnet in its own right, can have direct effects upon life on earth. Moreover, comparative studies of diverse species indicate that there have also been ancient evolutionary effects shaping the endogenous chronomic physiological characteristics of life. Thus the rhythms of the sun can affect us not only directly, but also indirectly through the chronomic patterns that solar magnetic rhythms have created within our physiology in the remote past. For example, we can document the direct exogenous effects of given specific solar wind events upon human blood pressure and heart rate. We also have evidence of endogenous internal rhythms in blood pressure and heart rate that are close to but not identical to the period length of rhythms in the solar wind. These were installed genetically by natural selection at some time in the distant geological past. This interpretive model of the data makes the prediction that the internal and external influences on heart rate and blood pressure can reinforce or cancel each other out at different times. A study of extensive clinical and physiological data shows that the interpretive model is robust and that internal and external effects are indeed augmentative at a statistically significant level. Chronoastrobiological studies are contributing to basic science--that is, our understanding is being expanded as we recognize heretofore unelaborated linkages of life to the complex dynamics of the sun, and even to heretofore unelaborated evolutionary phenomena. Once, one might have thought of solar storms as mere transient 'perturbations' to biology, with no lasting importance. Now we are on the brink of understanding that solar turbulences have played a role in shaping endogenous physiological chronomes. There is even documentation for correlations between solar magnetic cycles and psychological swings, eras of belligerence and of certain expressions of sacred or religious feelings. Chronoastrobiology can surely contribute to practical applications as well as to basic science. It can help develop refinements in our ability to live safely in outer space, where for example at the distance of the moon the magnetic influences of the sun will have an effect upon humans unshielded by the earth's native magnetic field. We should be better able to understand these influences as physiological and mechanical challenges, and to improve our estimations of the effects of exposure. Chronoastrobiology moreover holds great promise in broadening our perspectives and powers in medicine and public health right here upon the surface of the earth. Even the potential relevance of chronoastrobiology for practical environmental and agricultural challenges cannot be ruled out at this early stage in our understanding of the apparently ubiquitous effects of magnetism and hence perhaps of solar magnetism on life. The evidence already mentioned that fluctuations in solar magnetism can influence gross clinical phenomena such as rates of strokes and heart attacks, and related cardiovascular variables such as blood pressure and heart rate, should illustrate the point that the door is open to broad studies of clinical implications. The medical value of better understanding magnetic fluctuations as sources of variability in human physiology falls into several categories: 1) The design of improved analytical and experimental controls in medical research. Epidemiological analyses require that the multiple sources causing variability in physiological functions and clinical phenomena be identified and understood as thoroughly as possible, in order to estimate systematic alterations of any one variable. 2) Preventive medicine and the individual patients'care. There are no flat 'baselines', only reference chronomes. Magnetic fluctuations can be shown statistically to exacerbate health problems in some cases. The next step should be to determine whether vulnerable individuals can be identified by individual monitoring. Such vulnerable patients may then discover that they have the option to avoid circumstances associated with anxiety during solar storms, and/or pay special attention to their medication or other treatments. Prehabilitation by self-help can hopefully complement and eventually replace much costly rehabilitation. 3) Basic understanding of human physiological mechanisms. The chronomic organization of physiology implies a much more subtle dynamic integration of functions than is generally appreciated. All three categories of medical value in turn pertain to the challenges for space science of exploring and colonizing the solar system. The earth's native magnetic field acts like an enormous umbrella that offers considerable protection on the surface from harsh solar winds of charged particles and magnetic fluxes. The umbrella becomes weaker with distance from the earth and will offer little protection for humans, other animals, and plants in colonies on the surface of the moon or beyond. Thus it is important before more distant colonization is planned or implemented to better understand those magnetism-related biological- solar interactions that now can be studied conveniently on earth. (ABSTRACT TRUNCATED)

Chronobiology Phenomena↗

Correlation of acute and chronic defibrillation threshold with upper limit of vulnerability determined in normal sinus rhythm.

BACKGROUND: The upper limit of vulnerability (ULV) is the stimulus strength above which ventricular fibrillation cannot be induced, even when the stimulus occurs during the vulnerable period of the cardiac cycle. Determination of ULV using T-wave shocks during ventricular pacing has been shown to closely correlate with the defibrillation threshold (DFT) at ICD implantation. However, there are no data correlating ULV determined in sinus rhythm at ICD implantation, with DFT determined at implantation or during long-term follow-up. This is of clinical importance since ULV may be used to estimate DFT during ICD implantation, both during ventricular pacing or sinus rhythm. METHODS AND RESULTS: Twenty-one patients receiving a transvenous ICD system were studied prospectively. There were 16 males and 5 females, mean age 68 +/- 15 years, with mean ejection fraction 37.4 +/- 17.4%. All had structural heart disease. The ULV was defined as the lowest energy that did not induce ventricular fibrillation with shocks at 0, 20 and 40ms before the peak of the T-wave, using a step-down protocol. The initial energy tested was 15J and the lowest energy 2J. DFT was determined following a similar step-down protocol. The DFT was defined as the lowest energy that successfully defibrillated the ventricles. The linear correlation coefficient between ULV and DFT was r = 0.73 (p < 0.001). At implant, mean ULV was 9.2 +/- 5J, not statistically different from mean DFT 9.4 +/- 4J. ULV plus 5J successfully defibrillated 19 of 21 patients. During long-term follow-up of 10.1 +/- 1.8 months in eight patients, DFT was 8.8 +/- 5.8J, not significantly different than the DFT of 7.5 +/- 4.1J or ULV of 8.0 +/- 5.3 at implant. CONCLUSION: 1) When determined during normal sinus rhythm the ULV significantly correlates with DFT. 2) ULV testing might be used in lieu of standard DFT testing to confirm adequate lead placement thus minimizing or eliminating VF inductions, particularly in hemodynamically unstable patients. 3) Since ULV + 5J has a high probability of successful defibrillation in most patients, programming ICD first shock energy for VF at ULV + 5J may result in lower first shock energies compared to the standard methods of programming first shock energy at twice DFT. CONDENSED ABSTRACT: The purpose of this study was to determine if the upper limit of vulnerability (ULV) determined during normal sinus rhythm correlates with the defibrillation threshold (DFT), as has been previously shown when determined during ventricular pacing. The linear correlation coefficient between the ULV and DFT was r = 0.73 (p < 0.001). Mean ULV at implant was 9.2 +/- 5J, not statistically different from mean DFT of 0.4 +/- 4J. During long-term follow-up of 10.1 +/- 1.8 months in 8 patients, DFT was 8.75 +/- 8J, not significantly different than the DFT of 7.5 +/- 4.1J or ULV of 8.0 +/- 5.3 at implant. Shocks energies of ULV + 5J successfully defibrillated 19 of 21 patients at implant and 8 of 8 at follow-up. This study indicates that the ULV determined in normal sinus rhythm closely correlates with the DFT, and that ULV + 5J defibrillated most patients. ULV testing could be used to predict DFT and reduce or eliminate the need for DFT testing and VF induction. Programming ICD first shock energy for VF to ULV + 5J will result in lower energy than that used with standard DFT testing.

Aged↗

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗