Multidisciplinary structured lifestyle intervention reduces the estimated risk of cardiovascular morbidity and mortality.

BACKGROUND: Current guidelines for prevention and treatment of cardiovascular disease (CVD) emphasise the importance of a healthy lifestyle. However, successful lifestyle intervention is proving to be a challenge for healthcare professionals. OBJECTIVES: Evaluation of the effect of lifestyle intervention on cardiovascular risk factors, on reaching treatment targets and on the estimated risk of cardiovascular morbidity and mortality. METHODS: The effect of a six-month multidisciplinary structured lifestyle intervention programme was assessed in 186 patients with and without a history of CVD. RESULTS: Multidisciplinary structured lifestyle intervention reduced the estimated ten-year risk of cardiovascular morbidity and mortality. The relative risk reduction was similar in patients with and without a history of CVD, the absolute risk reduction was higher in patients with a history of CVD. In both groups blood pressure and body weight decreased, and the maximal work rate and maximal oxygen uptake increased significantly. Blood levels of total cholesterol and cholesterol/HDL ratio decreased significantly in patients with a history of CVD. In addition, target levels for blood pressure and physical fitness were more frequently reached in both patient groups. CONCLUSION: Multidisciplinary structured lifestyle intervention had beneficial effects on cardiovascular risk factors. Relative risk reduction was similar in patients with and without evidence of cardiovascular disease. Follow-up is needed to see how well these effects can be maintained.

Structural basis for recognition of the intron branch site RNA by splicing factor 1.

During spliceosome assembly, splicing factor 1 (SF1) specifically recognizes the intron branch point sequence (BPS) UACUAAC in the pre-mRNA transcripts. We show that the KH-QUA2 region of SF1 defines an enlarged KH (hn RNP K) fold which is necessary and sufficient for BPS binding. The 3' part of the BPS (UAAC), including the conserved branch point adenosine (underlined), is specifically recognized in a hydrophobic cleft formed by the Gly-Pro-Arg-Gly motif and the variable loop of the KH domain. The QUA2 region recognizes the 5' nucleotides of the BPS (ACU). The branch point adenosine acting as the nucleophile in the first biochemical step of splicing is deeply buried. BPS RNA recognition suggests how SF1 may facilitate subsequent formation of the prespliceosomal complex A.

SMN tudor domain structure and its interaction with the Sm proteins.

Spinal muscular atrophy (SMA) is a common motor neuron disease that results from mutations in the Survival of Motor Neuron (SMN) gene. The SMN protein plays a crucial role in the assembly of spliceosomal uridine-rich small nuclear ribonucleoprotein (U snRNP) complexes via binding to the spliceosomal Sm core proteins. SMN contains a central Tudor domain that facilitates the SMN-Sm protein interaction. A SMA-causing point mutation (E134K) within the SMN Tudor domain prevents Sm binding. Here, we have determined the three-dimensional structure of the Tudor domain of human SMN. The structure exhibits a conserved negatively charged surface that is shown to interact with the C-terminal Arg and Gly-rich tails of Sm proteins. The E134K mutation does not disrupt the Tudor structure but affects the charge distribution within this binding site. An intriguing structural similarity between the Tudor domain and the Sm proteins suggests the presence of an additional binding interface that resembles that in hetero-oligomeric complexes of Sm proteins. Our data provide a structural basis for a molecular defect underlying SMA.

Refinement of the protein backbone angle psi in NMR structure calculations.

Cross-correlated relaxation rates involving the Calpha-Halpha dipolar interaction and the carbonyl (C') chemical shift anisotropy (CSA) have been measured using two complementary 3D experiments. We show that the protein backbone angle psi can be directly refined against such cross-correlated relaxation rates (gammaHalphaCalpha,C') and the three-bond H/D isotope effect on the Calpha chemical shifts (3 deltaCalpha(ND)). By simultaneously using both experimental parameters as restraints during NMR structure calculations, a unique value for the backbone angle psi is defined. We have applied the new refinement method to the alpha-Spectrin SH3 domain (a beta-sheet protein) and to the Sgs1p HRDC domain (an alpha-helical protein) and show that the quality of the NMR structures is substantially improved, judging from the atomic coordinate precision and the Ramachandran map. In addition, the psi-refined NMR structures of the SH3 domain deviate less from the 1.8 A crystal structure, suggesting an improved accuracy. The proposed refinement method can be used to significantly improve the quality of NMR structures and will be applicable to larger proteins.

Refined solution structure of the C-terminal DNA-binding domain of human immunovirus-1 integrase.

The structure of the C-terminal DNA-binding domain of human immunovirus-1 integrase has been refined using nuclear magnetic resonance spectroscopy. The protein is a dimer in solution and shows a well-defined dimer interface. The folding topology of the monomer consists of a five-stranded beta-barrel that resembles that of Src homology 3 domains. Compared with our previously reported structure, the structure is now defined far better. The final 42 structures display a back-bone root mean square deviation versus the average of 0.46 A. Correlation of the structure with recent mutagenesis studies suggests two possible models for DNA binding. Proteins 1999;36:556-564.

Circulatory response evoked by a 3 s bout of dynamic leg exercise in humans.

1. The mechanisms underlying the pronounced transient fall in arterial blood pressure evoked by a 3 s bout of bicycle exercise were investigated in twenty healthy young adults and four patients with hypoadrenergic orthostatic hypotension. 2. In healthy subjects a 3 s bout of upright cycling induced a 28 +/- 3 mmHg fall in mean arterial pressure at 12 s. The fall in mean arterial pressure was preceded by a 12 +/- 2 mmHg rise in right atrial pressure at 3 s and accompanied by a 54 +/- 7% increase in left ventricle stroke volume at 6 s. Systemic vascular resistance dropped 48 +/- 2% at 7 s after the start of the manoeuvre to remain at that level for approximately 5 s. The total response lasted about 20 s. During sustained upright cycling the initial fall in mean arterial pressure was also present, but less pronounced (17 +/- 2 vs. 26 +/- 3 mmHg). A 3 s bout of supine cycling in four patients with hypoadrenergic orthostatic hypotension also elicited a pronounced fall in mean arterial pressure (22 +/- 4 mmHg) and in systemic vascular resistance (38 +/- 4%). 3. A bout of exercise with a large muscle mass induces two main effects. First, it mechanically increases filling of the heart due to activation of the muscle pump, resulting in an increase in cardiac output. Second, it induces a drop in systemic vascular resistance. The increase in cardiac output is not sufficient to compensate fully for the pronounced fall in systemic vascular resistance and the result is a transient fall in arterial pressure at the onset of whole-body exercise. The rise in right atrial pressure evoked by 3 s cycling is abrupt and large, but the almost immediate onset and rapid fall of the systemic vascular resistance is too fast for sympathetically mediated reflex effects due to stimulation of the cardiopulmonary afferents. An important factor involved in the drop in systemic vascular resistance appears to be local, non-autonomically mediated vasodilatation in exercising muscles, since it also occurs in patients with autonomic failure.

Excimer laser coronary angioplasty in The Netherlands: preamble for a randomized study.

The immediate outcome of ELCA by XeCl excimer laser radiation is described in 53 patients who were selected to undergo ELCA from December 1990 to September 1991 in two centers that are currently performing ELCA in the Netherlands. Immediate success rates on the basis of visual assessment of the angiogram were as follows. Laser success (> 20% reduction of diameter stenosis after ELCA alone) was observed in 77% of patients, procedural success (< 50% residual stenosis after ELCA with or without adjunctive balloon dilatation [PTCA]) in 91%, and clinical success (procedural success without clinical complications) in 83% of patients. Quantitative coronary angiography by automated contour detection was performed in 31 patients who underwent ELCA in the Thoraxcenter. The minimal luminal diameter (mean +/- SD) of the treated coronary segments increased from 0.77 +/- 0.41 mm to 1.24 +/- 0.25 mm after ELCA and further to 1.67 +/- 0.29 mm after adjunctive PTCA in 25 patients. The present experience is put in perspective of results initially reported by other centers and compared with data from multicenter registries of ELCA. Finally, a short description is given of the design of a prospective, randomized trial of ELCA versus conventional PTCA (AMRO trial).

Effect of force on ablation depth for a XeCl excimer laser beam delivered by an optical fiber in contact with arterial tissue under saline.

The effect of force applied to a 430 micron single fiber, delivering 60 pulses of 308 nm XeCl laser radiation at 20 Hz, on the ablation depth in porcine aortic tissue under saline has been investigated. Energy densities of 8, 15, 25, 28, 31, 37, and 45 mJ/mm2 were used. Force was applied by adding weights from 0 to 10 grams to the fiber. The fiber penetration was monitored by means of a position transducer. At 0 grams, the ablation depth increased linearly with incident energy density, but the fiber did not penetrate the tissue; with any weight added, the fiber penetrated the tissue at energy densities above 15 mJ/mm2. The fiber did not penetrate during the first several pulses, possibly due to gas trapped under the fiber. After these first pulses, a smooth linear advancement of the fiber began, which lasted until the pulse train stopped. The ablation depth increased with increasing energy densities and weights. This effect was largest above 25 mJ/mm2 where the ablation efficiencies (unit mm3/J), with weights added to the fiber, were substantially larger than values found in 308 nm ablation experiments described in the literature, which were conducted with either a focused laser beam or a fiber without additional force. The results imply that in 308 nm excimer laser angioplasty, force must be applied to the beam delivery catheter for efficient recanalization, and that experiments performed with a focused beam or without actual penetration of the fiber do not represent the situation encountered in excimer laser angioplasty.

Initial circulatory responses to changes in posture: influence of the angle and speed of tilt.

To assess if changes in the angle or speed of tilt could account for the differences between the initial (first 30 s) circulatory responses induced by active and passive changes in posture, as found in previous studies, we investigated the initial heart rate and blood pressure responses induced by stand up from supine and various head-up tilt manoeuvres in 12 healthy, male subjects. Comparison was made between 70 degrees head-up tilt in 3 s, 90 degrees head-up tilt also in 3 s and 70 degrees head-up tilt in 1.5 s, using an automatic pneumatic-driven tilt table with foot support. It was found that the initial heart rate and blood pressure responses induced by the three tilt manoeuvres were almost identical in time course and amplitude, but significantly different from those induced by stand up. The results of this study prove that regardless of the angle and speed of tilt, the initial circulatory responses induced by passive changes in posture are essentially different from the responses induced by active changes in posture.

Circulatory responses to stand up: discrimination between the effects of respiration, orthostasis and exercise.

The initial circulatory responses to an active change in posture (stand up from supine) were compared with the responses induced by a passive change in posture (head-up tilt) and a burst of muscular exercise on a bicycle ergometer (upright cycling) in order to differentiate between exercise- and orthostasis-induced effects. In eight subjects heart rate responses and in four subjects intra-arterial pressure transients were measured. In addition the effects of respiration on heart rate responses to the three manoeuvres were assessed. Both stand up and cycling induced almost superimposable and pronounced heart rate responses lasting for about 30 s. This contrasts with the more gradual increases following head-up tilt. Changing the respiratory phase during the performance of the manoeuvres exerted its effect on heart rate responses in the first 5 s only. Like stand up, cycling induced a transient blood pressure fall lasting for 30 s on average. As both manoeuvres were performed during inspiration the transients observed are not caused by involuntary Valsalva straining. In conclusion, the maximum and duration of the heart rate responses induced by stand up, cycling and head-up tilt are not influenced by respiratory activity. The initial fall in blood pressure following stand up is probably the result of the muscular effort of the manoeuvre and not due to the effects of orthostasis or Valsalva straining.

Angioplasty after laser perforation.

Perforation is the most important complication of laser angioplasty and leads to a decrease in success because the procedure has to be discontinued. In 3 patients we continued despite perforation and were able to stop extravasation with percutaneous transluminal angioplasty (PTA) and to finish the procedure with a good final result. From our experience we conclude that laser perforation is not an absolute indication to stop the procedure if PTA in the recanalized lumen is possible.

Initial blood pressure fall on stand up and exercise explained by changes in total peripheral resistance.

To elucidate the underlying mechanisms of the initial fall in blood pressure on standing upright from the supine position, we measured the beat-to-beat changes in intra-arterial pressure in eight healthy male subjects in response to standing. Changes in stroke volume, cardiac output, and total peripheral resistance were computed from the pressure waveform using a pulse contour method. To determine possible mechanisms for the changes observed on standing, similar measures were made on passive tilting and a brief (3-s) bout of cycle exercise. Standing elicited a transient 25% (23-mmHg) fall in mean blood pressure as a result of a 36% fall in total peripheral resistance. Head-up tilt elicited a gradual change in haemodynamic parameters, which reached plateau levels in 20-30 s. Cycling elicited a transient 17% (18-mmHg) fall in blood pressure and a 41% fall in total peripheral resistance. In addition, we measured right atrial and esophageal pressures in two subjects on standing and cycling and found a 10- to 15-mmHg rise in right atrial pressure without a corresponding change in esophageal pressure. This points to the cardiopulmonary reflex as the primary effector of peripheral vasodilation, but we cannot exclude the possibility that 1) local metabolic vasodilation and 2) central command-mediated cholinergic vasodilation contributed to the fall in vascular resistance.