A large population of galaxies 9 to 12 billion years back in the history of the Universe.

To understand the evolution of galaxies, we need to know as accurately as possible how many galaxies were present in the Universe at different epochs. Galaxies in the young Universe have hitherto mainly been identified using their expected optical colours, but this leaves open the possibility that a significant population remains undetected because their colours are the result of a complex mix of stars, gas, dust or active galactic nuclei. Here we report the results of a flux-limited I-band survey of galaxies at look-back times of 9 to 12 billion years. We find 970 galaxies with spectroscopic redshifts between 1.4 and 5. This population is 1.6 to 6.2 times larger than previous estimates, with the difference increasing towards brighter magnitudes. Strong ultraviolet continua (in the rest frame of the galaxies) indicate vigorous star formation rates of more than 10-100 solar masses per year. As a consequence, the cosmic star formation rate representing the volume-averaged production of stars is higher than previously measured at redshifts of 3 to 4.

alpha-adrenergic coronary vasoconstriction and myocardial ischemia in humans.

The use of quantitative coronary angiography, combined with Doppler and PET, has recently been directed at the study of alpha-adrenergic coronary vasomotion in humans. Confirming prior animal experiments, there is no evidence of alpha-adrenergic coronary constrictor tone at rest. Again confirming prior experiments, responses to alpha-adrenoceptor activation are augmented in the presence of coronary endothelial dysfunction and atherosclerosis, involving both alpha(1)- and alpha(2)-adrenoceptors in epicardial conduit arteries and microvessels. Such augmented alpha-adrenergic coronary constriction is observed during exercise and coronary interventions, and it is powerful enough to induce myocardial ischemia and limit myocardial function. Recent studies indicate a genetic determination of alpha(2)-adrenergic coronary constriction.

Impairment of the arterial baroreflex during symptomatic and silent myocardial ischemia in humans.

OBJECTIVES: The aim of this study was to assess whether transient episodes of symptomatic or silent myocardial ischemia after baroreceptor modulation of heart rate. BACKGROUND: Animal and human studies have shown that myocardial infarction is accompanied by an impairment of the baroreceptor influences on the sinus node. However, whether this also occurs during transient myocardial ischemia has never been documented. METHODS: In 12 patients undergoing coronary angiography, systolic blood pressure (intraarterial catheter) was reduced by an intravenous bolus of nitroglycerin during a spontaneous episode of transient chest pain and myocardial ischemia (ST segment depression on the electrocardiogram) and 30 min after recovery. The slope of the linear regression between the decrease in systolic blood pressure and the RR interval shortening was taken as the measure of baroreflex sensitivity. RESULTS: During ischemia, baroreflex sensitivity was 1.3 +/- 0.3 ms/mm Hg (mean +/- SEM), whereas after recovery it was markedly and significantly greater (2.6 +/- 0.5 ms/mm Hg, p < 0.01). Similar results were obtained in eight other patients who experienced a silent ischemic episode either spontaneously or during coronary angioplasty. The reduction in baroreflex sensitivity was similarly pronounced during inferior (10 patients) and anterior (10 patients) ischemia, and its magnitude showed little or no relation to the ischemia-dependent changes in blood pressure and heart rate. CONCLUSIONS: Transient myocardial ischemia is associated with marked baroreflex impairment. The impairment occurs even during symptomless ischemic episodes and is therefore not related to pain or to other nonspecific influences on the baroreflex.

Ticlopidine and aspirin pretreatment reduces coagulation and platelet activation during coronary dilation procedures.

OBJECTIVES: It is unknown whether a therapeutic combination of aspirin (ASA) and ticlopidine might effectively decrease activation of hemostasis. BACKGROUND: Percutaneous transluminal coronary angioplasty (PTCA), rotational atherectomy and stent implantation are procedures that fracture or ablate endothelium and plaque, a situation that activates hemostasis. METHODS: In 85 patients undergoing PTCA for a 77.8 +/- 1% stenosis, we measured markers of coagulation and platelet activation (thrombin-antithrombin complexes [TAT], prothrombin fragment 1 + 2 [F1 + 2] serotonin and the presence of circulating activated platelets reacting with monoclonal antibodies against glycoproteins exposed on platelet membranes). Blood samples were drawn from a peripheral vein and from the coronary ostium before the procedures. Both immediately and 10 min after angioplasty, and 10 min afterward, samples were collected from a probing catheter (0.018 in, [0.46 cm]) positioned beyond the stenosis. All patients were being treated with antianginal drugs and ASA, 250 mg/day. Seventy of them had taken ticlopidine, 250 mg, twice daily for < or = 1 day (< or = 24 h) (n = 28) or for > or = 3 days (> or = 72 h) (n = 42). Heparin (150 U/kg) was administered before angioplasty. Thirty patients underwent PTCA; 15 of them were not treated with ticlopidine and 15 were given ticlopidine (> or = 72 h). Thirty-five patients had stent implantation, 20 rotational atherectomy. RESULTS: Before and during the procedures, there was greater thrombin generation (expressed by higher TAT and F1 + 2 plasma levels) in patients not taking ticlopidine or taking it for < or = 24 h (p < 0.05). Platelet activation and plasma serotonin levels were also significantly higher in the no ticlopidine or < or = 24-h ticlopidine groups. CONCLUSIONS: The combined use of ticlopidine, ASA and heparin effectively controls activation of coagulation in patients with stable or unstable angina undergoing coronary dilation.

Postischemic left ventricular dysfunction is abolished by alpha-adrenergic blocking agents.

OBJECTIVES: We sought to evaluate the efficacy of alpha-adrenergic blocking agents in counteracting left ventricular (LV) dysfunction occurring after transient ischemia in humans. BACKGROUND: The mechanisms underlying postischemic LV dysfunction are largely unknown. METHODS: Percutaneous transluminal coronary angioplasty (PTCA) provides a clinical model of ischemia and reperfusion. In 50 patients undergoing coronary stenting for 77+/-5% stenosis, LV function was monitored by transesophageal echocardiography during and 30-min after PTCA. Fifteen minutes after stenting, 15 patients received 12 microg/kg body weight of the alpha-blocker phentolamine intracoronarily, 15 patients received 600 microg/kg of the alpha1-blocker urapidil intravenously, 10 patients received the combination of phentolamine and 1.2 mg of propranolol intracoronarily, and 10 patients received saline. RESULTS: Fifteen minutes after successful coronary dilation, significant contractile dysfunction occurred in previously ischemic and nonischemic myocardium. LV dysfunction was accompanied by an increase in coronary resistance and diffuse vasoconstriction. Alpha-blockers counteracted LV dysfunction and coronary resistance and the increase in vasoconstriction. Phentolamine and urapidil increased global LV shortening from 34+/-9% to 45+/-8% and to 49+/-8%, respectively (p < 0.05). After the administration of propranolol combined with phentolamine, LV dysfunction remained unchanged (34+/-6%), as in control subjects. CONCLUSIONS: LV dysfunction occurs after PTCA, as described in animal models after ischemia. Alpha-blockers abolished LV, macrocirculatory and microcirculatory dysfunction, whereas the alpha-blocker effect was prevented by combining alpha- and beta-blockers. The evidence of diffuse rather than regional dysfunction, together with the opposite effects of alpha- and beta-blockade, supports the hypothesis of neural mechanisms eliciting postischemic LV dysfunction.

Effects of altering the interval between the stimulus and the reflex response in the analysis of the baroreceptor control of the sinus and atrioventricular nodes in man.

Baroreceptor control of the sinus node may be determined by raising or lowering blood pressure with intravenous bolus injections of phenylephrine or glyceryl trinitrate and calculating the slope of the linear regression between the drug induced changes in systolic blood pressure and RR interval using shift 1 coupling--namely, coupling of each systolic blood pressure value with the interval of the following cardiac cycle. To assess whether shift 1 coupling provides the best linear fit and the highest regression slope nine subjects received phenylephrine and glyceryl trinitrate injections both during spontaneous sinus rhythm and during atrial pacing to evaluate baroreflex control of the sinus and of the atrioventricular node respectively. In regression analysis of the data, for each drug injection nine different shifts (from 0 to 8) were used to couple systolic blood pressure with RR or StQ intervals. When the mean results from all subjects were compared the use of shift 1 was equal or superior to the use of any other shift for both the RR and the StQ interval responses evoked by either phenylephrine or glyceryl trinitrate. In many instances, however, the shift that provided the highest correlation and regression coefficient was different from shift 1, and the use of these best individual shifts provided results considerably different from those obtained with the standard shift 1. It is concluded that in the regression analysis of baroreflex cardiac responses to vasoactive drugs the regular use of shift 1 does not invariably provide the best estimation of baroreflex sensitivity. This is better achieved by calculating the best shift in individual responses.

Modification of the baroreceptor control of atrio-ventricular conduction induced by digitalis in man.

Several studies in animals and in man have suggested that the inhibitory influence of baroreceptors on heart rate and peripheral circulation is enhanced by digitalis. Because the atrio-ventricular node represents a key site for the clinical action of digitalis we studied how baroreceptor control of atrio-ventricular conduction is modified by digitalis at therapeutical doses. In eight subjects heart rate was kept constant by atrial pacing to assess neural influences on atrio-ventricular conduction rate without the modifications caused by simultaneous changes in cardiac cycle length. Arterial baroreceptors were stimulated by increasing or reducing blood pressure (intra-arterial recording), via an iv bolus of phenylephrine or nitroglycerine. The baroreflex sensitivity was assessed in ms . mmHg-1 as the slope of the linear regressions relating the rise or fall in systolic blood pressure to the lengthening or shortening in St- (atrial stimulus artifact) Q interval (ECG recording). The study was performed before and 45 min after iv administration of digitalis (0.8 mg of Lanatoside C). Baroreflex sensitivity during baroreceptor stimulation was 2.9 +/- 1.1 ms . mmHg-1 (mean +/- SE) before digitalis, whereas after digitalis a significantly and markedly greater value of 5.6 +/- 1.5 ms . mmHg-1 was found. Baroreflex sensitivity during baroreceptor deactivation was 0.9 +/- 0.1 ms . mmHg-1 before digitalis, and was not significantly affected by the drug. Thus in man the baroreceptor control of atrio-ventricular conduction is strikingly potentiated by digitalis although this potentiation is only evident in the upper portion of the stimulus-response curve of the reflex.(ABSTRACT TRUNCATED AT 250 WORDS)

Clonidine and carotid baroreflex in essential hypertension.

Clonidine is believed to reduce blood pressure by a neural action and animal experiments suggest that this consists in potentiation of baroreflexes. In 16 patients with essential hypertension we studied the effects of alterations in carotid sinus baroreceptor activity (neck chamber technique) on arterial blood pressure (catheter measurements) and heart rate, before and after intravenous administration of 150 microgram and 300 microgram of clonidine. The magnitude of the reflex responses was assessed by the slope of the linear regressions relating applied increase and decrease in tissue pressure at the carotid sinus (and therefore applied decrease and increase in carotid sinus transmural pressure) and resulting changes in mean arterial pressure and R-R interval. Clonidine caused a marked reduction in mean arterial pressure (-26 +/- 3 mm Hg) and a slight but significant reduction in heart rate (-5 +/- 1 b/min). There was no evidence for a potentiation of the baroreceptor influence on blood pressure, although a slight potentiation of the baroreceptor influence on heart rate was observed in few instances. We conclude that in man clonidine can exert a pronounced hypotensive effect without potentiating baroreceptor influence on blood pressure. Therefore this mechanism does not play a prominent role in the clinical antihypertensive action of the drug.

Effects of isometric exercise on the carotid baroreflex in hypertensive subjects.

Previous studies indicate that arterial baroreceptor modulation of heart rate is drastically reduced during static or dynamic exercise. We have investigated whether this reduction also occurs with regard to blood pressure modulation by the baroreflex. The study was performed in 19 subjects with uncomplicated untreated essential hypertension in whom blood pressure was measured intraarterially, and R-R interval was obtained by an electrocardiogram. The carotid baroreceptors were stimulated by neck suction of 30 seconds' duration, and equal stimuli were applied at rest and during hand-grip exercise performed at 40% of the subjects' maximal strength. Baroreceptor stimulation at rest increased R-R interval and reduced blood pressure. During hand-grip, the R-R interval responses to the baroreceptor stimulus were diminished by 61%. In contrast, the blood pressure responses were not significantly altered. Similar results were obtained when two subgroups of subjects with a lesser or greater degree of hypertension were separately considered. Thus, the carotid baroreceptor influence on blood pressure is largely preserved during exercise in contrast to the carotid baroreceptor influence on the sinus node, which is markedly impaired.

Twenty-four-hour hemodynamic profile during treatment of essential hypertension by once-a-day nadolol.

The effect of nadolol (N) on 24-hour blood pressure (BP) and heart rate (HR) values and on their variability was examined in ambulant patients with essential hypertension, using the Oxford method to obtain continuous intraarterial recording and a computer to have a beat-to-beat analysis of the data. The recording was carried out without treatment and after 10 days' administration of N once daily by mouth (dose range: 80-320 mg). After N, 24-hour BP and HR were reduced by 17 +/- 3% and 27 +/- 4% respectively as compared to before N, the effect being similar for both systolic and diastolic BP. The hypertension and bradycardia were significantly more marked during the day than during the night, neither showing any attenuation in the hours furthest from the administration of the drug. During N, there was a reduction in the 24-hour variation coefficient for HR but the reduction was limited to the longer term component of this phenomenon, the moment-to-moment variations remaining unaffected. The long- and short-term variation coefficients for BP were not modified under N. These findings suggest that N once a day can reduce BP for 24 hours in ambulant hypertensive patients. The lack of alteration in variability of BP and moment-to-moment HR suggests that the hypotension is achieved without interfering with the mechanisms involved in cardiovascular homeostasis.

Effects of prazosin on autonomic control of circulation in essential hypertension.

Prazosin, an antihypertensive agent that reduces blood pressure (BP) mainly through a blockade of alpha-adrenergic receptors, may, in theory, affect sympathetic control of circulation to an extent that impairs circulatory hemeostasis. This possibility was studied in subjects with essential hypertension by examining the cardiovascular effects of several stimuli that induce a powerful and diversified activation of the sympathetic noradrenergic activity (dynamic and isometric exercise, cold exposure) and of stimuli that exert a powerful inhibitory influence upon the sympathetic nervous system (carotid baroreceptor reflex). Before and after 15 days of continuous administration of prazosin (2-5 mg), 3 times a day, measurements were made of BP (intraarterial catheter), heart rate, cardiac output (thermodilution), and peripheral resistance. Prazosin reduced mean arterial pressure (10%) and peripheral resistance (9%) at rest, and it did not affect heart rate and cardiac output. Neurally mediated changes in arterial pressure, cardiac output, and peripheral resistance during dynamic or isometric exercise and cold exposure were unaffected by the drug; also unaffected were the cardiovascular responses to increase and decrease in carotid baroreceptor activity obtained by varying carotid transmural pressure through a variable neck pressure chamber device. Thus, the hypotensive and vasodilating effect of prazosin in essential hypertension is not accompanied by an impaired response to neural excitation influences upon the cardiovascular system. Also, the inhibitory influences originating from the carotid baroreflex are unchanged. These data indicate that circulatory homeostasis is largely preserved during administration of prazosin at clinically effective doses.

Evaluation of an index of peripheral vascular resistance in human subjects.

Based on evidence in animal studies, an index of resistance in man has been evaluated. In 10 human subjects, ranging in age from 31 to 60 years, direct brachial arterial pressure was measured, and a computer program using linear regression calculated the index of resistance from the slope of the logarithm of the pressure versus time during the second half of diastole. Resistance was independently calculated from 20-s averages of pressure and cardiac output obtained by thermodilution. Resistance was varied by infusion of phenylephrine and nitroprusside. The values of the index of resistance were compared with independently calculated resistance by linear regression and correlation. The index of resistance was variably correlated with independently calculated resistance. However, when the comparison was limited to points with a model correlation coefficient greater than or equal to 0.98 (i.e. a good fit of a straight line to the logarithm of pressure versus time), the correlation of the index of resistance with calculated resistance approached or exceeded 0.9 in eight of 10 subjects. In the two subjects showing poor correlation of the index with calculated resistance, estimated compliance from the same model was much lower than in the other subjects. In the same two subjects pressure dependence of estimated compliance was much higher than in the other subjects, suggesting the presence of significant atherosclerosis. We concluded that the diastolic decay of pressure may be used to calculate a useful index of resistance, provided that a single exponential decay fits the observed diastolic waveform well, and arterial compliance is not significantly reduced by atherosclerosis.

The alpha-1 adrenergic blocking agent urapidil counteracts postrotational atherectomy "elastic recoil" where nitrates have failed.

Calcium antagonist pretreatment and intracoronary high doses of nitrates (9 mg of isosorbide dinitrate) do not counteract coronary vasoconstriction occurring after rotational atherectomy. In 30 patients undergoing Rotablator atherectomy, intracoronary injection of the alpha 1-sympathetic blocker urapidil abolished or prevented significant vasoconstriction occurring 15 minutes after the procedure despite repeated injections of nitrates.

Modification of arterial baroreflexes by captopril in essential hypertension.

Captopril lowers blood pressure without increasing heart rate and plasma norepinephrine, which suggests that this drug may potentiate arterial baroreflexes. In eight subjects with untreated essential hypertension, blood pressure was monitored intraarterially and the effects of baroreceptor stimulation or deactivation were assessed by measuring (1) the slopes of the relations between increase or reduction in systolic pressure (intravenous phenylephrine or nitroglycerin) and the resulting lengthening or shortening in R-R interval, and (2) the increase or decrease in mean arterial pressure induced by increasing and decreasing carotid transmural pressure (neck chamber). The measurements were made before and after a hypotensive oral dose of captopril (50 mg). Before captopril, the slopes of the R-R interval changes with increase and reduction in systolic pressure were 8 and 4 ms/mm Hg, respectively. The slopes of the mean arterial pressure changes with increase and reduction in carotid transmural pressure were 0.51 and 0.40 mm Hg, respectively. After captopril, the responses to baroreceptor stimulation were unaltered but those to baroreceptor deactivation were augmented. The pressor and heart rate responses to hand-grip and cold exposure were unchanged by captopril. Administration of captopril is accompanied by a baroreflex potentiation which involves the lower portion of the stimulus-response curve of the reflex. This phenomenon (which may originate at the afferent baroreceptor fibers or centrally) may avoid a reduction in the tonic baroreflex influence during captopril-induced hypotension, thus contributing to the hemodynamic effects of the drug.

Effect of aspirin and ticlopidine on plasma tissue factor levels in stable and unstable angina pectoris.

Patients with unstable angina have an increased activation of the coagulation system. Aspirin and ticlopidine given in combination may potentiate each other by the combination of different action mechanisms and may reduce the risk of coronary occlusion and clinical instability. Plasma tissue factor (TF) levels collected into the stenotic coronary artery may be an index of TF expression within the vasculature. In 160 patients undergoing angioplasty for a 81+/-5% coronary lesion, we measured TF in blood samples collected from a vein and from the coronary ostium. Immediately after and 10 minutes after the dilation procedures the samples were withdrawn also beyond the lesion. Heparin 150 U/kg was given as an anticoagulant. All patients were pretreated with 250 mg/day of aspirin. One hundred twenty patients were randomly assigned to receive 24, 48, or 72 hours of ticlopidine treatment (250 mg/twice daily). TF levels did not increase during angioplasty but there was a significantly higher TF expression in unstable than in stable patients, irrespective of the invasiveness of debulking procedures. When ticlopidine was given for 72 hours, TF levels were similar to normal laboratory values both in stable and unstable patients. This combined antiplatelet pretreatment may be of benefit in unstable angina patients, with a favorable cost/benefit ratio.

Ticlopidine and aspirin interactions.

The risk-benefit balance when aspirin is compared with aspirin combined with ticlopidine is being investigated in several multicentre trials (MUSIC and WEST II versus TASTE, MUST, and STARS respectively). Cardiologists follow one of two strategies. Some prefer a more aggressive antiplatelet regimen, disregarding the risk of neutropenia (0.7%) because they want to avoid lessening the therapeutic effect of vessel patency obtained with stent implantation. Others give only aspirin (a money saving approach) confident that IVUS inspection (an expensive approach) will allow an adequate evaluation of full stent expansion and lesion coverage, despite a more pronounced activation of the coagulation cascade. Our impression so far is that the combination of ticlopidine and aspirin has a more favourable risk-effect balance.

Acute profound thrombocytopenia after abciximab therapy during coronary angioplasty.

Since the extensive use of abciximab, a potent antiplatelet agent directed against GP IIb/IIIa platelet receptors, to prevent ischemic complications of percutaneous transluminal coronary angioplasty, few cases of thrombocytopenia have been observed. This paper reports a case of acute profound thrombocytopenia (platelet count: 800/mm3) occurring 16 h after abciximab therapy during coronary angioplasty. As thrombocytopenia occurrence is not predictable, platelet count should be evaluated periodically after drug administration. Mechanisms of this adverse effect remain unknown. Platelet transfusion results in a rapid and sustained improvement of platelet count, avoiding the occurrence of major hemorrhagic complications.

Calcium antagonists and neural control of circulation in essential hypertension.

Data from animals and from man suggest that calcium antagonists interfere with alpha-adrenergic receptors and that this mechanism may be responsible for some of the vasodilation induced by these drugs. However, alpha-adrenergic receptors play a primary role in baroreceptor regulation of the cardiovascular system and blood pressure homeostasis, which might therefore be adversely affected by calcium antagonist treatment. We addressed this question in 14 essential hypertensives studied before treatment, 1 h after 20 mg oral nitrendipine and 5-7 days after daily administration of 20 mg oral nitrendipine. Blood pressure was measured by an intra-arterial catheter, heart rate by an electrocardiogram, cardiac output by thermodilution and forearm blood flow by venous occlusion plethysmography. Total peripheral and forearm vascular resistances were calculated by dividing mean blood pressure by blood flow values. Plasma norepinephrine was also measured (high performance liquid chromatography) in blood taken from the right atrium. Compared with the pretreatment values, acute nitrendipine administration caused a fall in resting blood pressure, an increase in the resting heart rate and cardiac output, and a fall in resting peripheral and forearm vascular resistance. The resting hypotension and vasodilation were also evident during the prolonged nitrendipine administration, which was, however, accompanied by much less resting cardiac stimulation than that observed in the acute condition. Baroreceptor control of the heart rate (vasoactive drug method) was similar before and after acute and prolonged nitrendipine treatment. This was also the case for carotid baroreceptor control of blood pressure (neck chamber technique) and for control of forearm vascular resistance as exerted by receptors in the cardiopulmonary region (lower-body negative-pressure and passive leg-raising techniques).(ABSTRACT TRUNCATED AT 250 WORDS)