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Depth for dose calibration in high energy photon beams.

BACKGROUND AND PURPOSE: The normalisation depth for determination of output factors in photon fields has frequently been the depth of dose maximum. At high energies the contribution from contaminating electrons is significant at dose maximum and is critically dependent on the beam geometry parameters, which is why a larger depth should be preferred. MATERIALS AND METHODS: The effect of electron contamination was studied using a purging magnet to remove charged particles from the treatment head and a helium bag to minimise production between the head and the phantom. RESULTS: A depth of 10 cm was found to be beyond the range of the contaminating electrons for photon energies up to 20 MV (TPR(20)(10) = 0.772). However, at 50 MV (TPR(20)(10) = 0.810) contaminating electrons contribute 2-3% to the absorbed dose at 10 cm depth. CONCLUSIONS: 10 cm is recommended as both reference and normalisation depth for all megavoltage photon beam qualities, i.e. 60Co and X-rays from accelerators up to 50 MV.

Calibration↗

Intravenous calcitriol regresses myocardial hypertrophy in hemodialysis patients with secondary hyperparathyroidism.

To evaluate the response of circulating intact parathyroid hormone (iPTH) on myocardial hypertrophy in hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT), echocardiographic and neurohormonal assessments were performed over a 15-week period in 15 HD patients with SHPT before and after calcitriol treatment and 10 HD control patients with SHPT not receiving calcitriol therapy. We prospectively studied a group of 15 patients with significantly elevated iPTH levels (iPTH >450 pg/mL) receiving calcitriol (2 microg after dialysis twice weekly). Clinical assessment, medication status, and biochemical and hematological measurements were performed once a month. Throughout the study, calcium carbonate levels were modified to maintain serum phosphate levels at less than 6 mg/dL, but body weight, antihypertensive medication, and ultrafiltration dose remained constant. In patients treated with calcitriol, an adequate reduction of iPTH levels was found (1,112 +/- 694 v 741 +/- 644 pg/mL; P < 0.05) without changes in values of serum ionized calcium (iCa++), phosphate, or hematocrit. Blood pressure (BP), cardiac output (CO), and total peripheral resistance (TPR) did not significantly change. After 15 weeks of treatment with calcitriol, M-mode echocardiograms showed pronounced reductions in interventricular wall thickness (13.9 +/- 3.6 v 12.8 +/- 3.10 mm; P = 0.01), left ventricular posterior wall thickness (12.5 +/- 2.4 v 11.3 +/- 1.8 mm; P < 0.05), and left ventricle mass index (LVMi; 178 +/- 73 v 155 +/- 61 g/m2; P < 0.01). However, in control patients, these changes were not found after the treatment period. In addition, sequential measurements of neurohormonal mediator levels in patients receiving calcitriol showed that plasma renin (18.5 +/- 12.7 v 12.3 +/- 11.0 pg/mL; P = 0.007), angiotensin II (AT II; 79.7 +/- 48.6 v 47.2 +/- 45.7 pg/mL; P = 0.001), and atrial natriuretic peptide (ANP; 16.6 +/- 9.7 v 12.2 +/- 4.4 pg/mL; P = 0.03) levels significantly decreased, whereas antidiuretic hormone (ADH), epinephrine, and norepinephrine levels did not change significantly. The percent change in LVMi associated with calcitriol therapy had a strong correlation with the percent change in iPTH (r = 0.52; P < 0.05) and AT II (r = 0.47; P < 0.05) levels. We conclude that the partial correction of SHPT with intravenous calcitriol causes a regression in myocardial hypertrophy without biochemical or hemodynamic changes, such as heart rate, BP, and TPR. The changes in plasma levels of iPTH and, secondarily, plasma levels of neurohormones (especially AT II) after calcitriol therapy may have a key role in attenuating ventricular hypertrophy in SHPT.

Adult↗

Study of the peptide prebiotic synthesis in context of exobiological investigations on earth orbit.

Dry films of amino acids mixtures glycine+ tryptophan and tryptophan were exposed on the surface of "Mir" station. Similar films were irradiated by vacuum ultra violet (145 nm) and ultra violet (254 nm) in the laboratory experiments. Gly-Gly, Trp-Gly, Gly-Trp, Tpr-Trp and Trp-Trp-Trp were the main reaction products for the experimental mixture glycine + tryptophan and Tpr-Trp and Trp-Trp-Trp for tryptophan. The presence of Lunar soil both in flight and in laboratory experiments increases the reaction yield by 1.5-2.0 times. Therefore, the hypothesis concerning the possibility of safe delivery of peptides and amino acids required for the emergence of life and associated with mineral have got yet another approval.

Evolution, Molecular↗

Effect of cold face stimulation on cerebral blood flow in humans.

BACKGROUND AND PURPOSE: In humans, activation of the diving reflex by a cold stimulus to the face results in bradycardia, peripheral vasoconstriction and an increase in blood pressure. However, responses of the cerebral blood flow have not yet been evaluated. We undertook this study to assess the effect of cold face stimulation on the cerebral circulation in humans. METHODS: Seventeen healthy volunteers, aged 27+/-5 years were evaluated during application of a cold stimulus (0 degrees C) to the forehead for 60s. We continuously monitored mean arterial pressure (MAP), mean flow velocity (MFV) of the middle cerebral artery, cardiac output, skin blood flow, heart rate and end-tidal CO2. Total peripheral resistance (TPR) was calculated as MAP divided by cardiac output. Cerebrovascular resistance index (CVRi) was calculated as MAP divided by MFV. RESULTS: Cold face stimulation did not significantly affect cardiac output but resulted in significant decreases in heart rate and skin blood flow and an increase in MAP. MFV in the mid-cerebral artery showed a slight, but significant increase. The maximum increase in CVRi (14.2+/-11.4%) was significantly (P<0.01) less than the maximum increase in TPR (23.9+/-5.7%). End-tidal CO2 did not change significantly during the cold stimulation. CONCLUSIONS: In contrast to other sympathetic stimulations (e.g. lower body negative pressure), facial cooling results in an increase in cerebral blood flow. The amount of cerebral vasoconstriction was less than the amount of total peripheral vasoconstriction. These results suggest that although there is some constriction of the cerebral resistance vessels during cold face stimulation, cerebral perfusion was maintained, possibly by opposing parasympathetic activation.

Adult↗

[Hemodynamic effects of the induction of general anesthesia after low thoracic epidural anesthesia].

Sixteen ASA 1 or 2 patients scheduled for abdominal surgery were included in the study after they had given their informed consent. Thirty minutes after starting a low-thoracic epidural anaesthesia (median level of sensitivity loss: T5), the patients were randomly given an intravenous bolus injection of either thiopentone (4 mg.kg-1, n = 8) or etomidate (0.5 mg.-1, n = 8), associated with succinylcholine 1 mg.kg-1. One minute after induction of general anaesthesia, the patients were intubated and mechanically ventilated (V(T) 8 ml.kg-1, rate 12 c.min-1). Mean arterial blood pressure (MAP) (oscillometric method), cardiac output (CO) (transthoracic bioimpedance) and heart rate were recorded semi-continuously. Total peripheral resistances (TPR) were calculated using the formula TPR = (MA/CO)*80. There were no differences between the groups in patient age, height, weight, and cardiovascular consequences of epidural anaesthesia. After anaesthetic induction and before endotracheal intubation, there was a slight decrease in CO in both groups, without any change in MAP. After intubation, MAP increased in both groups through peripheral vasoconstriction, whereas CO did not increase further. A significant tachycardia was occurred only seen in the thiopentone group, before and after tracheal intubation. This study showed that thiopentone and etomidate were suitable drugs for anaesthetic induction in a patient under epidural blockade. However, the absence of tachycardia following etomidate may be beneficial in cardiac patients. The monitoring of cardiac output determinants during thiopentone and etomidate anaesthesia require further invasive investigations.

Adult↗

Abstract, closing summary, and table of contents for Laragh's 25 lessons in pathophysiology and 12 clinical pearls for treating hypertension.

These 25 lessons 1) review the roles of plasma renin levels for causing malignant and most essential hypertension and their related vascular injuries (heart attack, heart failure, kidney failure and stroke); 2) review how antihypertensive anti-R drugs that block renin activity (beta blockers, the first converting enzyme inhibitor from venom, and the first angiotensin receptor blocker) were used to reveal plasma renin involvement in the hypertension of medium and high renin patients and to show; 3) that the 30% with low renin essential hypertension do not respond to R drugs, are not prone to heart attack or stroke, and BP is corrected instead by the natriuretic anti-V drugs (diuretics, spironolactone, CCB, alpha blockers); 4) thus, all hypertensives can be divided into R patients who have too much renin vasoconstriction or V patients who instead have predominant sodium-volume mediation. Furthermore, all antihypertensive drug classes can be divided into R drugs that block the renin factor, or V drugs that reduce body sodium volume; 5) these findings document our conception of two biochemically and physiologically different final factors that sustain all BP in which the sodium-volume factor continuously sustains cardiac output and flow while plasma renin-angiotensin sets total peripheral resistance (TPR), which, within the Poiseuille Equation (BP = cardiac output [CO] x TPR) describes our [Na+-volume x renin-angiotensin vasoconstriction] model that supports all normotension or hypertension; 6) in this light, we designed a visit-by-visit method for treating untreated hypertensives using the ambient plasma renin level and BP responses to guide primary drug therapy against either the V or R factor; and 7) for also correcting nonresponders receiving multiple drugs where renin testing correctly guides addition or subtraction of drugs depending on whether the test indicates unresponsiveness due to a reactive sodium-volume excess, or to lack of effectiveness of an R drug in a V patient or of a V drug in an R patient, or from large reactive increases in renin that override the R drug, calling for strengthening the R and/or removing V drugs. This objective, biochemically based method results in effective longterm BP control of nearly all patients using fewer, but the correct drug(s) for each individual.

Antihypertensive Agents↗

Effects of N omega-nitro-L-arginine and N-acetyl-L-cysteine on the reversal of one-kidney, one-clip hypertension.

The present study evaluated whether nitric oxide (NO) synthesis blockade or potentiation (with N omega-nitro-L-arginine or N-acetyl-L-cysteine, respectively) modulates the systemic and renal responses to unclipping in anesthetized one-kidney, one-clip hypertensive rats (1K-1C). Cardiac output was measured by thermodilution. In time-control rats, mean arterial pressure (MAP) decreased from 197 +/- 8 mm Hg to 139 +/- 4 mm Hg 3 h after unclipping, and cardiac index (CI) decreased by 35%, with a transient rise in sodium and water excretion and no changes in total peripheral resistance (TPR), glomerular filtration rate (GFR), or renal plasma flow (RPF). Administration of N omega-nitro-L-arginine methyl ester (NAME, 10 micrograms/kg/ min) blunted the hypotensive (from 190 +/- 6 mm Hg to 157 +/- 3 mm Hg), diuretic and natriuretic responses and potentiated the decrease in CI (40%) observed after unclipping, whereas TPR increased by 103%. Also, in rats given NAME, GFR and RPF decreased by 20% and 45%, respectively, at the end of the experiment. The effect of N-acetyl-L-cysteine (NAC, 300 mg/kg), a sulfhydryl group donor that may protect NO from free radical destruction by forming an S-nitrosothiol compound, was also evaluated. NAC potentiated the depressor response to unclipping (from 180 +/- 5 mm Hg to 97 +/- 3 mm Hg), and GFR and RPF increased by 80% and 35%, respectively. These effects of NAC appear to be NO dependent, as they were blocked by simultaneous administration of NAME. However, no significant differences were observed among groups in cumulative excretion of sodium and water, demonstrating that the hemodynamic effects of NAME and NAC after unclipping are due to mechanisms other than renal excretory changes. The results of the present study indicate that the cardiovascular depressor effects of unclipping are modulated by endothelium-derived nitric oxide.

Acetylcysteine↗

Left ventricular geometric patterns and QT dispersion in untreated essential hypertension.

The spectrum of left ventricular adaptation to hypertension, different types of hypertrophy patterns, and QT dispersion in different types of hypertrophy was investigated in 107 patients with untreated essential hypertension and 30 age- and gender-matched normal adults studied by 12-derivation electrocardiogram (ECG), two-dimensional, and M-mode echocardiography. Left ventricular mass (LVM), body mass index, total peripheral resistance (TPR), relative wall thickness (RWT), and QT dispersion were found to be statistically significantly higher in the hypertension group (P < .001 for all). Among hypertensive patients, 41.1% had both normal LVM and RWT, here called normal left ventricle in hypertension; 10.3% had concentric hypertrophy with increased LVM and RWT; 14.95% had eccentric hypertrophy with increased LVM and normal RWT; and 32.7% had concentric remodeling with normal LVM and increased RWT. Echocardiographically derived cardiac index was higher in the concentric hypertrophy and eccentric hypertrophy patterns (P = .002 and P < .0001, respectively), whereas TPR was higher in the concentric hypertrophy and concentric remodeling patterns (P = .017 and .02, respectively). QT dispersion values were found to be increased in the hypertensive group (P = .001), whereas similar values were calculated for different types of hypertrophy patterns. We conclude that the more common types of ventricular adaptation to essential hypertension are eccentric hypertrophy and concentric remodeling. Concentric hypertrophy is found to be associated with both volume and pressure overload, whereas eccentric hypertrophy is associated with volume overload only and concentric remodeling is associated with pressure overload. But different left ventricular geometric patterns seem to have similar effects on QT dispersion.

Echocardiography↗

Two tetratricopeptide repeat proteins facilitate human aryl hydrocarbon receptor signalling in yeast.

A human aryl hydrocarbon (Ah) receptor signalling pathway was constructed in yeast and used to identify regulatory proteins that may be related to those present in mammalian cells. The sequence similarity of human hepatitis B protein X-associated protein 2 (XAP2) protein to yeast Cpr7 and Cns1 proteins suggested that these proteins might be involved in Ah receptor signalling in this model system. Ah receptor signalling from a lacZ reporter gene was reduced by approximately 60% in cells that lacked Cpr7. In vitro interaction experiments indicated that a Cpr7-GST fusion protein and Ah receptor formed a complex. Expression of Cpr7, Cns1 and the isolated tetratricopeptide repeat (TPR) region of Cpr7 from plasmids restored Ah receptor signalling function in the Cpr7-deficient strain. Thus, Cpr7 and Cns1 proteins facilitate the signalling of human Ah receptor expressed in yeast, perhaps in the same manner as the TPR-containing XAP2 protein and related chaperone proteins in mammalian cells.

Carrier Proteins↗

A model for the cytoplasmic trafficking of signalling proteins involving the hsp90-binding immunophilins and p50cdc37.

A number of transcription factors and protein kinases involved in signal transduction exist in heterocomplexes with the ubiquitous and essential protein chaperone hsp90. These signalling protein x hsp90 heterocomplexes are assembled by a multiprotein chaperone system comprising hsp90, hsp70, Hop, hsp40, and p23. In the case of transcription factors, the heterocomplexes with hsp90 also contain a high molecular weight immunophilin with tetratricopeptide repeat (TPR) motifs, such as FKBP52 or CyP-40. In the case of the protein kinases, the heterocomplexes contain p50cdc37. The immunophilins bind to a single TPR acceptor site on hsp90, and p50cdc37 binds to an adjacent site so that binding is exclusive for p50cdc37 or an immunophilin. Direct interaction of immunophilins with the transcription factors or p50cdc37 with the protein kinases leads to selection of different heterocomplexes after their assembly by a common mechanism. Studies with the glucocorticoid receptor, for which translocation from the cytoplasm to the nucleus is under hormonal control, suggest that dynamic assembly of the heterocomplexes is required for rapid movement of the receptor through the cytoplasm along cytoskeletal tracts. As for the similar short-range trafficking of vesicles along microtubules, there must be a mechanism for linking the signalling protein solutes to the molecular motors involved in movement. We present here a model in which the immunophilins and p50cdc37 target, respectively, the retrograde or anterograde direction of signalling protein movement by functioning as connectors that link the signalling proteins to the movement machinery.

Animals↗

Proton double quantum coherence and cross-relaxation in (NH4)2SnBr6.

A proton double quantum coherence signal can be observed exclusively from the T species NH4 groups (with the total spin I = 1) in ammonium compounds at low temperatures by the three-pulse sequence 90x degrees - tpr - 90x degrees - tev - 90x degrees - ta, where tpr and ta are of the magnitude of the inverse line width and tev very short. The usefulness of this pulse sequence, preceded by the additional pulse sequence 90x degrees - t1 -90(-x) degrees - t2 for creating an unbalance between the A and T species magnetizations, was demonstrated by applying it to cross-relaxation studies in (NH4)2SnBr6.

Magnetic Resonance Spectroscopy↗

Angioscopic video-assisted pulmonary endarterectomy for post-embolic pulmonary hypertension.

OBJECTIVES: To assess whether the use of video-assisted angioscopy would increase the outcome of pulmonary thromboendarterectomy (PTE). METHODS: PTE included a median sternotomy, intrapericardial dissection of the superior vena cava, institution of cardiopulmonary bypass, deep hypothermia and sequential circulatory arrest periods. It was always performed through two separate arteriotomies on both main intrapericardial pulmonary arteries, into which a rigid 5 mm angioscope connected to a video camera was introduced to increase the visibility and endarterectomies. RESULTS: From January 1996 to July 1998, 68 consecutive patients (35 males and 33 females) aged 54.3 +/- 13.5 years underwent PTE. Patients were in New York Heart Association (NYHA) class II (n = 2), III (n = 43) or IV (n = 23) with the following hemodynamics: mean pulmonary arterial pressure (PAP) 54 +/- 13 mmHg; cardiac output (CO): 3.8 +/- 0.8 l/min, and total pulmonary resistance (TPR): 1207 +/- 416 dyne x s x cm(-5). The cumulated circulatory arrest time was 23 +/- 12 min and postoperative length of ventilatory support 10 +/- 12 days. Nine patients died, for an overall in-hospital mortality of 13.2%. The functional outcome in surviving patients was significantly improved (P < 0.0001) both clinically (NYHA class 3.2 +/- 0.5 vs. 1.3 +/- 0.6) and hemodynamically (PAP (mmHg) 53.1 +/- 13 vs. 30.2 +/- 11.8, CI (l/min per m2) 2.1 +/- 0.5 vs. 2.8 +/- 0.6, TPR (dyne x s x cm(-5)) 1174 +/- 416 vs. 519 +/- 250). CONCLUSIONS: Video-assisted angioscopy improves the quality and degree of pulmonary endarterectomy expanding the indications to include patients with previously inaccessible distal disease.

Adult↗

Protein phosphatase 5 in signal transduction.

Protein phosphatase 5 (PP5) possesses unique biochemical properties, which include its tetratricopeptide repeat (TPR) targeting/regulatory domain and its ability to be activated by lipids. PP5 has been studied as a paradigm for TPR protein structure and function. Roles for PP5 in signal transduction are emerging: from cell cycle regulation and signaling by nuclear receptors, to possible regulation of membrane receptors and ion channels.

Animals↗

Effect of conivaptan, a combined vasopressin V(1a) and V(2) receptor antagonist, on vasopressin-induced cardiac and haemodynamic changes in anaesthetised dogs.

The neurohormonal factor arginine vasopressin (AVP) produces potent systemic vasoconstriction as well as water retention in the kidneys via the V(1a) and V(2) receptors, respectively. Therefore, AVP may be considered as an aggravating factor of cardiac failure. In the present study, the effects of intravenous (i.v.) infusion of AVP on cardiovascular parameters and the effect of conivaptan (YM087, 4'-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide monohydrochloride), a vasopressin V(1a)/V(2) receptor antagonist, on AVP-induced cardiac and haemodynamic changes were investigated in pentobarbitone-anaesthetised dogs. The i.v. infusion of AVP (0.12-4mUkg(-1)min(-1)) dose-dependently produced decreases in the cardiac contractility indicator LV dP/dt(max) and cardiac output (CO) and increases in left ventricular end-diastolic pressure (LVEDP) and total peripheral resistance (TPR). These changes accurately mimic the cardiovascular symptoms of congestive heart failure. The i.v. bolus injection of conivaptan (0.1mgkg(-1)) rapidly attenuated the AVP (4mUkg(-1)min(-1))-induced decrease in CO and reversed the AVP-induced elevation in both LVEDP and TPR. In conclusion, i.v. infusion of AVP produced cardiac dysfunction and vasoconstriction in pentobarbitone-anaesthetised dogs. Conivaptan demonstrated the ability to dramatically improve the impaired cardiovascular parameters induced by AVP. The results suggest the potential usefulness of conivaptan in treating congestive heart failure.

Anesthesia↗

Mucosal blood flow during various intravenous and inhalational anesthetics in the rabbit.

OBJECTIVE: The goal of this study was to compare the effects of nitrous oxide (N2O), isoflurane (ISO), fentanyl (FENT), and propofol (PROP) on the tongue mucosal blood flow (TMBF) in rabbits. STUDY DESIGN: TMBF was measured with a laser Doppler flow meter before and after the administration of 50% N2O (n = 7), 1.0 and 1.5 minimum alveolar concentration ISO (n = 6), 10, 20, and 40 micrograms/kg FENT (n = 8) or 100, 200 and 400 micrograms/kg/min PROP (n = 7). Hemodynamic variables including heart rate, systolic blood pressure (SBP), mean arterial pressure (MAP) and aortic blood flow (AoF) were continuously monitored. Total peripheral resistance (TPR) was calculated as MAP divided by AoF. RESULTS: An increase in TMBF along with reductions in SBP, MAP and TPR were observed in ISO group. In FENT group, TMBF was decreased, whereas other hemodynamic variables showed no change. TMBF in groups N2O and PROP did not change. CONCLUSION: These results indicate that TMBF depends on the anesthetic used.

Anesthetics, Inhalation↗

CHIP: a quality-control E3 ligase collaborating with molecular chaperones.

It is notable that both the chaperone and ubiquitin-proteasome systems are required for removal of aberrant cellular proteins to ensure protein homeostasis in cells. However, the entity that links the two systems had remained elusive. Carboxyl-terminus of Hsc70 interacting protein (CHIP), originally identified as a co-chaperone of Hsc70, has both a tetratricopeptide repeat (TPR) motif and a U-box domain. The TPR motif associates with Hsc70 and Hsp90, while the U-box domain executes a ubiquitin ligase activity. Thus, CHIP is an ideal molecule acting as a protein quality-control ubiquitin ligase that selectively leads abnormal proteins recognized by molecular chaperones to degradation by the proteasome. Accumulating evidence from in vitro studies indicates that this is apparently the case. Here, we present and discuss several unresolved but critical issues related to the molecular mechanism and in vivo roles of CHIP.

Animals↗

Catecholamine-induced pulmonary edema and pleural effusion in rats--alpha- and beta-adrenergic effects.

We investigated the contribution of alpha- and beta-adrenergic pathways to catecholamine-induced pulmonary edema and the role of pleural effusion in preventing alveolar edema. Female Sprague-Dawley rats received continuous intravenous infusion of norepinephrine and of separate alpha- or beta-adrenergic stimulation over 6-24 h. We performed heart catheterization in vivo and excised post mortem lung tissue for histological analysis. Interleukin (IL)-6 and total protein concentrations were determined in serum, pleural fluid (PF) and bronchoalveolar lavage fluid. alpha-Adrenergic treatment increased right ventricular systolic pressure (RVSP) and total peripheral resistance (TPR) and caused severe alveolar edema associated with IL-6 activation in serum and diffuse pulmonary inflammation. PF amounts were moderate (0.9+/-0.2 ml). beta-Adrenergic stimulation also increased RVSP but decreased TPR. Interstitial but not alveolar edema and focal inflammation without IL-6 activation developed. Large PF amounts (6.2+/-1.5 ml) occurred which were considered to prevent alveolar edema. We conclude that both alpha- and beta-adrenergic stimulation contribute to pulmonary fluid shifts in rats, but alpha-adrenergic pathways cause more acute and more severe lung injury than beta-adrenergic mechanisms.

Adrenergic alpha-Agonists↗

Shifting hemodynamics of blood pressure control during prolonged mental stress.

The present study examined the hemodynamics underlying blood pressure elevations for evidence of a shift in the control of blood pressure during prolonged mental stress. Mean arterial pressure (MAP), cardiac output (CO), and total peripheral resistance (TPR) were measured at rest, during a 28-min mental arithmetic stress task, and during recovery, in 30 young healthy men and women. The stress task elicited a sustained increase in MAP: CO rose during the first half of the task but returned to baseline levels during the last quarter of the task, whereas TPR increased as the task progressed. When participants' hemodynamic reactions were classified as cardiac, vascular, or neither, there were more cardiac reactors early relative to late in the task, whereas there were more vascular reactors late relative to early. Thus, the sustained pressor response was initially supported mainly by cardiac mechanisms but subsequently by predominantly vascular mechanisms.

Adult↗