Axial flow velocity patterns in a pulmonary artery model with varying degrees of valvular pulmonic stenosis: pulsatile in vitro studies

With the advent of noninvasive clinical techniques which can measure blood flow velocities (Doppler ultrasound), it is suggested that a fundamental knowledge of the axial flow velocity patterns in the pulmonary artery, and the changes caused by stenosis, may be used to support accurate diagnosis of valvular pulmonic stenosis. The present study was designed to characterize the axial flow velocity patterns in an in vitro model of a human adult pulmonary artery with varying degrees of valvular pulmonic stenosis. A two-dimensional laser Doppler anemometer (LDA) system was used to map the flow fields in the main (MPA), left (LPA), and right (RPA) branches of the pulmonary artery model. The study was conducted in the Georgia Tech. right heart pulse duplicator system. It was observed that the axial flow velocity patterns in the MPA and the LPA change dramatically with increasing degree of valvular stenosis. This indicates that the axial flow velocity patterns in these two branches are strongly influenced by the degree of valvular stenosis. The axial flow velocity patterns in the RPA, however, do not change much with varying degrees of valvular stenosis, indicating that the axial flow fields in the RPA are mainly influenced by the geometry of the bifurcation. It may be concluded therefore, that the changes in the axial flow velocity patterns in the MPA and LPA (rather than in the RPA) could be sensitive and reliable indicators of the severity of the defect.     

Secondary flow velocity patterns in a pulmonary artery model with varying degrees of valvular pulmonic stenosis: pulsatile in vitro studies

The objective of this study was to characterize in detail the secondary flow velocity patterns in an in vitro model of a human (adult) pulmonary artery with varying degrees of valvular pulmonic stenosis. A two-dimensional laser Doppler anemometer (LDA) system was used to map the flow fields in the main (MPA), left (LPA), and right (RPA) branches of the pulmonary artery model. The study was conducted in the Georgia Tech right heart pulse duplicator system. A pair of counter-rotating secondary flows were observed in each daughter branch in which the fluid moved outwardly along the side walls and then circled back inwardly toward the center of the vessel. For the case of the "normal" valve, the two counter-rotating secondary flows were symmetric about the centerline. The strength of secondary flows in the RPA was much stronger than in the LPA. However, as the pulmonic valve became more stenotic, the two counter-rotating secondary flows in both the LPA and RPA were no longer symmetric. In addition, the strength of secondary flows in both daughter branches increased with increasing degree of valvular stenosis. The increment in the LPA was, however, greater than in the RPA. The study demonstrates the importance of analyzing complex biological flows from a three-dimensional viewpoint.     

Quantitative characterization of postnatal growth trends in proximal pulmonary arteries in rats by phase-contrast magnetic resonance imaging

Malformations of the pulmonary arteries can increase right heart workload and result in morbidity, heart failure, and death. With the increased use of murine models to study these malformations, there is a pressing need for an accurate and noninvasive experimental technique that is capable of characterizing pulmonary arterial hemodynamics in these animals. We describe the growth trends of pulmonary arteries in 13 male Sprague-Dawley rats at 20, 36, 52, 100, and 160 days of age with the introduction of phase-contrast MRI as such a technique. PCMRI results correlated closely with cardiac output measurements by ultrasound echocardiography and with fluorescent microspheres in right-left lung flow split (flow partition). Mean flow, average cross-sectional area, distensibility, and shear rates for the right and left pulmonary arteries (RPA and LPA) were calculated. The RPA was larger and received more flow at all times than the LPA (P < 0.0001). Right-left flow split did not change significantly with age, and arterial distensibility was not significantly different between RPA and LPA, except at 160 days (P < 0.01). Shear rates were much higher for the LPA than the RPA (P < 0.0001) throughout development. The RPA and LPA showed different structure-function relationships but obeyed similar allometric scaling laws, with scaling exponents comparable to those of the main pulmonary artery. This study is the first to quantitatively describe changes in RPA and LPA flows and sizes with development and to apply phase-contrast MRI techniques to pulmonary arteries in rats.     

Pulmonary artery hemodynamics with varying degrees of valvular stenosis: an in vitro study

The study was to investigate the effects of varying degrees of valvular stenosis on the hemodynamics of the main (MPA), left (LPA), and right (RPA) pulmonary arteries. Particle flow visualization was used to examine the flow patterns in a series of pulmonary artery models manufactured out of glass. These glass models were made based on the geometry of the porcine pulmonary arteries with dilatation in the MPA and LPA. Also, detailed pressure mappings in the models were conducted using a side-hole catheter. As the valve became stenotic, a jet-like flow was observed in the MPA. A higher degree of valvular stenosis corresponded to a narrower jet. This jet-like flow was noted to deflect away from the centerline and impinge on the roof of the dilated MPA. Additionally, a notable pressure gradient across the deflected jet-like flow in the direction of its radius of curvature was seen. Moreover, secondary flows started to appear in the dilated MPA. This suggested that the change in geometry in the MPA, due to its dilatation, had a marked effect on the pulmonary artery hemodynamics. In the LPA and RPA, the strengths of the secondary flows increased as the valve became more stenotic. The flow patterns observed in the LPA appeared to be more disturbed than in the RPA, due to the poststenotic, dilatation present in the LPA. Pressure recovery along the axial direction in the MPA was observed for all the stenotic valves studied. As the degree of valvular stenosis increased, the transvalvular energy loss increased. Moreover, it was observed that the energy loss decreased progressively as the flow traveled downstream. This tendency was consistent with the phenomenon of pressure recovery observed in the pressure measurement. The study demonstrates the importance of analyzing biological flows from a three-dimensional viewpoint.     

Hemodynamics of patient-specific aorta-pulmonary shunt configurations

Optimal hemodynamics in aorta-pulmonary shunt reconstruction is essential for improved post-operative recovery of the newborn congenital heart disease patient. However, prior to in vivo execution, the prediction of post-operative hemodynamics is extremely challenging due to the interplay of multiple confounding physiological factors. It is hypothesized that the post-operative performance of the surgical shunt can be predicted through computational blood flow simulations that consider patient size, shunt configuration, cardiac output and the complex three-dimensional disease anatomy. Utilizing only the routine patient-specific pre-surgery clinical data sets, we demonstrated an intelligent decision-making process for a real patient having pulmonary artery atresia and ventricular septal defect. For this patient, a total of 12 customized candidate shunt configurations are contemplated and reconstructed virtually using a sketch-based computer-aided anatomical editing tool. Candidate shunt configurations are evaluated based on the parameters that are computed from the flow simulations, which include 3D flow complexity, outlet flow splits, shunt patency, coronary perfusion and energy loss. Our results showed that the modified Blalock-Taussig (mBT) shunt has 12% higher right pulmonary artery (RPA) and 40% lower left pulmonary artery (LPA) flow compared to the central shunt configuration. Also, the RPA flow regime is distinct from the LPA, creating an uneven flow split at the pulmonary arteries. For all three shunt sizes, right mBT innominate and central configurations cause higher pulmonary artery (PA) flow and lower coronary artery pressure than right and left mBT subclavian configurations. While there is a trade-off between energy loss, flow split and coronary artery pressure, overall, the mBT shunts provide sufficient PA perfusion with higher coronary artery pressures and could be preferred for similar patients having PA overflow risk. Central shunts would be preferred otherwise particularly for cases with very low PA overflow risk.     

Steady flow velocity measurements in a pulmonary artery model with varying degrees of pulmonic stenosis

Velocity and flow visualization studies were conducted in an adult size pulmonary artery model with varying degrees of valvular stenosis, using a two dimensional laser Doppler anemometer system. Velocity measurements in the main, left and right branches of the pulmonary artery revealed that as the degree of pulmonic stenosis increased, the jet type flow created by the valve hit the distal wall of the LPA farther downstream from the junction of the bifurcation. This in turn led to higher levels of turbulent and disturbed flow, and larger secondary flow motion in the LPA compared to the RPA. The high levels of turbulence measured in the main and left pulmonary arteries with the stenotic valves, could lead to the clinically observed phenomenon of post stenotic dilatation in the MPA extending into the LPA.     

Blood flow conditions in the proximal pulmonary arteries and vena cavae: healthy children during upright cycling exercise

Diagnostic testing in patients with congenital heart disease is usually performed supine and at rest, conditions not representative of their typical hemodynamics. Upright exercise measurements of blood flow may prove valuable in the assessment of these patients, but data in normal subjects are first required. With the use of a 0.5-T open magnet, a magnetic resonance-compatible exercise cycle, and cine phase-contrast techniques, time-dependent blood flow velocities were measured in the right (RPA), left (LPA), and main (MPA) pulmonary arteries and superior (SVC) and inferior (IVC) vena cavae of 10 healthy 10- to 14-yr-old subjects. Measurements were made at seated rest and during upright cycling exercise (150% resting heart rate). Mean blood flow (l/min) and reverse flow index were computed from the velocity data. With exercise, RPA and LPA mean flow increased 2.0 +/- 0.5 to 3.7 +/- 0.7 (P < 0.05) and 1.6 +/- 0.4 to 2.9 +/- 0.8 (P < 0.05), respectively. Pulmonary reverse flow index (rest vs. exercise) decreased with exercise as follows: MPA: 0.014 +/- 0.012 vs. 0.006 +/- 0.006 [P = not significant (NS)], RPA: 0.005 +/- 0.004 vs. 0.000 +/- 0.000 (P < 0.05), and LPA: 0.041 +/- 0.019 vs. 0.014 +/- 0.016 (P < 0.05). SVC and IVC flow increased from 1.5 +/- 0.2 to 1.9 +/- 0.6 (P = NS) and 1.6 +/- 0.4 to 4.9 +/- 1.3 (P < 0.05), respectively. A 56/44% RPA/LPA flow distribution at both rest and during exercise suggests blood flow distribution is dominated by distal pulmonary resistance. Reverse flow in the MPA appears to originate solely from the LPA while the RPA is in relative isolation. During seated rest, the SVC-to-IVC venous return ratio is 50/50%. With light/moderate cycling exercise, IVC flow increases by threefold, whereas SVC remains essentially constant.     

Aortopulmonary Collateral Flow Is Related to Pulmonary Artery Size and Affects Ventricular Dimensions in Patients after the Fontan Procedure

Background

Aortopulmonary collaterals (APCs) are frequently found in patients with a single-ventricle (SV) circulation. However, knowledge about the clinical significance of the systemic-to-pulmonary shunt flow in patients after the modified Fontan procedure and its potential causes is limited. Accordingly, the aim of our study was to detect and quantify APC flow using cardiovascular magnetic resonance (CMR) and assess its impact on SV volume and function as well as to evaluate the role of the size of the pulmonary arteries in regard to the development of APCs.

Methods

60 patients (mean age 13.3 ± 6.8 years) after the Fontan procedure without patent tunnel fenestration underwent CMR as part of their routine clinical assessment that included ventricular functional analysis and flow measurements in the inferior vena cava (IVC), superior vena cava (SVC) and ascending aorta (Ao). APC flow was quantified using the systemic flow estimator: (Ao) - (IVC + SVC). Pulmonary artery index (Nakata index) was calculated as RPA + LPA area/body surface area using contrast enhanced MR angiography. The patient cohort was divided into two groups according to the median APC flow: group 1 < 0.495 l/min/m² and group 2 > 0.495 l/min/m².

Results

Group 1 patients had significant smaller SV enddiastolic (71 ± 16 vs 87 ± 25 ml/m²; p=0.004) and endsystolic volumes (29 ± 11 vs 40 ± 21 ml/m²; p=0.02) whereas ejection fraction (59 ± 9 vs 56 ± 13%; p=0.38) differed not significantly. Interestingly, pulmonary artery size showed a significant inverse correlation with APC flow (r=-0.50, p=0.002).

Conclusions

Volume load due to APC flow in Fontan patients affected SV dimensions, but did not result in an impairment of SV function. APC flow was related to small pulmonary artery size, suggesting that small pulmonary arteries represent a potential stimulus for the development of APCs.     

Comparison of hemodynamic endpoints between normal subject and tetralogy patient using Womersley velocity profile and MR based flow measurements

Right ventricular (RV) enlargement and pulmonary valve insufficiency (PI) are well-known, unavoidable long term sequelae encountered by patients who undergo tetralogy of Fallot (TOF) surgery. Despite their lifelong need for cardiac surveillance and occasional re-intervention, there is a paucity of numerical data characterizing blood flows in their pulmonary arteries (PA). Specifically, although PA regurgitation is well-known to be ubiquitously present in adult repaired TOF (rTOF) patients yet, there have been only limited numerical studies to fully characterize this process. The few studies available have utilized idealized, simplistic geometric models or overly simplistic boundary conditions that fail to account for flow reversals near the arterial walls as observed in in-vitro and MRI based in-vivo studies. The objective of this study was to establish and validate a numerical methodology of PA blood flow using actual patient specific geometry and flow measurements obtained using phase-contrast MRI, employing Womersley type velocity profiles that model flow reversals near walls. The results from computation were validated with measurements. For the normal subject, the time averaged right PA pressure from computation (13.8 mmHg) and experiment (14.6 mmHg) differed by 6%. The time-averaged main PA pressure from computation (16.5 mmHg) and experiment (16.3 mmHg) differed by 1%. The numerically computed left PA regurgitant fraction was 89% compared to measured 77.5%, while the same for the rTOF was 43% (computation), compared to 39.6% (measured). We conclude that the use of numerical computations using the Womersley boundary condition allows reliable modeling of the pathophysiology of PA flow in rTOF.     

Effects of BAY 41-2272, a soluble guanylate cyclase activator, on pulmonary vascular reactivity in the ovine fetus

Nitric oxide (NO)-cGMP signaling plays a critical role during the transition of the pulmonary circulation at birth. BAY 41-2272 is a novel NO-independent direct stimulator of soluble guanylate cyclase that causes vasodilation in systemic and local circulations. However, the hemodynamic effects of BAY 41-2272 have not been studied in the perinatal pulmonary circulation. We hypothesized that BAY 41-2272 causes potent and sustained fetal pulmonary vasodilation. We performed surgery on 14 fetal lambs (125-130 days gestation; term = 147 days) and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery (LPA) to measure blood flow, and a catheter was placed in the LPA for drug infusion. Pulmonary vascular resistance (PVR) was calculated as pulmonary artery pressure minus left atrial pressure divided by LPA blood flow. BAY 41-2272 caused dose-related increases in pulmonary blood flow up to threefold above baseline and reduced PVR by 75% (P < 0.01). Prolonged infusion of BAY 41-2272 caused sustained pulmonary vasodilation throughout the 120-min infusion period. The pulmonary vasodilator effect of BAY 41-2272 was not attenuated by N(omega)-nitro-l-arginine, a NO synthase inhibitor. In addition, compared with sildenafil, a phosphodiesterase 5 inhibitor, the pulmonary vasodilator response to BAY 41-2272 was more prolonged. We conclude that BAY 41-2272 causes potent and sustained fetal pulmonary vasodilation independent of NO release. We speculate that BAY 41-2272 may have therapeutic potential for pulmonary hypertension associated with failure to circulatory adaptation at birth, especially in the setting of impaired NO production.     

Simultaneous pulmonary trunk and pulmonary arterial wave intensity analysis in fetal lambs: evidence for cyclical, midsystolic pulmonary vasoconstriction

The physiological basis of a characteristically low blood flow to the fetal lungs is incompletely understood. To determine the potential role of pulmonary vascular interaction in this phenomenon, simultaneous wave intensity analysis (WIA) was performed in the pulmonary trunk (PT) and left pulmonary artery (LPA) of 10 anesthetized late-gestation fetal sheep instrumented with PT and LPA micromanometer catheters to measure pressure (P) and transit-time flow probes to obtain blood velocity (U). Studies were performed at rest and during brief complete occlusion of the ductus arteriosus to augment pulmonary vasoconstriction (n = 4) or main pulmonary artery to abolish wave transmission from the lungs (n = 3). Wave intensity (dI(W)) was calculated as the product of the P and U rates of change. Forward and backward components of dI(W) were determined after calculation of wave speed. PT and LPA WIA displayed an early systolic forward compression wave (FCW(is)) increasing P and U, and a late systolic forward expansion wave decreasing P and U. However, a marked midsystolic fall in LPA U to near-zero was related to an extremely prominent midsystolic backward compression wave (BCW(ms)) that arose approximately 5 cm distal to the LPA, was threefold larger than the PT BCW(ms) (P < 0.001), of similar size to FCW(is) at rest (P > 0.6), larger than FCW(is) following ductal occlusion (P < 0.05) and abolished after main pulmonary artery occlusion. These findings suggest that the absence of pulmonary arterial midsystolic forward flow which accompanies a low fetal lung blood flow is due to a BCW(ms) generated in part by cyclical vasoconstriction within the pulmonary microcirculation.     

Outcomes of Surgical Repair for Persistent Truncus Arteriosus from Neonates to Adults: A Single Center's Experience

Objective

This study aimed to report our experiences with surgical repair in patients of all ages with persistent truncus arteriosus.

Methods

From July 2004 to July 2014, 50 consecutive patients with persistent truncus arteriosus who underwent anatomical repair were included in the retrospective review. Median follow-up time was 3.4 years (range, 3 months to 10 years).

Results

Fifty patients underwent anatomical repair at a median age of 19.6 months (range, 20 days to 19.1 years). Thirty patients (60%) were older than one year. The preoperative pulmonary vascular resistance and mean pulmonary artery pressure were 4.1±2.1 (range, 0.1 to 8.9) units.m² and 64.3±17.9 (range, 38 to 101) mmHg, respectively. Significant truncal valve regurgitation was presented in 14 (28%) patients. Hospital death occurred in 3 patients, two due to pulmonary hypertensive crisis and the other due to pneumonia. Three late deaths occurred at 3, 4 and 11 months after surgery. The actuarial survival rates were 87.7% and 87.7% at 1 year and 5 years, respectively. Multivariate analysis identified significant preoperative truncal valve regurgitation was a risk factor for overall mortality (odds ratio, 7.584; 95%CI: 1.335–43.092; p = 0.022). Two patients required reoperation of truncal valve replacement. One patient underwent reintervention for conduit replacement. Freedom from reoperation at 5 years was 92.9%. At latest examination, there was one patient with moderate-to-severe truncal valve regurgitation and four with moderate. Three patients had residual pulmonary artery hypertension. All survivors were in New York Heart Association class I-II.

Conclusions

Complete repair of persistent truncus arteriosus can be achieved with a relatively low mortality and acceptable early- and mid-term results, even in cases with late presentation. Significant preoperative truncal valve regurgitation remains a risk factor for overall mortality. The long-term outcomes warrant further follow-up.     

Pulmonary artery relative area change is inversely related to ex vivo measured arterial elastic modulus in the canine model of acute pulmonary embolization

A low relative area change (RAC) of the proximal pulmonary artery (PA) over the cardiac cycle is a good predictor of mortality from right ventricular failure in patients with pulmonary hypertension (PH). The relationship between RAC and local mechanical properties of arteries, which are known to stiffen in acute and chronic PH, is not clear, however. In this study, we estimated elastic moduli of three PAs (MPA, LPA and RPA: main, left and right PAs) at the physiological state using mechanical testing data and correlated these estimated elastic moduli to RAC measured in vivo with both phase-contrast magnetic resonance imaging (PC-MRI) and M-mode echocardiography (on RPA only). We did so using data from a canine model of acute PH due to embolization to assess the sensitivity of RAC to changes in elastic modulus in the absence of chronic PH-induced arterial remodeling. We found that elastic modulus increased with embolization-induced PH, presumably a consequence of increased collagen engagement, which corresponds well to decreased RAC. Furthermore, RAC was inversely related to elastic modulus. Finally, we found MRI and echocardiography yielded comparable estimates of RAC. We conclude that RAC of proximal PAs can be obtained from either MRI or echocardiography and a change in RAC indicates a change in elastic modulus of proximal PAs detectable even in the absence of chronic PH-induced arterial remodeling. The correlation between RAC and elastic modulus of proximal PAs may be useful for prognoses and to monitor the effects of therapeutic interventions in patients with PH.     

Cell Cycle- and Proteasome-Dependent Formation of Etoposide-Induced Replication Protein A (RPA) or Mre11/Rad50/Nbs1 (MRN) Complex Repair Foci

In response to DNA damage, cells activate a complex protein network designed to sustain genomic integrity. Many of the proteins involved in the network form discrete repair foci, the composition of which is determined by the specific type of damage. Replication protein A (RPA) and the Mre11/Rad50/Nbs1 (MRN) complex both participate in foci and co-localize at certain types of lesions. Following etoposide (ETOP) treatment, cells form foci containing either RPA or the MRN complex, but not both. To investigate this preferential foci formation, we used cell cycle synchronization experimentation. We demonstrate that cells in S phase contain RPA foci but lack phospho-Nbs1 foci. This is consistent with RPA’s role in homologous recombination repair of DNA double-strand breaks (DSBs), the predominant form of repair during S phase. Cells synchronized at G0/G1 phase contain phospho-Nbs1 foci, consistent with the MRN complex involvement in non-homologous end joining, the predominant form of repair in G1 phase. Treatment of cells with the proteasome inhibitor MG132 dramatically reduced the percentage of cells forming phospho-Nbs1 foci but did not alter the percentage of cells containing RPA or phospho-RPA foci. ETOP induced similar amounts of damage in all phases of the cell cycle as measured by the comet assay. These data suggest that in response to DNA DSBs, cell cycle-preferred repair pathways differentially engage RPA and the MRN complex in repair foci.     

Per-operative stent placement in the right pulmonary artery; a hybrid technique for the management of pulmonary artery branch stenosis at the time of pulmonary valve replacement in adult Fallot patients

After having undergone surgical correction at an early age, many patients with tetralogy of Fallot develop long-term complications including progressive pulmonary regurgitation and peripheral pulmonary stenosis. A high percentage of these patients need to undergo a second operation in their adolescence or early adulthood. If simultaneous treatment of both pulmonary regurgitation and peripheral pulmonary stenosis is warranted, a complete surgical approach has several disadvantages. We describe four cases of Fallot patients with severe pulmonary regurgitation and peripheral pulmonary stenosis who were treated using a hybrid approach involving surgical implantation of a pulmonary homograft and peroperative stenting of the pulmonary artery.     

Bronchovascular responses to intravenous contrast media for helical CT pulmonary angiography

CT angiography is now commonly used for the diagnosis of pulmonary embolism, but the contrast media used for imaging produces various hemodynamic changes. In this study, we investigated the bronchovascular and hemodynamic responses to intravenous iopromide, a non-ionic contrast agent used for pulmonary CT angiograms, in anesthetized, mechanically ventilated sheep (n = 6). Bronchial blood flow and cardiac output were measured with ultrasonic flow probes. Systemic and pulmonary arterial pressures were continuously monitored. Injections of 0.9% NaCl (120 ml over 30 s) or iopromide (300 mg/ml, 120 ml over 30 s) were given in random order in a peripheral vein with an angiogram infuser and hemodynamic changes were determined. After these parameters returned to baseline, the left pulmonary artery (LPA) was occluded with a snare and the animals were allowed to stabilize. Injections of NaCl and iopromide were repeated in random order as before. There were no significant hemodynamic effects with infusion of NaCl. With intact pulmonary vasculature, NaCl and iopromide did not cause significant changes in arterial blood gases, however, cardiac output (QT, L/min), mean systemic and pulmonary arterial pressures (PSA and PPA, Torr) increased and bronchovascular resistance (BVR, Torr x min/ml), decreased. Following LPA ligation, pH and PO2 significantly decreased over baseline, whereas PCO2 increased. After LPA ligation, iopromide produced a greater decrease in BVR as compared with preligation intact pulmonary vasculature. In conclusion, iopromide caused rapid hemodynamic changes and decreased BVR, likely secondary to osmolar stress. Bronchovascular effects were more pronounced after pulmonary arterial occlusion.     

Angiogenesis in bronchial circulatory system after unilateral pulmonary artery obstruction

Charan, Nirmal B., and Paula Carvalho. Angiogenesis inbronchial circulatory system after unilateral pulmonary artery obstruction. J. Appl. Physiol. 82(1):284-291, 1997.We studied the effects of left pulmonary artery(LPA) ligation on the bronchial circulatory system (BCS) by using asheep model. LPA was ligated in the newborn lambs soon after birth(n = 8), and when the sheep were ~3yr of age anatomic studies revealed marked angiogenesis in BCS.Bronchial blood flow and cardiac output were studied by placing flowprobes around the bronchial and pulmonary arteries in four adult sheep.After LPA ligation, bronchial blood flow increased from 35 ± 6 to134 ± 42 ml/min in ~3 wk (P < 0.05). We also studied gas-exchange functions of BCS ~3 yr after the ligation of LPA in newborn lambs (n = 4) and used a control group (n = 12)in which LPA was ligated acutely. In the left lung,O₂ uptake after acute ligation was16 ± 3 ml/min and was similar to the chronic model, whereasCO₂ output in the control group was 27 ± 3 ml/min compared with 79 ± 12 ml/min in the chronic preparation (P < 0.05).We conclude that LPA ligation causes marked angiogenesis in BCS that iscapable of performing some gas-exchange functions.

     

BRCA1 modulates ionizing radiation-induced nuclear focus formation by the replication protein A p34 subunit

Mutations in BRCA1 account for a significant proportion of familial breast and ovarian cancers. BRCA1 has been implicated in DNA damage responses including double-strand break (DSB) repair. However, its exact role in DSB repair and its functional relationship with other known repair proteins remain to be elucidated. In this study, we carried out a cytological analysis of the effect of BRCA1 on damage-induced nuclear focus formation mediated by the replication protein A (RPA). RPA is a multi-functional protein that participates in both DNA replication and various types of DNA repair including DSB repair. Following ionizing radiation (IR), RPA and BRCA1 formed punctate nuclear staining patterns that co-localized with each other, consistent with the implicated roles of both proteins in the same repair process. The number of damage-induced RPA foci in BRCA1-deficient cells, however, was significantly greater than that in BRCA1-positive cells. Moreover, the effect of BRCA1 on the RPA staining pattern appeared to be specific for IR but not ultraviolet (UV) irradiation. These data suggest that BRCA1 plays an important role in processing the RPA-associated intermediates during DSB repair.     

Mechanisms of calcitonin gene-related peptide-induced increases of pulmonary blood flow in fetal sheep

Fetal pulmonary blood flow is regulated by various vasoactive substances. One, calcitonin gene-related peptide (CGRP), increases pulmonary blood flow. We examined four key physiological mechanisms underlying this response using the blocker drugs CGRP receptor blocker (CGRP(8-37)), nitric oxide synthase inhibitor [N(omega)-nitro-L-arginine (L-NNA)], adenosine triphosphate-dependent potassium (K(ATP)) channel blocker (glibenclamide), and cyclooxygenase inhibitor (indomethacin) in 17 near-term fetal sheep. Catheters were placed in the left (LPA) and main pulmonary arteries, and an ultrasonic flow transducer was placed around the LPA to measure flow continuously. CGRP was injected directly into the LPA (mean 1.02 microgram/kg) before and after blockade, and responses to CGRP were statistically compared. Before blockade, CGRP increased LPA blood flow from 23 +/- 25 to 145 +/- 77 ml/min (means +/- SD), and these increases were significantly attenuated by CGRP(8-37) (n = 6; 91% inhibition), L-NNA (n = 6; 86% inhibition), and glibenclamide (n = 6; 69% inhibition). No significant changes were found with indomethacin (n = 6; 4% inhibition). Thus, in the fetal pulmonary circulation, CGRP increases pulmonary blood flow not only through its specific receptor but also, in part, through nitric oxide release and K(ATP) channel activation.