Functional Closure Research Articles

Coping with bladder exstrophy: diverse results from early attempts at functional urinary tract surgery.

To report the long-term surgical outcome in a group of patients with bladder exstrophy treated from 1960 to 1982, and to assess physical health, social integration and sexual function, as attempts at functional closure during the development of this surgery resulted in patients with differing surgical status of the genitourinary organs. A review of medical record archives revealed 36 patients; of these, seven had died, six were untraceable and six declined to participate, leaving 15 evaluable subjects (seven men and eight women, mean age at follow-up, 35 years). Data were collected from medical records and direct interviews were conducted using a semi-structured questionnaire, after obtaining informed consent. The Short Form-36 (SF-36) v2 Health Survey instrument was used to assess health and well-being. Three patients have retained the use of their bladder, and 11 had initial bladder closure but required (at a mean age of 3.1 years) various urinary diversions. Eight patients had a pelvic osteotomy. Of 27 functioning renal units, 25 are in reasonable to good condition. Six men and six women had genital reconstruction. Four men are capable of penetrative intercourse and ejaculate; six women manage penetrative intercourse and five have orgasms. All patients attended mainstream school and 13 achieved examination success. Nine patients took vocational training and 11 work full-time. Five patients are married and five are in long-term relationships. Two men have achieved three pregnancies and one women has had a child. The mean total SF-36 score (maximum 3600) was 2763 in men and 2235 in women. Surgery for bladder exstrophy has been developing for more than 40 years and the legacy of early attempts at functional closure is a population of adults who have a diversity of lower urinary tracts, good preservation of renal function overall and acceptable sexual function. They are usually robust, healthy and well-adjusted individuals functioning well in society, often in full-time employment and long-term relationships. Adolescent follow-up must be clearly focused, incorporating a multidisciplinary team approach to facilitate a seamless transition into adulthood.

Infracyanine-assisted internal limiting membrane peeling in macular hole repair: does it make a difference?

To investigate whether Infracyanine-assisted internal limiting membrane (ILM) peeling in macular hole repair affects the anatomical and functional outcome and complication rate. A retrospective analysis of 139 consecutive cases of stage 2 and stage 3 macular hole repairs with or without Infracyanine-assisted ILM peeling. There were 67 eyes with Infracyanine staining of the ILM and 72 eyes in the non-ILM-stained group. The results are analyzed functionally, anatomically and in terms of complications. A similar anatomical and functional closure rate was obtained with one unclosed macular hole in the stained group and two in the non-stained group (P=1.0). Fifty-two percent of the eyes in the stained group and 59% of those in the non-stained group achieved 0.5 vision or better (P=0.40). The mean postoperative vision was 0.55 in the stained group and 0.54 in the non-stained group (P=0.65). The mean improvement in vision was 0.40 in the stained group and 0.36 in the non-stained group (P=0.21). Anatomical and functional results are similar with or without Infracyanine-assisted ILM peeling. There was no apparent adverse effect of Infracyanine use on visual function, and no apparent retinal toxicity was found.

O2 sensing in the human ductus arteriosus: redox-sensitive K+ channels are regulated by mitochondria-derived hydrogen peroxide.

The ductus arteriosus (DA) is a fetal artery that allows blood ejected from the right ventricle to bypass the pulmonary circulation in utero. At birth, functional closure of the DA is initiated by an O2-induced, vasoconstrictor mechanism which, though modulated by endothelial-derived endothelin and prostaglandins, is intrinsic to the smooth muscle cell (DASMC) [Michelakis et al., Circ. Res. 91 (2002); pp. 478-486]. As pO2 increases, a mitochondrial O2-sensor (electron transport chain complexes I or III) is activated, which generates a diffusible redox mediator (H2O2). H2O2 inhibits voltage-gated K+ channels (Kv) in DASMC. The resulting membrane depolarization activates L-type Ca2+ channels, thereby promoting vasoconstriction. Conversely, inhibiting mitochondrial ETC complexes I or III mimics hypoxia, depolarizing mitochondria, and decreasing H2O2 levels. The resulting increase in K+ current hyperpolarizes the DASMC and relaxes the DA. We have developed two models for study of the DA's O2-sensor pathway, both characterized by decreased O2-constriction and Kv expression: (i) preterm rabbit DA, (ii) ionically-remodeled, human term DA. The O2-sensitive channels Kv1.5 and Kv2.1 are important to DA O2-constriction and overexpression of either channel enhances DA constriction in these models. Understanding this O2-sensing pathway offers therapeutic targets to modulate the tone and patency of human DA in vivo, thereby addressing a common form of congenital heart disease in preterm infants.

Tratamiento quirúrgico del complejo extrofia-epispadias. revisión y conceptos actuales

Surgical Treatment of Exstrophy-Epispadias Complex. Review and New ConceptsSince earlier descriptions the surgical management of the bladder exstrophy and epispadias complex (BEEC) has experimented gradual changes in the search for good aesthetic and functional results. The initial urinary diversion and bladder plate removal has evolved under various authors either by improving or supplementing the above described advances, until reaching the staged functional closure and more recently the complete primary BEEC closure. These later techniques allow to obtain encouraging continence indexes and successful aesthetic results; the low incidence and complexity of this condition however, advises both in terms of early management and later complications that this should be managed in reference centres.Sharing on this spirit of technique combination in search for a satisfactory result for exstrophic newborns and inspired by Leadbetter’s contribution to Young-Dees’s procedure for vesicoureteral reflux (VUR) correction, we have added a new step to the complete primary BEEC closure known as the Mitchell’s technique by performing Gil-Vernet’s trigonoplasty to prevent VUR, closely associated to bladder exstrophy.We believe VUR can be prevented right from the first surgical approach in the exstrophic newborn.

O2 sensing in the human ductus arteriosus: regulation of voltage-gated K+ channels in smooth muscle cells by a mitochondrial redox sensor.

Functional closure of the human ductus arteriosus (DA) is initiated within minutes of birth by O2 constriction. It occurs by an incompletely understood mechanism that is intrinsic to the DA smooth muscle cell (DASMC). We hypothesized that O2 alters the function of an O2 sensor (the mitochondrial electron transport chain, ETC) thereby increasing production of a diffusible redox-mediator (H2O2), thus triggering an effector mechanism (inhibition of DASMC voltage-gated K+ channels, Kv). O2 constriction was evaluated in 26 human DAs (12 female, aged 9+/-2 days) studied in their normal hypoxic state or after normoxic tissue culture. In fresh, hypoxic DAs, 4-aminopyridine (4-AP), a Kv inhibitor, and O2 cause similar constriction and K+ current inhibition (I(K)). Tissue culture for 72 hours, particularly in normoxia, causes ionic remodeling, characterized by decreased O2 and 4-AP constriction in DA rings and reduced O2- and 4-AP-sensitive I(K) in DASMCs. Remodeled DAMSCs are depolarized and express less O2-sensitive channels (including Kv2.1, Kv1.5, Kv9.3, Kv4.3, and BK(Ca)). Kv2.1 adenoviral gene-transfer significantly reverses ionic remodeling, partially restoring both the electrophysiological and tone responses to 4-AP and O2. In fresh DASMCs, ETC inhibitors (rotenone and antimycin) mimic hypoxia, increasing I(K) and reversing constriction to O2, but not phenylephrine. O2 increases, whereas hypoxia and ETC inhibitors decrease H2O2 production by altering mitochondrial membrane potential (DeltaPsim). H2O2, like O2, inhibits I(K) and depolarizes DASMCs. We conclude that O2 controls human DA tone by modulating the function of the mitochondrial ETC thereby varying DeltaPsim and the production of H2O2, which regulates DASMC Kv channel activity and DA tone.

Surgical reconstruction of exstrophy-epispadias complex: analysis of 13 patients.

Because exstrophy-epispadias complex is uncommon and satisfactory surgical reconstruction outcomes are difficult to achieve, the surgical repairs by one surgeon (PS) were analysed over a 14-year period. Retrospective analysis was performed on 13 patients with the complex who underwent surgery between January 1986 to August 2000. Cosmesis and continence were evaluated. Complications including wound dehiscence and urethrocutaneous fistula were reported. Of six patients with classical exstrophy who underwent functional bladder closure, all had good cosmesis except one who had partial dehiscence. Four patients with isolated epispadias had satisfactory cosmesis. Urethrocutaneous fistula was found in one boy in the classical exstrophy group. Continence was achieved in three out of four patients who had bladder neck reconstruction. One girl whose bladder neck was severely obstructed after functional bladder closure, had continent catheterizable stoma. Functional bladder closure yielded satisfactory cosmetic outcome. Bladder neck reconstruction made the patient dry in 75% of cases.

The Systemic Inflammatory Response to Cardiac Surgery

The Systemic Inflammatory Response to Cardiac Surgery

Sildenafil reverses O2 constriction of the rabbit ductus arteriosus by inhibiting type 5 phosphodiesterase and activating BK(Ca) channels.

Oxygen constriction causes functional closure of the ductus arteriosus (DA) at birth. Although DA closure is crucial for postnatal adaptation, patency of the DA is critical for survival of newborns with duct-dependent cardiac malformations. In these cases, DA patency is achieved by i.v. infusion of prostaglandin E1, which, though effective, is often associated with complications. We hypothesized that sildenafil, a specific phosphodiesterase type 5 inhibitor, is an effective DA vasodilator. In isolated DA rings from term (d 30) fetal rabbits, sildenafil (10(-6)-10(-4) M) and diethylamine NONOate (10(-7)-10(-5) M) induced dose-dependent relaxation of oxygen-constricted DA (-52 +/- 4% and -51 +/- 6%, respectively) that was inhibited by the soluble guanylyl-cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (5 x 10(-5) M). Sildenafil increased cyclic GMP levels. Iberiotoxin (200 nM), an inhibitor of calcium-sensitive potassium channels, decreased the vasodilatory effect of sildenafil and diethylamine NONOate (-30 +/- 2% and -27 +/- 4%, respectively). Oxygen inhibition of whole-cell K+ current and membrane depolarization were partially restored by sildenafil, and this was inhibited by iberiotoxin. Immunohistochemistry and immunoblotting confirmed the presence of phosphodiesterase type 5 and calcium-sensitive potassium channels in the DA smooth muscle cells. This is the first study to demonstrate that sildenafil dilates the DA by increasing soluble guanylyl-cyclase-derived cGMP levels and thereby activating calcium-sensitive potassium channels, causing membrane hyperpolarization. Sildenafil, already approved for human usage, might be an alternative or a useful adjunct to prostaglandin E1 as a bridge to cardiac surgery.

Functional Closure of Schwinger–Dyson Equations in Quantum Electrodynamics: 1. Generation of Connected and One-Particle Irreducible Feynman Diagrams

Using functional derivatives with respect to free propagators and interactions we derive a closed set of Schwinger–Dyson equations in quantum electrodynamics. Its conversion to graphical recursion relations allows us to systematically generate all connected and one-particle irreducible Feynman diagrams for the n-point functions and the vacuum energy together with their correct weights.

Combined prostaglandin and nitric oxide inhibition produces anatomic remodeling and closure of the ductus arteriosus in the premature newborn baboon.

After birth, the full-term ductus arteriosus actively constricts and undergoes extensive histologic changes that prevent subsequent reopening. These changes are thought to occur only if a region of intense hypoxia develops within the ductus wall after the initial active constriction. In preterm infants, indomethacin-induced constriction of the ductus is often transient and is followed by reopening. Prostaglandins and nitric oxide both play a role in inhibiting ductus closure in vitro. We hypothesized that combined inhibition of both prostaglandin and nitric oxide production (with indomethacin and N-nitro-L-arginine (L-NA), respectively) may be required to produce the degree of functional closure that is needed to cause intense hypoxia. We used preterm (0.67 gestation) newborn baboons that were mechanically ventilated for 6 d: 6 received indomethacin alone, 7 received indomethacin plus L-NA, and 16 received no treatment (control). Just before necropsy, only 25% of control ductus and 33% of indomethacin-treated ductus were closed on Doppler examination; in contrast, 100% of the indomethacin-plus-L-NA-treated ductus were closed. Control and indomethacin-treated baboons developed negligible-to-mild ductus hypoxia (EF5 technique). Similarly, there was minimal evidence of ductus remodeling. In contrast, indomethacin-plus-L-NA-treated baboons developed intense hypoxia in regions where the ductus was most constricted. The hypoxic muscle strongly expressed vascular endothelial growth factor, and proliferating luminal endothelial cells filled and occluded the lumen. In addition, cells in the most hypoxic regions were undergoing DNA fragmentation. In conclusion, preterm newborns are capable of remodeling their ductus, just like the full-term newborn, if they can reduce their luminal blood flow to a point that produces intense ductus wall hypoxia. Combined prostaglandin and nitric oxide inhibition may be necessary to produce permanent closure of the ductus and prevent reopening in preterm infants.

Arterial air embolism after venous air infusion in newborn piglets

In the newborn period, decreased right atrial pressure results in functional closure of the foramen ovale (FO). The objective of this study was to investigate whether air bubbles infused in the vena cava will pass through the FO into the arterial circulation in a newborn animal. Since air tends to rise to the highest point in a fluid, the study also investigated whether the animal's position could influence arterialization of air. Twelve 1-3-d-old piglets were anaesthetized and mechanically ventilated, and had catheters placed in the vena cava for infusion of air, in the aorta for blood gas and blood pressure measurements, and in the pulmonary artery for pressure measurements. After stabilization, 0.05 ml kg(-1) per minute of air was infused for 25 min followed by a 3 h observation period. Six piglets were placed in the left, and six in the right lateral recumbent position. Air bubbles in the left atrium or ventricle was monitored by echocardiography. Ultrasound Doppler probes were placed on both carotid arteries for detection of air embolism. Gas bubbles were detected in the left ventricle within 45 s of air infusion in 11 of 12 piglets. Eight piglets had air bubbles in the carotid arteries. Mean pulmonary arterial pressure (PAP) increased significantly after 1 min of air infusion, whereas mean systemic arterial pressure remained unchanged. When arterial air embolism occurred, PAP had not increased significantly. The time to reach maximum PAP with the animals in the left recumbent position was significantly shorter than in the right. This study shows that venous gas bubbles enter the arterial circulation through the FO in newborn piglets and that body position may influence the haemodynamic effect of these bubbles.

Formaldehyde fasciaform tympanoplasty: a reliable technique for closing large tympanic membrane perforations.

Formaldehyde fasciaform grafting tympanoplasty is a reliable method, in experienced hands, to close large tympanic membrane perforations. The technique involves using autogenous temporalis fascia shaped by formaldehyde cross-linking on a special fasciaform mold (Hear America, Palo Alto, CA). This study was undertaken with the objective of assessing if an otologist with less experience in using this technique could obtain comparable results. The results of the initial 23 patients treated in this manner by one surgeon between August 1996 and January 1998 are reviewed. Success was measured by the rate of closure of the tympanic membrane perforation and by functional closure of the air-bone gap. Favourable results were obtained, with complete closure of 86% of the perforations and closure of the air-bone gap to 20 dB or less in 90% of subjects when the ossicular chain was intact. The formaldehyde fasciaform tympanoplasty technique produces consistent, reliable, and reproducible results for large tympanic membrane perforations.

RESULTS OF UMBILICOPLASTY FOR BLADDER EXSTROPHY

The umbilicus is an important aesthetic landmark and its absence or deformity may be associated with poor self-image. In patients born with bladder exstrophy the umbilicus is attached to the upper margin of the bladder and reconstructive surgery often removes the navel. The umbilicus marks the waistline and serves to complete the harmony of the curved lines above and below the waist. We present our experience with children born with exstrophic anomalies during the last 2 decades. Our database included 61 children born with classic bladder and 8 born with cloacal exstrophy treated between 1980 and 1998. We performed primary reconstruction in 35 children, while 34 children and young adults were referred for secondary surgical repair, including bladder augmentation, continent diversion, genitoplasty and so forth. Neoumbilicoplasty was done in all of the former and in 30 of the 34 latter cases. Early in the series a V-shaped flap was raised and buried subcutaneously. The flap eventually became a tube around the cystotomy tube and the cicatrix formed the umbilical dimple. This method necessitated packing with iodoform gauze for 4 weeks with weekly dressing. The technique evolved into a tubularized U-shaped flap. A rubber tube was placed indwelling as a stent to maintain inward projection of the neoumbilicus. In 66 of the 69 cases the early results of umbilicoplasty were described by the surgeon as excellent or satisfactory. In 3 cases the neoumbilicus appeared flat, lost depth and was described as unsatisfactory. Long-term followup of more than 1 year was available in 48 patients, of whom 2 underwent umbilical repositioning for an off center or low umbilicus and 3 underwent repeat umbilicoplasty for a flat umbilicus that had lost depth. The best cosmetic results were achieved in patients with a relatively thick layer of subcutaneous fat, whereas cosmesis was suboptimal in thin children. Nevertheless, the patients and parents were generally pleased with the umbilical appearance even when the surgeon was not. Although the navel is a functionless depressed scar, it represents an important and pleasing landmark. Umbilical construction should be attempted early during functional closure or urinary diversion.

Abdominal Wall Closure after Intestinal Transplantation

Successful surgical closure of the abdominal wall after either combined or isolated intestinal transplantation may present a challenging dilemma for the plastic and reconstructive surgeon because of the following factors: restricted volume of the recipient abdominal cavity; donorrecipient size discrepancies as expressed by the donor to recipient weight ratio; and significant intraoperative edema. The purpose of this investigation is to present clinical experience with 51 consecutive patients who underwent a total of 57 sequential intestinal transplantations at the University of Miami-Jackson Memorial Hospital. A retrospective chart review of 36 pediatric (63 percent) and 21 adult (37 percent) transplantations was performed. Age of the pediatric population ranged from 1 month to 13 years (mean, 2.4 years) and of the adult population from 22 to 55 years (mean, 33.5 years). Several diagnostic classifications necessitated organ transplantation. Because of insufficient donor graft size for the recipient abdominal cavity in 19 transplantations (33 percent), several technical modifications were used to achieve anatomic and functional abdominal wall closure in all patients. In summary, the plastic and reconstructive surgeon should have a significant role in the comprehensive planning and management of abdominal wall closure in this challenging group of patients. (Plast. Reconstr. Surg. 106: 805, 2000.)

FIXATION PATTERNS OF IDIOPATHIC MACULAR HOLES AFTER VITREOUS SURGERY

Evaluation of idiopathic macular holes with the scanning laser ophthalmoscope (SLO) has shown fixation to be located at or near the margin of the hole and above the horizontal meridian in most cases. However, changes between preoperative and postoperative fixation have not been well studied. We used SLO microperimetry to determine scotomas and fixation points in 13 patients with idiopathic macular holes before and after vitreous surgery. The distance between preoperative and postoperative fixation points and the direction of movement were measured. Preoperatively, fixation was found to be at or near the margin of the macular hole in all eyes and was located above the horizontal meridian in most (84.6%) eyes. Postoperatively, there was a shift in the position of the fixation points. The distance between preoperative and postoperative fixation correlated with the degree of visual improvement (P = 0.032), but the direction of movement was variable. A shift in the position of fixation occurs after macular hole surgery, and the amount of shift correlates with visual improvement. From this observation, we define the term functional macular hole closure, characterized by centripetal movement of the neurosensory retina and improvement in vision, and the broader term anatomic macular hole closure, in which apparent hole closure may result from gliosis in the absence of movement of the neurosensory retina, not associated with visual improvement.

Role of apoptosis in the closure of neonatal ductus arteriosus.

Apoptosis regulates the remodeling of tissue during embryonic development by eliminating unwanted cells and structures. The present study investigated smooth muscle cell (SMC) proliferation and apoptosis in the neonatal ductus arteriosus (DA) during closure. In the DA of 39 swine neonates and 5 autopsy human neonates, apoptosis was detected using in situ end-labeling and electron microscopy, and proliferation was evaluated using proliferating cell nuclear antigen. In swine, apoptosis of SMC was first observed at 24h after birth. After 48h, both apoptosis and proliferation quickly increased and became most prominent at 3 days, mainly in the intima and inner media. From 5 days, both apoptosis and proliferation quickly disappeared, and were present to a minor extent at the 2 weeks after birth. During these processes, there was no sign of inflammation or necrosis. In humans, apoptosis was found in tissue specimens obtained from 2 term neonates who died at 1 and 5 days after birth. These findings suggest that SMC contribute to the functional closure of the DA by active constriction, and soon after, they switch to proliferation and apoptosis, which may contribute to the anatomical closure of the DA.

Functional Evaluation of the Medtronic Stentless Porcine Xenograft Mitral Valve in Sheep

Background —Recently, renewed interest in allograft and stentless “freehand” bileaflet xenograft mitral valve replacement has arisen. The variability of human papillary tip anatomy and scarcity of donors limit allograft availability, making xenograft mitral valves an attractive alternative; however, these valves require new surgical implantation techniques, and assessment of their hemodynamics and functional geometry is lacking. Methods —Seven sheep underwent implantation of a new stentless, glutaraldehyde-preserved porcine mitral valve (Physiological Mitral Valve [PMV], Medtronic) and were studied acutely under open-chest conditions. A new method of retrograde cardioplegia was developed. Hemodynamic valve function was assessed by epicardial Doppler echocardiography. 3D motion of miniature radiopaque markers sutured to the valve leaflets, annulus, and papillary tips was measured. Six other sheep with implanted markers served as controls. Results —Both papillary muscle tips avulsed in the first animal, leaving 6 other animals. Mitral regurgitation was not observed in any xenograft valve. The peak and mean transvalvular gradients were 4.6±1.8 mm Hg and 2.6±1.5 mm Hg, respectively. The average mitral valve area was 5.7±1.6 cm 2 . Valve closure in the xenograft group occurred later (30±11 ms, P <0.015) and at higher left-ventricular pressure (61±9 mm Hg, P <0.001) than in the control group; furthermore, leaflet coaptation was displaced more apically (5.6±2.2 mm, P <0.001) and septally (5.8±1.5 mm, P <0.001), and the anterolateral papillary tip underwent greater septal-lateral displacement (2.7±1.5 mm, P <0.001). Annular contraction during the cardiac cycle was similar in the 2 groups (xenograft 9.2±4.5% versus control 10.6±4.5% [mean±SD; 2-factor ANOVA model]). Conclusions —Successful freehand stentless porcine mitral valve implantation is feasible in sheep and was associated with excellent early postoperative hemodynamics. Physiological mitral valve annular contraction and functional leaflet closure mechanics were preserved. Long-term valve durability, calcification, and hemodynamic performance remain to be determined in models.

Functional evaluation of the medtronic stentless porcine xenograft mitral valve in sheep.

Recently, renewed interest in allograft and stentless "freehand" bileaflet xenograft mitral valve replacement has arisen. The variability of human papillary tip anatomy and scarcity of donors limit allograft availability, making xenograft mitral valves an attractive alternative; however, these valves require new surgical implantation techniques, and assessment of their hemodynamics and functional geometry is lacking. Seven sheep underwent implantation of a new stentless, glutaraldehyde-preserved porcine mitral valve (Physiological Mitral Valve [PMV], Medtronic) and were studied acutely under open-chest conditions. A new method of retrograde cardioplegia was developed. Hemodynamic valve function was assessed by epicardial Doppler echocardiography. 3D motion of miniature radiopaque markers sutured to the valve leaflets, annulus, and papillary tips was measured. Six other sheep with implanted markers served as controls. Both papillary muscle tips avulsed in the first animal, leaving 6 other animals. Mitral regurgitation was not observed in any xenograft valve. The peak and mean transvalvular gradients were 4.6+/-1.8 mm Hg and 2.6+/-1.5 mm Hg, respectively. The average mitral valve area was 5.7+/-1.6 cm(2). Valve closure in the xenograft group occurred later (30+/-11 ms, P<0. 015) and at higher left-ventricular pressure (61+/-9 mm Hg, P<0.001) than in the control group; furthermore, leaflet coaptation was displaced more apically (5.6+/-2.2 mm, P<0.001) and septally (5. 8+/-1.5 mm, P<0.001), and the anterolateral papillary tip underwent greater septal-lateral displacement (2.7+/-1.5 mm, P<0.001). Annular contraction during the cardiac cycle was similar in the 2 groups (xenograft 9.2+/-4.5% versus control 10.6+/-4.5% [mean+/-SD; 2-factor ANOVA model]). Successful freehand stentless porcine mitral valve implantation is feasible in sheep and was associated with excellent early postoperative hemodynamics. Physiological mitral valve annular contraction and functional leaflet closure mechanics were preserved. Long-term valve durability, calcification, and hemodynamic performance remain to be determined in models.

Response of fetal rabbit ductus arteriosus to bradykinin: role of nitric oxide, prostaglandins, and bradykinin receptors.

Nitric oxide plays a major role in vascular tone control. Increased blood levels of bradykinin (BK), which stimulates nitric oxide biosynthesis, occur at birth. BK effects on ductus arteriosus (DA) tone were investigated in fetal rabbit under fetal (2.5% O2 "low PO2") and neonatal (30% O2 "high PO2") conditions using in vitro isometric tension studies. Intact and endothelium-denuded DA, contracted with norepinephrine (ED75-90), showed a biphasic response to BK, with relaxation at 10(-9) to 10(-7) M BK and contraction at 10(-6) to 10(-5) M BK. BK (10(-6) to 10(-5) M) contracted intact DA from baseline tension, with greater contraction under high PO2. The B2-receptor antagonist D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-BK (Hoe-140, 10(-7) M) abolished relaxation, but not contraction, to BK in intact and denuded DA. The B1-receptor antagonist des-Arg9-[Leu5]-BK (10(-7) M) reduced BK-induced contraction but not relaxation in intact DA only. Nitric oxide synthase inhibitors, N(omega)-nitro-L-arginine methyl ester (10(-4) M) and N(omega)-monomethyl-L-arginine (10(-4) M) partially inhibited relaxation to BK in intact DA, with L-arginine (3 x 10(-4) M) reversing N(omega)-monomethyl-L-arginine inhibition. N(omega)-nitro-L-arginine methyl ester (10(-4) M) caused a small but significant inhibition of relaxation to BK in denuded DA. Indomethacin (2.8 x 10(-6) M), a cyclooxygenase inhibitor, abolished relaxation but not contraction to BK in intact and denuded DA. BK-induced relaxation of the DA acts through B2-receptors, releasing both nitric oxide and prostaglandins, whereas endothelial B1-receptors may mediate contraction. BK action on isolated DA changes from relaxation to contraction as its concentration increases, with greater contraction at neonatal PO2. Thus increased BK levels at birth may aid functional closure of the DA.

Evaluation of fibrin sealants in cutaneous wound closure.

Human fibrin sealant (HFS) and bovine fibrin sealant (BFS) were delivered as preformulated fibrinogen-thrombin mixtures that are light activated. These formulations were evaluated in the healing of incised cutaneous wounds in beagle dogs. Four groups were differentiated by sealant type and study duration with group: BFS for 10 days, HFS for 10 days, BFS for 30 days, and HFS for 30 days. Healing was evaluated by noting incidences of open wounds, laser Doppler perfusion imaging (LDPI), planimetry, breaking strength, and histopathology. In the absence of tension, both sealants tended to hold wound edges together; however, HFS tended to be better than its controls and BFS. Both sealants augmented suture closure, necessitating fewer sutures for wound closure. At 5 and 30 days BFS wounds had more perfusion than HFS wounds, indicating more inflammation. At 10 and 30 days BFS wounds had larger scar areas than their controls, while scar areas of HFS wounds were smaller than either BFS wounds or controls. Breaking strengths indicated that HFS wounds were stronger than their controls and BFS wounds. Histologically, mild to moderate chronic-active inflammation was observed in wounds receiving either sealant, and this persisted longer in BFS wounds. Overall, HFS had positive qualities, thus showing potential for functional and cosmetic wound closure.