Targeting plasminogen activator inhibitor-1: role in cell signaling and the biology of domain-specific knock-in mice.

It is well documented that elevated levels of PAI-1 in plasma can decrease the fibrinolytic activity in blood with an associated increased risk of thrombus formation. A diverse range of molecules including bacterial lipopolysaccharide (LPS), the inflammatory mediators tumor necrosis factor alpha (TNFalpha) and interleukins, thrombin, transforming growth factor-beta (TGF-beta), and hormones regulate the synthesis of plasma PAI-1. Therefore, it is of clinical importance to restore the fibrinolytic balance. For a drug to be effective in controlling the synthesis of PAI-1, sufficient insight into the signal transduction pathways that control its regulation is desirable, which could serve as logical targets for the development of pharmaceuticals. Some key signaling pathways have been identified with the aid of pharmacological inhibitors, involved in the up-regulation of PAI-1 in context with several diseases, including obesity, insulin resistance, diabetic nephropathy, glomulonephritis, and pulmonary fibrosis. Furthermore, independent of its inhibitory activity PAI-1 mediates interactions with vitronectin (VN) and low density lipoprotein receptor-related protein (LRP) which modifies basic cell behaviors of proliferation, migration, and attachment. Intriguingly, it has been shown that both anti-fibrinolytic and non-fibrinolytic-related functions of PAI-1 may have overlapping roles in many diseases that are poorly understood. Tailoring knock-in mice with site-specific alterations that diminish the inhibitory activity, VN-binding, and LRP-binding activity of PAI-1 are useful tools for manipulation of biochemical properties, in vivo, and evaluating therapeutics.

Molecular basis of UV-sensitive mutant strain MBH3 of Haemophilus influenzae Rd: identification of mutation in the uvrA gene.

We have previously reported on cloning a DNA repair gene designated as uvr3 by virtue of its ability to phenotypically complement the UV sensitivity of mutant strain MBH3. Subsequently, we identified the uvr3 gene to be the uvrA gene (gene identification number HI0249) of Haemophilus influenzae Rd. The uvrA gene is a component of the UvrABC excision repair pathway. We studied molecular basis of the UV sensitivity of the MBH3 strain and identified a G-->A transition at nucleotide position 2700 of the uvrA gene, altering the Trp-900 codon (TGG) to a nonsense codon (TGA). Thus, the UvrA protein produced in the mutant strain MBH3 is likely to be truncated and unable to carry out the UV-induced DNA repair, thereby rendering the strain UV sensitive.

Comparison of thoracoscopic and open thoracic discectomy in a live ovine model for anterior spinal fusion.

STUDY DESIGN: The authors undertook a randomized comparison of 30 thoracoscopic and 30 open thoracic discectomies for anterior spinal fusion in a live sheep model. OBJECTIVES: To compare in a live sheep model discectomies performed using a thoracoscopic technique with those using an open thoracotomy technique to validate the efficacy of thoracoscopic disc and end plate removal for potential fusion. SUMMARY OF BACKGROUND DATA: In 1993, Mack and Regan described a technique for video-assisted thoracic surgery that resulted in less morbidity than open techniques. Subsequent reports support the finding that thoracoscopic spinal surgery results in less morbidity. METHODS: Sixty discectomies were performed in 10 live sheep. In each sheep, three randomly selected discectomies were performed thoracoscopically, and, subsequently, three open discectomies were performed. The animal then was killed, and the spine was sectioned and analyzed by computer imaging. RESULTS: Statistical analysis found no significant difference in the amount of disc resected (t' = 1.9639, t0.025, 60 = 2.000, alpha = 0.05). The mean percentage of disc resected was 67.8% (range, 0-92.2%) in the thoracoscopic group and 76.1% (range, 44.9-95.4%) in the open group. More than 50% of the disc was excised in 27 of 30 spines (90%) in the thoracoscopic group and in 29 of 30 (96.7%) in the open group. This difference was not statistically significant (theta 2(0.05, 1) = 3.84, theta 2' = 1.07). CONCLUSION: The findings in this study indicate that the thoracoscopic discectomy technique is equivalent to the open technique in the amount of disc and end plate resected. In addition, these findings suggest that thoracoscopic discectomies provide adequate disc resection to provide for an acceptable fusion rate according to the criteria demonstrated by Bunnell in 1982 and therefore support the efficacy of a thoracoscopic technique for anterior spinal fusion.

Alterations in sheep fetal right ventricular tissue with induced hemodynamic pressure overload.

We report on the cellular and molecular effects of acute and chronic hemodynamic overload on the fetal sheep heart. In one fetus of a twin gestation, the pulmonary artery was banded to create a condition of hemodynamic pressure overload in the right ventricle. The effects of this overload on the right ventricle (RV), left ventricle (LV), and intra-ventricular septum (IVS) of the heart were studied and compared to that in a control, unbanded twin fetus. At the cellular level, the histological data showed that both the size of the nuclei and the overall cell size of cardiac myocytes were increased after five days of banding; although, with one hour of banding no effects were detected at the cellular level. Based on prior studies on connexins which showed their involvement in differentiation, remodeling, and response to load we looked at their expression in control and experimental hearts. At the molecular level, changes in expression of connexin isoforms, the main gap junction protein in the heart, were observed after both one hour and five days of banding. Changes were observed in expression of connexins 40, 43, and 45. For connexin 43 there was a significant reduction confined to the right ventricle, in the chronically treated fetus, whereas, connexins 40 and 45 expression decreased after acute overload. These early molecular changes are significant because the "functional syncytium" of the myocardium is established through the gap junction connections. Alterations in connexin isoform expression affect the development, mechanical, and electrophysiological properties of the heart muscle. These changes may contribute to the ultimate result of continued hemodynamic stress on the right ventricle: heart failure.

Placement of a bladder neck purse-string cuff for the management of incontinence in children with myelodysplasia.

OBJECTIVES: Numerous surgical procedures have been developed in an attempt to increase bladder compliance and/or outlet resistance for the treatment of intractable incontinence in children with neurogenic lower urinary tract dysfunction. We report our experience with the development of a biocompatable purse-string cuff to increase outlet resistance by providing circumferential compression at the bladder neck. METHODS: A total of 12 children (6 boys, 6 girls) with myelodysplasia and persistent incontinence despite clean intermittent catheterization (CIC) and pharmacotherapy underwent urodynamic testing and cystoscopy that revealed neurogenic bladders with concomitant intrinsic sphincter deficiency. Through an anterior approach, the bladder neck was mobilized and wrapped with 5-mm polytetrafluoroethylene tubing. Five-millimeter woven polyester tape was then placed circumferentially within the polytetrafluoroethylene tubing lumen, purse-stringed under tension with a silicone tubing shod to appose the mucosa of the bladder neck, and secured under such tension with a surgical clip. Ten of the 12 patients underwent concomitant augmentation cystoplasty. RESULTS: Nine of 12 children (age range at time of operation 2.5 to 16 years) are continent on CIC in follow-up ranging from 6 months to 12 years. Four cuffs had to be surgically removed postoperatively. Two were removed secondary to inadvertent transvaginal placement. Two other cuffs were removed for infection. One child with persistent postoperative incontinence had the cuff retightened through a minor surgical procedure and has remained dry. Annual renal ultrasound examinations reveal stabilization of upper urinary tracts throughout the follow-up period in all but 1 patient. Postoperative urodynamic studies reveal increased bladder capacity, decreased intravesical pressures, and increased leak point pressures. CONCLUSIONS: The purse-string bladder neck cuff in combination with augmentation cystoplasty, when warranted, provides excellent, durable continence rates in children with myelodysplasia and neurogenic bladders. Attributes of the cuff are its relative low cost, ease of construction, unchanged angle of the bladder neck making catheterization easy, and potential adjustability in patients with persistent incontinence.

Prevalence of perioperative complications after anterior spinal fusion for patients with idiopathic scoliosis.

Anterior spinal fusion (ASF) has been proven to improve curve correction, save motion segments, and decrease the rate of pseudarthrosis when compared with posterior spinal fusion alone. However, in patients with idiopathic scoliosis, the complication rate of the anterior approach to the spine using current techniques has only been scantly defined in the literature. This is a retrospective review of consecutive patients who underwent primary ASF for idiopathic scoliosis to determine the prevalence and types of complications specifically related to the anterior approach. All patients who underwent primary ASFs for idiopathic scoliosis done by one of two orthopaedic surgeons between October 1986 and July 1992 were reviewed. Adequate records were available for 98 of 103 patients. The average age at time of surgery was 22 years (range, 10-60 years). Complications were divided into three groups: major (resulting in permanent sequelae or necessitating a second major operation); minor (resulting in a prolonged hospital stay, necessitating a minor operation, and/or resulting in a significant temporary hardship or persistent minor problem); and insignificant (anything less than minor). One of 98 patients had a major complication (a pelvic deep venous thrombosis that required operative thrombectomy). Twenty-five of 98 patients had 28 complications classified as minor, and 28 of 98 patients had 30 complications classified as insignificant. Smoking was a significant risk factor for the development of minor complications. There was no statistically significant relationship between the development of complications and the degree of curve, the approach used, the procedure performed, or the performance of rib resections. The anterior approach to the spine in patients with idiopathic scoliosis in this series was very safe, with only one major complication in 98 patients. However, minor and insignificant complications were quite common, occurring in 45 of 98 patients (46%). Smoking was a significant risk factor for minor complications.

Diagnostic dilemma: left aortic arch with right descending aorta--a rare vascular ring.

An infant had a rare type of vascular ring comprising a left aortic arch, a retroesophageal transverse aorta, a right descending aorta, and a right ligamentum arteriosum. Noninvasive studies including echocardiography with Doppler color flow mapping and magnetic resonance imaging were diagnostic of a vascular ring. However, only angiography prospectively established the exact type of ring. This report discusses the pitfalls of noninvasive studies used to diagnose unusual arch anomalies.

Innominate artery compression of the trachea: diagnosis and treatment by anterior suspension. A 25-year experience.

Suspension of the innominate artery to the sternum has been a widely accepted therapy for the relief of tracheal compression. Recently, reimplantation of the innominate artery has been advocated as a superior operative procedure. While generally successful, arterial transfer carries the risk of early bleeding and stroke, and the potential for late stenosis at the anastomotic site. Between 1969 and 1994, 25 infants and children at our institution received diagnoses of innominate artery compression and were treated by anterior suspension. All presented with stridor and one third had a history of suspected or proven apnea. Twenty-four children had excellent results, while 1 required resuspension after stridor returned. There were no major complications. Our series strongly supports the belief that anterior suspension of the innominate artery is a successful and reliable operation with minimal morbidity and mortality. More complex procedures are rarely indicated.

Coarctation of the aorta: diagnostic imaging after corrective surgery.

The clinical evaluation and management of the patient with coarctation of the aorta continues to evolve. Traditional imaging evaluation by plain film chest radiography, barium esophagography, and arteriography with pressure measurements across the coarctation has been largely supplanted by Doppler echocardiography and magnetic resonance imaging (MRI). The complications of surgery and balloon angioplasty, including residual or recurrent coarctation and aneurysm, can also be evaluated noninvasively by echocardiography and MRI. Chest radiography continues to play an important role in "first discovery" imaging in asymptomatic patients.

Tetralogy of Fallot: diagnostic imaging after palliative and corrective surgery.

Tetralogy of Fallot was invariably fatal until the development of palliative and later corrective surgical procedures. The prognosis for children with tetralogy of Fallot continues to improve almost a half century after the earliest palliative surgical procedure was performed successfully. Imaging of the child and adult after surgery for tetralogy of Fallot remains an important challenge because surgical complications or limitations frequently require imaging for complete evaluation and further management of the patient. Traditional imaging by chest radiography and arteriography has been largely replaced by echocardiography and ultrafast and conventional CT, as well as magnetic resonance imaging. This article reviews those aspects of diagnostic imaging that are appropriate to study the postoperative chest in the child or adult with tetralogy of Fallot.

The safety of continuous pleural lignocaine after thoracotomy in children and adolescents.

Several studies have proven pleural bupivacaine effectively provides postthoracotomy analgesia for both children and adults. When 0.25% bupivacaine is administered as a continuous infusion or repeated bolus, serum bupivacaine levels frequently approach the toxic range. The hazards of bupivacaine toxicity are more difficult to monitor, especially in children who may not report symptoms of local anaesthetic toxicity. Because of this concern, we initiated the use of pleural lignocaine to provide postthoracotomy analgesia for paediatric patients. The records of all patients receiving pleural lignocaine from January 1991 to December 1992 were reviewed. A total of 98 pleural catheters were inserted in 96 patients ranging in age from five months to 20 years. Seven patients had lignocaine levels that exceeded 5 micrograms.ml-1 and no patient manifested symptoms of systemic toxicity. This study shows that the administration of pleural lignocaine is a safe method of providing postthoracotomy analgesia. Lignocaine infusions in the dosage range of 20 to 40 micrograms.kg-1.min-1 rarely produce toxic levels, and monitoring of lignocaine levels every 12 h is an effective method of screening for toxicity.

Chronic alterations in cardiac mechanics after fetal closed heart operation.

Pulmonary artery banding was performed in 8 fetal sheep at 125 days' gestation to evaluate the feasibility of fetal closed cardiac operation. At 135 days' gestation, the fetuses were delivered and the cardiac mechanics were evaluated using a modified Langendorff isolated heart preparation. Two of the 8 fetuses aborted spontaneously 2 and 7 days after operation. Six fetuses (75%) survived the 10 days after delivery. The left ventricular cardiac mechanics in the banded fetuses (group I) were compared with those in 8 control fetuses (group II). All fetal hearts in both groups displayed a significant volume-pressure relationship. The volume-pressure curve was found to be shifted upward and to the left in the fetal hearts after pulmonary artery banding. The left ventricles subjected to increased in utero preload secondary to pulmonary artery banding were capable of generating greater peak systolic and developed pressures. Because the fetal heart manifests a Starling type of preload reserve, as such, it demonstrates that the possibility exists for subsequent fetal development to be altered by intrauterine intervention.

Pacemaker contact sensitivity: clinical recognition and management.

We report a patient in whom vesicular lesions of the skin developed overlying the pacemaker at intervals of 3 to 8 months after each of three consecutive insertions. Patch skin tests were positive for titanium and polyurethane sensitization. Although pacemaker contact sensitivity is rare, its recognition is of vital importance to the pacemaker-dependent patient.

Staged repair of pentalogy of Cantrell with tetralogy of Fallot.

We report a successful two-stage repair of tetralogy of Fallot associated with pentalogy of Cantrell. The first stage, performed in the neonatal period, consisted of repairing the omphalocele, separating the peritoneal from the pericardial cavities, and covering the heart. The second stage, performed at 6 years of age, consisted of complete intracardiac repair and placing the heart in the chest. The patient is alive and well 18 months after the operation.

Pressure-volume relationship of the fetal lamb heart.

In contrast to the adult heart, the fetal heart reportedly has little functional reserve. With increased clinical emphasis on fetal cardiac diagnosis, neonatal surgery, and the potential for future fetal cardiac intervention, it is essential that we better understand fetal cardiac function. Therefore, to demonstrate the extent of fetal cardiac preload reserve, we studied 10 fetal lambs using an isolated, isovolumic, blood-perfused heart preparation. We maintained constant afterload, inotropic state, coronary blood flow, heart rate, and perfusate blood gas values. As left ventricular (LV) volume (preload) was incrementally increased, LV end-diastolic pressure and LV peak systolic pressure were recorded. Linear regression analysis demonstrated that increases in LV developed pressures were predicted by the LV volume, demonstrating the presence of the Frank-Starling mechanism in each case. The plateau of the Starling pressure-volume curve occurred at an LV end-diastolic pressure of 12.5 +/- 4.79 mm Hg (95% confidence interval, 9.07 to 15.9 mm Hg), lower than the plateau expected in the adult heart. This implies that, in the management of fetal and immature neonatal hearts, preload reserve plays an important but limited role in cardiac reserve.

Thymolipoma: computed tomographic appearances.

The computed tomographic (CT) appearances of a thymolipoma are described in a 5 1/2-year-old girl. The location and CT appearances of the tumor appear to be specific for the diagnosis of thymolipoma.

De novo circumscribed pulmonary lobar cystic lymphatic anomaly in a young boy. A possible sequela of bronchopulmonary dysplasia.

This report describes a massive pulmonary lymphatic cystic anomaly affecting the right lower lobe of a nine-year-old boy. A year earlier, only an ill-defined small infiltrate could be seen in the affected lobe radiologically. The pathogenesis of this highly unusual lesion is discussed, taking into consideration the possible role of three months of mechanical ventilation in the neonatal period.

Pediatric heart transplantation at St. Christopher's Hospital for Children.

Heart transplantation has become the standard of care for patients with end-stage heart failure. The efficacy and therapeutic advantages of transplantation in the pediatric population have not been fully determined. Between March 1985 and September 1986, nine pediatric heart transplantations were performed; the ages ranged from 39 days to 19 years; weight ranged from 2.3 to 100 kg. The underlying disease was acquired cardiomyopathy (four patients); cardiomyopathy caused by congenital mitral valve disease (two patients); unresectable fibroma of the left ventricle in a newborn (one patient); hypoplastic left heart syndrome (one patient); and hypertrophic obstructive cardiomyopathy (one patient). Initial immunosuppression therapy consisted of cyclosporine, prednisone, and antithymocyte globulin. Recently, newer protocols have evolved through experience. Seven patients survived the perioperative period and had follow-up from 1 to 19 months, for a total of 41 transplant months. Rejection occurred at a rate of 1.4 episodes per month in children compared with 0.8 episodes per month in our adult patients. There was no statistical difference in the number, severity, or timing of rejection episodes in the pediatric versus adult population. Major complications included cyclosporine-induced seizures in two patients, mild hypertension in two, five infectious episodes (three bacterial and two viral), and three late deaths. All children who survived are in New York Heart Association functional class I with no developmental delays. This series is heavily weighted with children (33% less than age 1 year). Early results demonstrate that pediatric and infant heart transplantation is technically practical. Improved results are to be expected with additional experience and further modification of adult protocols to assure patient growth and minimize the high infection rate.