Reactive site-dependent phenotypic alterations in plasminogen activator inhibitor-1 transgenic mice.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of plasminogen activators (PAs) and plays a role in the regulation of a number of physiological processes including the degradation of extracellular matrix proteins, cell proliferation and migration, and intracellular signaling. AIM: To characterize the effects of durable expression of a stable form of human PAI-1 and to characterize important structure-function relationships in PAI-1 in vivo. METHODS: We developed transgenic mice lines overexpressing stable variants of human PAI-1 under the control of the murine preproendothelin-1 promoter and characterized the phenotypic alterations displayed by transgenic mice. RESULTS: Transgenic mice expressing an active form of human PAI-1 (PAI-1-stab) display complex phenotypic abnormalities including alopecia and hepatosplenomegaly. Reactive site mutant transgenic mice expressing inactive PAI-1 exhibit complete phenotypic rescue, while transgenic mice expressing PAI-1 with reduced affinity for vitronectin manifest all of the phenotypic abnormalities present in PAI-1-stab transgenic mice. CONCLUSIONS: The protease inhibitory activity of PAI-1 toward PAs and/or other serine proteases is necessary and sufficient to promote complex phenotypic abnormalities and mediates many of the physiological effects of PAI-1 in vivo.

Experience with the Arndt paediatric bronchial blocker.

Previously reported techniques for single lung ventilation in children have failed to provide consistent, single lung ventilation with relative ease and reliability. We report our experience with the use of a new device, the Arndt 5 French (Fr) paediatric endobronchial blocker, for single lung ventilation in a series of 24 children. We were able to achieve single lung ventilation in 23 of the 24 patients (aged 2-16 yr). Placement required approximately 5-15 min. Attempts at placement were aborted in one patient who was unable to tolerate even short periods of apnoea because of lung pathology. Although it has some limitations, our experience suggests that the paediatric bronchial blocker can be used as a consistent, safe method of single lung ventilation in most young children.

Ontogeny of cholinergic regulation of fetal upper gastrointestinal motility.

OBJECTIVE: In the fetal rabbit immediately prior to birth (day 30; 0.97 gestation), intragastric atropine suppresses upper gastrointestinal (GI) motility, indicating that cholinergic receptors are expressed and functional at birth. To explore the developmental timing of upper GI cholinergic receptor function, we assessed the effect of intragastric atropine administration in rabbit fetuses during the last 10% of gestation. METHODS: Pregnant rabbits were studied at day 27, day 28 and day 29 of their normal 31-day gestation. In each litter, two fetuses were selected as study fetuses and two as control fetuses. Under ultrasound guidance, fluorescein and either atropine (0.04 microg/g fetal body weight) or normal saline were injected into the fetal stomach. Two hours after injection, fetuses were delivered and the small intestine was harvested. The per cent motility was calculated as the fluorescein travel distance, which was measured by ultraviolet light optical density, divided by the total small intestinal length. RESULTS: Fetal body weight, small intestinal length and per cent motility increased from day 27 to day 29 (p < 0.01). There were no differences in fetal body weight and small intestinal length between atropine and control groups. Atropine significantly decreased per cent motility (versus control values) in fetuses at day 29 and day 28 (56.1 +/- 13.5 vs. 66.1 +/- 11.7% and 59.7 +/- 15.6 vs. 68.3 +/- 11.7%, respectively; p < 0.05), but not at day 27 (52.4 +/- 12.9 vs. 52.8 +/- 11.2%). CONCLUSIONS: These results indicate that upper GI functional cholinergic receptors develop between 0.87 and 0.90 of rabbit gestation. Extrapolation to human development suggests that reduced GI motility in preterm human infants results, in part, from immature GI cholinergic receptors.

Tissue- and agonist-specific regulation of human and murine plasminogen activator inhibitor-1 promoters in transgenic mice.

Numerous studies have described regulatory factors and sequences that control transcriptional responses in vitro. However, there is a paucity of information on the qualitative and quantitative regulation of heterologous promoters using transgenic strategies. In order to investigate the physiological regulation of human plasminogen activator inhibitor type-1 (hPAI-1) expression in vivo compared to murine PAI-1 (mPAI-1) and to test the physiological relevance of regulatory mechanisms described in vitro, we generated transgenic mice expressing enhanced green fluorescent protein (EGFP) driven by the proximal -2.9 kb of the hPAI-1 promoter. Transgenic animals were treated with Ang II, TGF-beta1 and lipopolysaccharide (LPS) to compare the relative activation of the human and murine PAI-1 promoters. Ang II increased EGFP expression most effectively in brain, kidney and spleen, while mPAI-1 expression was quantitatively enhanced most prominently in heart and spleen. TGF-beta1 failed to induce activation of the hPAI-1 promoter but potently stimulated mPAI-1 in kidney and spleen. LPS administration triggered robust expression of mPAI-1 in liver, kidney, pancreas, spleen and lung, while EGFP was induced only modestly in heart and kidney. These results indicate that the transcriptional response of the endogenous mPAI-1 promoter varies widely in terms of location and magnitude of response to specific stimuli. Moreover, the physiological regulation of PAI-1 expression likely involves a complex interaction of transcription factors and DNA sequences that are not adequately replicated by in vitro functional studies focused on the proximal -2.9 kb promoter.

Robotic surgery and resident training.

BACKGROUND: Robotic technology promises to have an important future in surgery, but few residency programs incorporate robotics into surgical training. We sought to compare the speed and accuracy with which junior residents could perform laparoscopic tasks using both a robotic surgical device (Zeus MicroWrist) and conventional laparoscopic instruments. METHODS: Twelve residents performed exercises of progressive difficulty in an inanimate model using both the robot and conventional laparoscopy. Analysis of variance statistical analysis was used to compare task time and suturing accuracy scores. RESULTS: Grasping and suturing exercises were performed significantly faster with conventional laparoscopic instruments than with the robot. However, no difference in task time was noted for intracorporeal knot tying. Accuracy scores for suturing were higher for the robot. CONCLUSIONS: Junior residents can be instructed easily and quickly in both robotic and conventional advanced laparoscopic skills. The utility of robotic surgical devices in resident training requires further investigation.

Anticholinergic suppression of fetal rabbit upper gastrointestinal motility.

OBJECTIVE: At birth the newborn digestive tract must assume the responsibility of assimilating nutrients for survival. Immature gastrointestinal motility in the neonate may result in impaired feeding and nutrition. Newborn gastrointestinal motility development requires the expression and functional maturation of gastrointestinal receptors. To explore the timing of fetal responses to gastrointestinal cholinergic motility agents, we assessed the effect of the anticholinergic agent atropine in the late-gestation rabbit fetus. METHODS: Seven pregnant New Zealand White rabbits were studied at day 30 of their normal 31-day gestation. In each litter, two fetuses were selected as study (n = 14) and two as control (n = 14). Under ultrasound guidance, a spinal needle was percutaneously inserted through the maternal uterus into the fetal stomach and 0.5 ml of gastric content was aspirated. Fluorescein, labelled with colored microspheres, and either atropine (0.04 microg/g fetal body weight) or normal saline were injected in a total volume of 0.5 ml. Two hours after injection, fetuses were delivered, the small intestine harvested, and the total small intestinal length and the distance the gastrointestinal fluorescein travelled were measured by ultraviolet light optical density. The fluorescein travelled distance and the per cent motility, defined as the length of fluorescein travelled divided by the total length of the small intestine, were calculated. RESULTS: All fetuses survived the intragastric injection. Mean fetal body weight at delivery was 44.2 +/- 6.7 and 46.8 +/- 7.2 g in atropine and control fetuses, respectively. The fluorescein travelled distance (15.4 +/- 4.2 vs. 19.0 +/- 4.3 cm;. p < 0.01) and per cent motility (51.0 +/- 8.9 vs. 63.8 +/- 11.7%; p < 0.01) of atropine-treated fetuses were significantly lower than those of control fetuses. CONCLUSION: Fetal upper gastrointestinal motility is suppressed in response to intragastric atropine. These results indicate that fetal gastrointestinal cholinergic receptors are expressed and functional in the term (0.97 gestation) rabbit fetus. In utero administration of cholinergic agonists/antagonists may potentially modulate fetal gastrointestinal motility and absorption of amniotic fluid water and solutes.

Impact of mentor guidance in surgical career selection.

PURPOSE: The aim of this study was to survey graduates of a university general surgical residency training program to determine factors that influenced their selection of a specialty field. METHODS: A 39-item questionnaire was mailed to 86 graduates of a university general surgery program who matriculated from 1975 to 1989. The impact of lifestyle, technology, clinical opportunity, and mentor guidance in the residents' selection of a specialty field and eventual clinical practice was assessed. Results were analyzed using Fisher's Exact test with significance determined at P less than.05. RESULTS: The response rate was 65% (56 of 86). Eighty percent of respondents identified the most important aspect influencing their choice of specialty was interest in that field; additional factors included perception of prestige, presence of clinical opportunity, mentor influence, and family priorities. Sixty-six percent of respondents chose the same career as their mentor, attributing this to the mentor's skill (n = 36, 68%), achievements (n = 35, 66%), and verbal recommendations about their specialty field (n = 24, 45%), p < 0.05. CONCLUSIONS: Surgical residents use many criteria in selecting a field of specialty with mentor guidance an important component. Knowledge of these influential areas should help training programs offer appropriate career guidance. J Pediatr Surg 36:1802-1804.

Down-regulation of decorin, a transforming growth factor-beta modulator, is associated with scarless fetal wound healing.

PURPOSE: Transforming growth factor beta (TGF-beta) bioactivity has been implicated as a potential regulator of the transition from scarless healing to scar formation in fetal wounds. Decorin is an extracellular matrix proteoglycan that regulates TGF-beta bioactivity and assists in collagen fibrillogenesis. To determine its role in scarless repair, the authors examined decorin expression in fetal fibroblasts, skin, and wounds. METHODS: A single, full-thickness, 2-mm open wound was created on the dorsal surface of fetal rats at 16.5 days (E16) and 18.5 days (E18) gestational age (term, 21.5 days [E21]). Wounds were harvested at 24 and 72 hours (n = 12 wounds per time-point). Nonwounded fetal skin at E17, E19, and E21 was harvested for analysis of decorin expression during skin development and as controls for wounds. In addition, fetal (E14, E18) and adult dermal fibroblasts were cultured for in vitro analysis. Reduced-cycle, specific primer, reverse transcriptase polymerase chain reaction was performed to quantitate decorin expression. RESULTS: Decorin expression increased rapidly with increasing gestational age in both fetal fibroblasts and skin. Expression was increased 22-fold in E18 fibroblasts (P <.002) and 300-fold in adult fibroblasts (P <.001) compared with E14 fibroblasts. In skin, expression increased 74% (P <.01) during the fetal wound healing transition period between E17 and E19. However, in E16 wounds (scarless), decorin expression decreased 59% (P <.006) at 24 hours and 45% (P <.02) at 72 hours. Decorin expression did not change in E18 (scar) wounds at 24 and 72 hours (P >.05). CONCLUSIONS: Early gestation fetal fibroblasts and fetal skin express decorin at lower levels than late gestation fetal and adult fibroblasts and skin. Decorin expression is down-regulated in scarless (E16) compared with scar (E18) wounds. Thus, increased decorin expression is associated with both skin development and scar formation. Conversely, decreased decorin expression is associated with scarless repair.

Methodology standards associated with quality reporting in clinical studies in pediatric surgery journals.

BACKGROUND/PURPOSE: Reports of clinical trials often lack adequate descriptions of design and analysis; recent attention has focused on improving this omission so readers can properly assess the strength of the findings and draw their own conclusions. Similar analysis of study design and methodologic standards associated with quality reporting has not been carried out for pediatric surgery journals. METHODS: All studies (n = 642) published in 1998 in Journal of Pediatric Surgery (JPS) and Pediatric Surgery International (PSI), were reviewed for demographic data and study design. The frequency of reporting of 11 basic elements of design and analysis was evaluated in randomized clinical trials (RCT), nonrandomized clinical trials (NRCT), and retrospective cohorts (RC) from JPS by consensus of 2 assessors. RESULTS: Of the 642 studies, 17% of articles (111 of 642) were classified as clinical studies. Sixty-three were comparative studies and consisted of RC (n = 48), NRCT (n = 12), and RCT (n = 3). Two-thirds of articles published were either case reports or case series (431 of 642), and 16% were basic science articles. Demographic analysis showed a wide range of topics addressed, 4 authors per article, and multiple country of origin of authors. More than 66% of all RCT in JPS reported on eligibility criteria, admission before allocation, random allocation, method of randomization, patients' blindness to treatment, treatment complications, statistical analyses, statistical methods, loss to follow-up, and statistical methods; 2 elements of design and analysis, however, were poorly reported: blind assessment of outcome (33%) and power (17%). CONCLUSIONS: There were few randomized, controlled trials in pediatric surgery journals, and further attention should be given to evaluate the causal factors. Nine elements of quality reporting were well reported; however, 2 others were poorly reported; this may improve if editors of pediatric surgical journals provide authors with guidelines on how to report clinical trial design and analysis.

Gene transfer to the embryo: strategies for the delivery and expression of proteins at 48 to 56 hours postfertilization.

BACKGROUND/PURPOSE: Although gene and protein transfer may potentiate the cure of genetic disease, current strategies involving fetal gene therapy remain nonfocal and confounded by the lack of imaging techniques and in vivo markers for precise gene transfer. METHODS: Fourteen white Leghorn chick eggs were incubated for 48 to 56 hours postfertilization until they reached stages 11 to 16, about 3 mm in size. In 7 chick embryos, a glass needle was placed at the midbrain/hindbrain level and 1 x 10(7) pfu of an adenovirus containing the green fluorescent protein (GFP) reporter gene was injected into the lateral head. In another 7 chicken embryos, colored agarose beads coated with Sonic hedgehog (Shh) protein were implanted at the level of the hindbrain under direct microscopy. The eggs were then sealed, incubated at 37 degrees C for 24 hours, and reimaged using fluorescent microscopy and confocal laser microscopy. RESULTS: At 24 hours postinjection, all embryos were alive and were imaged in vivo. Fluorescent microscopic imaging showed green fluorescence in the region of the injection site in all the embryos. In embryos that underwent bead placement, the beads were visualized under microscopy in the lateral hindbrain of all embryos, and the presence of the Shh protein was confirmed using fluorescein isothiocyanate (FITC)-conjugated secondary antibody. CONCLUSIONS: This study shows that embryonic 3-mm chick embryos survive adenoviral transduction or agarose bead implantation in a focal manner in vivo and that this delivery results in production of imageable levels of protein. This may be used in mammalian systems, including humans, to introduce genes and proteins.

Determination of Interatomic Potentials for the X0(+), A0(+), and B1 States of HgKr from Fluorescence and Excitation Spectra.

We present an analysis of the A0(+)(6(3)P(1))-->X0(+)(6(1)S(0)) bound-bound and bound-free fluorescence spectrum, and of the A0(+)(6(3)P(1))<--X0(+)(6(1)S(0)) and B1(6(3)P(1))<--X0(+)(6(1)S(0)) bound-bound excitation spectrum of the HgKr van der Waals molecule. The A-->X fluorescence spectrum, which was observed for the first time, as well as the excitation spectra were recorded using a pulsed supersonic molecular beam crossed with a pulsed dye laser beam. An analysis of the A(v')<--X(v"), B(v')<--X(v"), and A(v'=8)-->X(v") bound-bound bands indicates that a Morse function combined with a long-range approximation represents the interatomic potential energy curve of the A, B, and X states below the dissociation limit. In the simulation of the A(v'=8)-->X bound-free spectrum the Morse, Lennard-Jones (n-6), and Maitland-Smith (n(0), n(1)) functions were tested, and the Maitland-Smith (11.39, 10.50) potential was found to be a good representation of the repulsive part of the X-state PE curve above the dissociation limit, over the internuclear separation range R=2.85-3.55 Å. The spectroscopic characteristics for the A, B, and X states obtained in this work are compared with other available experimental and theoretical results. Copyright 2001 Academic Press.

Indications for pediatric intestinal transplantation: a position paper of the American Society of Transplantation.

Parenteral nutrition represents standard therapy for children with short bowel syndrome and other causes of intestinal failure. Most infants with short bowel syndrome eventually wean from parenteral nutrition, and most of those who do not wean tolerate parenteral nutrition for protracted periods. However, a subset of children with intestinal failure remaining dependent on parenteral nutrition will develop life-threatening complications arising from therapy. Intestinal transplantation (Tx) can now be recommended for this select group. Life-threatening complications warranting consideration of intestinal Tx include parenteral nutrition-associated liver disease, recurrent sepsis, and threatened loss of central venous access. Because a critical shortage of donor organs exists, waiting times for intestinal Tx are prolonged. Therefore, it is essential that children with life-threatening complications of intestinal failure and parenteral nutrition therapy be identified comparatively early, i.e. in time to receive suitable donor organs before they become critically ill. Children with liver dysfunction should be considered for isolated intestinal Tx before irreversible, advanced bridging fibrosis or cirrhosis supervenes, for which a combined liver and intestinal transplant is necessary. Irreversible liver disease is suggested by hyperbilirubinemia persisting beyond 3-4 months of age combined with features of portal hypertension such as splenomegaly, thrombocytopenia, or prominent superficial abdominal veins; esophageal varices, ascites, and impaired synthetic function are not always present. Death resulting from complications of liver failure is especially common during the wait for a combined liver and intestinal transplant, and survival following combined liver and intestinal Tx is probably lower than following an isolated intestinal transplant. The incidence of morbidity and mortality following intestinal Tx is greater than that following liver or kidney Tx, but long-term survival following intestinal Tx is now at least 50-60%. It is probable that outcomes shall improve in the future with continued refinements in operative technique and post-operative management, including immunosuppression.

The effects of tubulin-binding agents on stretch-induced ventricular arrhythmias.

Stretch-activated ion channels have been identified as transducers of mechanoelectric coupling in the heart, where they may play a role in arrhythmogenesis. The role of the cytoskeleton in ion channel control has been a topic of recent study and the transmission of mechanical stresses to stretch-activated channels by cytoskeletal attachment has been hypothesized. We studied the arrhythmogenic effects of stretch in 16 Langendorff-perfused rabbit hearts in which we pharmacologically manipulated the microtubular network of the cardiac myocytes. Group 1 (n=5) was treated with colchicine, which depolymerizes microtubules, and Group 2 (n=6) was treated with taxol, which polymerizes microtubules. Stretch-induced arrhythmias were produced by transiently increasing the volume of a fluid-filled left ventricular balloon with a volume pump driven by a computer-controlled stepper motor. Electrical events were recorded by a contact electrode which provided high-fidelity recordings of monophasic action potentials and stretch-induced depolarizations. The probability of eliciting a stretch-induced arrhythmia increased (0.22+/-0.11 to 0.62+/-0.19, p=0.001) in hearts treated with taxol (5 microM), whereas hearts treated with colchicine (100 microM) showed no statistically significant change. We conclude that proliferation of microtubules increased the arrhythmogenic effect of transient left ventricle diastolic stretch. This result indicates a possible mode of arrhythmogenesis in chemotherapeutic patients and patients exhibiting uncompensated ventricular hypertrophy. The data would indicate that the cytoskeleton represents a possible target for antiarrhythmic therapies.

Centrilobular endothelial cell injury by diquat in the selenium-deficient rat liver.

Low doses of diquat cause massive liver necrosis and death of selenium-deficient rats within a few hours. Protection against this injury by selenium correlates with the presence of selenoprotein P, an extracellular selenoprotein that associates with endothelial cells. Selenium-deficient rats were injected with diquat (10 mg/kg) and their livers were removed for light and electron microscopy at times up to 120 minutes after injection. Selenium-replete animals were studied before and 120 minutes after the same dose of diquat. With selenium deficiency, diquat caused injury to centrilobular endothelial cells. This injury was evident 20 minutes after diquat injection and progressed to cell loss at 60 minutes after diquat injection. At 120 minutes, endothelial cells were virtually absent from the centrilobular regions and hepatocytes in those areas were undergoing necrosis. Portal and midzonal areas remained normal in selenium-deficient livers, as did the entire liver lobule of selenium-replete rats. These findings indicate that the initial liver lesion in selenium-deficient rats given diquat is injury of the endothelial cells in the centrilobular region. After detachment of the endothelial cells, centrilobular hepatocytes undergo necrosis. We postulate that selenoprotein P protects the centrilobular endothelial cells against injury by oxidant molecules that result from diquat administration.

Surgical aspects of dialysis in newborns and infants weighing less than ten kilograms.

PURPOSE: Renal failure occurs in children with moderate frequency. Surgical aspects of establishing and maintaining dialysis access in small infants are exceptionally challenging. The purpose of this review is to evaluate the authors' experience with dialysis access for infants less than 10 kg, particularly with respect to the surgical care required. METHODS: A retrospective review was conducted between 1991 and 1999 of all pediatric dialysis patients weighing 10 kg or less (n = 29). Age at start of dialysis, duration of dialysis, modes of dialysis, and complications specific to peritoneal (PD) and hemodialysis (HD) were examined. RESULTS: The mean age at start of dialysis was 10.4 months and continued for an average duration of 16.3 months. Seventy-two percent of all patients required both modes of dialysis. HD and PD duration averaged 7.8 and 10.5 months, respectively. Catheter durability was 3.1 and 4.5 months per catheter for HD and PD, respectively. There was no significant difference in complications when comparing HD and PD. Patients who weighed 5 to 10 kg had significantly longer PD catheter durability than patients 0 to 5 kg (P = .001). Forty-one percent of patients terminated dialysis after transplantation, whereas 24% died awaiting transplantation. CONCLUSION: Despite a large number of operations required, infants less than 10 kg can be bridged successfully, by surgical intervention and subsequent dialysis, to transplantation.

Extracorporeal membrane oxygenation for cardiac support in pediatric patients.

Extracorporeal membrane oxygenation (ECMO) has been used for pediatric cardiac support in settings of expected mortality due to severe myocardial dysfunction. We reviewed the records of 34 children (<18 years) placed on ECMO between March 1995 and May 1999. Demographic, cardiac, noncardiac, and outcome variables were recorded. Data were subjected to univariate analysis to define predictors of outcome. Eighteen patients were placed on ECMO after cardiac surgery (Group A); seven of 18 were weaned off ECMO, and four survived to discharge (22%). Thirteen patients were placed on ECMO as a bridge to cardiac transplantation (Group B), six of 13 received a heart transplant, one recovered spontaneously, and six survived to discharge (46%). Three patients were placed on ECMO for failed cardiac transplantation while awaiting a second transplant (Group C); one recovered graft function, two received a second heart transplant, and two of three survived (66%). The primary cause of death was multiorgan system failure (68%). Group A patients supported on ECMO for more than 6 days did not survive. Mediastinal bleeding complications and renal failure requiring dialysis were associated with nonsurvival. We conclude that ECMO as a bridge to cardiac transplant was more successful than ECMO support after cardiotomy. Mediastinal bleeding and renal failure were associated with poor outcome. Recovery of cardiac function occurred within the first week of ECMO support if at all. Longer support did not result in survival without transplantation.

Pyloroplasty improves long-term gastric emptying in rats undergoing fundoplication.

BACKGROUND: Conflicting reports exist regarding the permanence of improved gastric emptying (GE) after fundoplication for gastroesophageal reflux in children. METHODS: Changes in gastric volume (GV) and GE of a radiolabeled mixed meal induced by a Nissen fundoplication (NF) were compared with those with a NF plus pyloroplasty (NF + P). GE was measured preoperatively, 15 and 30 days postoperation, in 24 Sprague-Dawley rats; 12 had NF alone, and 12 had NF + P Results were expressed as percent gastric retention at 90 minutes (GR90). GV was measured at the same time periods in 20 additional rats. RESULTS: NF rats had enhanced GE with reduction of preoperative GR90 from 37.6% to 23.7% at 15 days (P < .05); however, at 30 days the GR90 increased to 34.3%. NF + P rats had enhanced GE with reduction in GR90 from 37.2% to 20.8% at 15 days (P< .05), which persisted at 30 days (20.4%). Mean GV decreased from (1.36 mL/100 g body weight) preoperation to 0.86 at 15 days (P< .05) at 15 days in the NF group, and returned to 1.29 at 30 days. Mean GV decreased from 1.36 to 0.91 at 15 days in the NF + P rats and persisted at 0.90 at 30 days. CONCLUSION: In the rat model, NF enhances GE transiently, whereas NF + P produces long-term enhancement of GE.

Hepatic cryoablation, but not radiofrequency ablation, results in lung inflammation.

OBJECTIVE: To compare the effects of 35% hepatic cryoablation with a similar degree of radiofrequency ablation (RFA) on lung inflammation, nuclear factor kappaB (NF-kappaB) activation, and production of NF-kappaB dependent cytokines. SUMMARY BACKGROUND DATA: Multisystem injury, including acute lung injury, is a severe complication associated with hepatic cryoablation of 30% to 35% or more of liver parenchyma, but this complication has not been reported with RFA. METHODS: Sprague-Dawley rats underwent 35% hepatic cryoablation or RFA and were killed at 1, 2, and 6 hours. Liver and lung tissue were freeze-clamped for measurement of NF-kappaB activation, which was detected by electrophoretic mobility shift assay. Serum concentrations of tumor necrosis factor alpha and macrophage inflammatory protein 2 were measured by enzyme-linked immunosorbent assay. Histologic studies of pulmonary tissue and electron microscopy of ablated liver tissue were compared among treatment groups. RESULTS: Histologic lung sections after cryoablation showed multiple foci of perivenular inflammation, with activated lymphocytes, foamy macrophages, and neutrophils. In animals undergoing RFA, inflammatory foci were not present. NF-kappaB activation was detected at 1 hour in both liver and lung tissue samples of animals undergoing cryoablation but not after RFA, and serum cytokine levels were significantly elevated in cryoablation versus RFA animals. Electron microscopy of cryoablation-treated liver tissue demonstrated disruption of the hepatocyte plasma membrane with extension of intact hepatocyte organelles into the space of Disse; RFA-treated liver tissue demonstrated coagulative destruction of hepatocyte organelles within an intact plasma membrane. To determine the stimulus for systemic inflammation, rats treated with cryoablation had either immediate resection of the ablated segment or delayed resection after a 15-minute thawing interval. Immediate resection of the cryoablated liver tissue prevented NF-kappaB activation and lung injury; however, pulmonary inflammatory changes were present when as little as a 15-minute thaw interval preceded hepatic resection. CONCLUSIONS: Hepatic cryoablation, but not RFA, induces NF-kappaB activation in the nonablated liver and lung and is associated with acute lung injury. Lung inflammation is associated with the thawing phase of cryoablation and may be related to soluble mediator(s) released from the cryoablated tissue. These findings correlate the clinical observation of an increased incidence of multisystem injury, including adult respiratory distress syndrome (ARDS), after cryoablation but not RFA.

Repair of pectus excavatum deformities: 30 years of experience with 375 patients.

OBJECTIVE: To review the surgical experience with pectus excavatum chest deformities at UCLA Medical Center during a 30-year period. BACKGROUND: Pectus excavatum is a relatively common malformation that is often symptomatic; however, children's physicians often do not refer patients for surgical correction. METHODS: Hospital records from 375 patients who underwent repair of pectus excavatum deformities between 1969 and 1999 were reviewed. Decrease in stamina and endurance during exercise was reported by 67%; 32% had frequent respiratory infections, 8% had chest pain, and 7% had asthma. The mean pectus severity score (width of chest divided by distance between posterior surface of sternum and anterior surface of spine) was 4.65 (normal chest = 2.56). All patients had marked cardiac deviation into the left chest. Repair was performed with subperiosteal resection of the abnormal cartilages, transverse wedge osteotomy of the anterior sternum, and internal support with a steel strut for 6 months. Repair was performed on 177 children before age 11 years; 38 adults with severe symptoms underwent repair. RESULTS: The mean hospital stay was 3.1 days. With a mean follow-up of 12.6 years, all patients with preoperative respiratory symptoms, exercise limitation, and chest pain experienced improvement. Vital capacity increased 11% (mean) within 9 months in 35 patients evaluated. There were no deaths. Complications included hypertrophic scar formation (35), atelectasis (12), pleural effusion (13), recurrent sternal depression (5), and pericarditis (3). More than 97% had a very good or excellent result. CONCLUSION: Pectus excavatum deformities can be repaired with a low rate of complications, a short hospital stay, and excellent long-term physiologic and cosmetic results.

Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study.

PURPOSE: Stage IV-S neuroblastoma is a metastatic disease associated with spontaneous regression and good survival, but 10% to 20% of infants die from early complications. The purpose of this study was to evaluate outcome and prognostic factors in infants with stage IV-S neuroblastoma treated prospectively with supportive care only or, in symptomatic patients, with low-dose cytotoxic therapy. PATIENTS AND METHODS: Eighty eligible infants were studied for response and survival with supportive care or, for symptomatic patients, cyclophosphamide 5 mg/kg/d for 5 days with or without hepatic radiation of 4.5 Gy over 3 days. Staging was reviewed centrally, and MYCN gene copy number, Shimada histopathologic classification, serum ferritin levels, and bone marrow immunocytology were determined. RESULTS: Stage IV-S and International Neuroblastoma Staging System stage 4S were 98% concordant. MYCN was not amplified in any of the tumors tested (n = 58), and Shimada histopathologic classification was favorable in 96% (n = 68/71). The 5-year event-free survival (EFS) rate for all infants was 86% and the survival rate was 92%. Supportive care was the only treatment provided for 44 (55%) of 80 infants, and their 5-year survival rate was 100%, compared with 81% survival for those requiring cytotoxic therapy for symptoms (P =.005). Five of six deaths were in infants younger than 2 months of age at diagnosis and were due to complications of extensive abdominal involvement with respiratory compromise or disseminated intravascular coagulation. Although age