Objective To identify clinical factors associated with pulmonary hypertension (PH) and mortality in patients with congenital diaphragmatic hernia (CDH). Study design A prospective cohort of neonates ...with a diaphragm defect identified at 1 of 7 collaborating medical centers was studied. Echocardiograms were performed at 1 month and 3 months of age and analyzed at a central core by 2 cardiologists independently. Degree of PH and survival were tested for association with clinical variables using Fischer exact test, χ2 , and regression analysis. Results Two hundred twenty patients met inclusion criteria. Worse PH measured at 1 month of life was associated with higher mortality. Other factors associated with mortality were need for extracorporeal membrane oxygenation, patients inborn at the treating center, and patients with a prenatal diagnosis of CDH. Interestingly, patients with right sided CDH did not have worse outcomes. Conclusions Severity of PH is associated with mortality in CDH. Other factors associated with mortality were birth weight, gestational age at birth, inborn status, and need for extracorporeal membrane oxygenation.
Objective The objective of the study was to examine the effect of selective fetoscopic laser photocoagulation (SFLP) vs serial amnioreduction (AR) on perinatal mortality in severe twin-twin ...transfusion syndrome (TTTS). Study Design This was a 5 year multicenter, prospective, randomized controlled trial. The primary outcome variable was 30 day postnatal survival of donors and recipients. Results There was no statistically significant difference in 30-day postnatal survival between SFLP or AR treatment for donors at 55% (11 of 20) vs 55% (11 of 20) ( P = 1.0, odds ratio OR 1, 95% confidence interval CI 0.242 to 4.14) or recipients at 30% (6 of 20) vs 45% (9 of 20) ( P = .51, OR 1.88, 95% CI 0.44 to 8.64). There was no difference in 30 day survival of 1 or both twins on a per-pregnancy basis between AR at 75% (15 of 20) and SFLP at 65% (13 of 20) ( P = .73, OR 1.62, 95% CI 0.34 to 8.09). Overall survival (newborns divided by the number of fetuses treated) was not statistically significant for AR at 60% (24 of 40) vs SFLP 45% (18 of 40) ( P = .18, OR 2.01, 95% CI 0.76 to 5.44). There was a statistically significant increase in fetal recipient mortality in the SFLP arm at 70% (14 of 20) vs the AR arm at 35% (7 of 20) ( P = .25, OR 5.31, 95% CI 1.19 to 27.6). This was offset by increased recipient neonatal mortality of 30% (6 of 20) in the AR arm. Echocardiographic abnormality in recipient twin Cardiovascular Profile Score is the most significant predictor of recipient mortality ( P = .055, OR 3.025/point) by logistic regression analysis. Conclusion The outcome of the trial did not conclusively determine whether AR or SFLP is a superior treatment modality. TTTS cardiomyopathy appears to be an important factor in recipient survival in TTTS.
Background The diabetic phenotype of wound healing is in part characterized by impaired neovascularization and deficient endothelial progenitor cell (EPC) recruitment. Angiopoietin-1 (Ang-1) is a ...potent mobilizer of EPCs from the bone marrow (BM). A suggested mechanism for EPC mobilization from the BM is mediated by matrix metalloproteinase 9 (MMP-9) and stem cell factor (SCF). Taken together, we hypothesized that overexpression of Ang-1 in diabetic wounds will recruit EPCs and improve neovascularization and wound healing. Methods An endothelial lineage BM-labeled murine model of diabetes was developed to track BM-derived EPCs. FVBN mice were lethally irradiated and then reconstituted with BM from syngeneic Tie2/LacZ donor mice. Diabetes was induced with streptozotocin. Dorsal wounds in BM-transplanted mice were treated with Ad-Ang-1, Ad-GFP, or phosphate-buffered saline. At day 7 after injury, wounds were harvested and analyzed. A similar experiment was conducted in EPC mobilization deficient MMP-9 –/– mice to determine whether the effects of Ang-1 were EPC-dependent. Results Overexpression of Ang-1 resulted in greatly improved re-epithelialization, neovascularization, and EPC recruitment in diabetic BM-transplanted wounds at day 7. Ang-1 treatment resulted in increased serum levels of proMMP-9 and SCF but had no effect on vascular endothelial growth factor levels. According to our FACS results, peripheral blood EPC (CD34+ /Cd133+ /Flk1+ ) counts at day 3 after wounding showed impaired EPC mobilization in MMP-9 –/– mice compared with those of wild-type controls. EPC mobilization was rescued by SCF administration, validating this model for EPC-mobilization–deficient mechanistic studies. In MMP-9 –/– mice, Ad-Ang-1 accelerated re-epithelialization in a similar manner, but had no effect on neovascularization. Conclusion Our results show that Ang-1 administration results in improved neovascularization which is dependent on EPC recruitment and has direct effects on wound re-epithelialization. These data may represent a novel strategy to correct the phenotype of impaired diabetic neovascularization and may improve diabetic wound healing.
Abstract Background Chronic wounds are characterized by a wound healing and neovascularization deficit. Strategies to increase neovascularization can significantly improve chronic wound healing. ...Insulin-like growth factor (IGF)-1 is reported to be a keratinocyte mitogen and is believed to induce angiogenesis via a vascular endothelial growth factor (VEGF)-dependent pathway. Using a novel ex vivo human dermal wound model and a diabetic-impaired wound healing murine model, we hypothesized that adenoviral overexpression of IGF-1 (Ad-IGF-1) will enhance wound healing and induce angiogenesis through a VEGF-dependent pathway. Methods Ex vivo : 6-mm full-thickness punch biopsies were obtained from normal human skin, and 3-mm full-thickness wounds were created at the center. Skin explants were maintained at air liquid interface. Db/db murine model: 8-mm full-thickness dorsal wounds in diabetic (db/db) mice were created. Treatment groups in both human ex vivo and in vivo db/db wound models include 1 × 108 particle forming units of Ad-IGF-1 or Ad-LacZ, and phosphate buffered saline ( n = 4–5/group). Cytotoxicity (lactate dehydrogenase) was quantified at days 3, 5, and 7 for the human ex vivo wound model. Epithelial gap closure (hematoxylin and eosin; Trichrome), VEGF expression (enzyme-linked immunosorbent assay), and capillary density (CD 31 + CAPS/HPF) were analyzed at day 7. Results In the human ex vivo organ culture, the adenoviral vectors did not demonstrate any significant difference in cytotoxicity compared with phosphate buffered saline. Ad-IGF-1 overexpression significantly increases basal keratinocyte migration, with no significant effect on epithelial gap closure. There was a significant increase in capillary density in the Ad-IGF-1 wounds. However, there was no effect on VEGF levels in Ad-IGF-1 samples compared with controls. In db/db wounds, Ad-IGF-1 overexpression significantly improves epithelial gap closure and granulation tissue with a dense cellular infiltrate compared with controls. Ad-IGF-1 also increases capillary density, again with no significant difference in VEGF levels in the wounds compared with control treatments. Conclusions In two different models, our data demonstrate that adenoviral-mediated gene transfer of IGF-1 results in enhanced wound healing and induces angiogenesis via a VEGF-independent pathway. Understanding the underlying mechanisms of IGF-1 effects on angiogenesis may help produce novel therapeutics for chronic wounds or diseases characterized by a deficit in neovascularization.
Objective The purpose of this study was to evaluate the incidence of complications after selective fetoscopic laser photocoagulation for twin-twin transfusion syndrome (TTTS). Study Design One ...hundred fifty-two cases of TTTS were treated with selective fetoscopic laser photocoagulation from 2005-2008. Complications were TTTS recurrence, amniotic band syndrome, iatrogenic monoamnionicity, and twin anemia-polycythemia sequence. Data were placed in the following categories: no complications; early complications ≤7 days; late complications >7 days; both early and late complications. Results The incidence of early, late, and both early and late complications was 31%, 39%, and 10%. Complications included 2 cases (1.3%) of monoamnionicity, 3 cases (2.0%) of recurrent TTTS, 3 cases (2.0%) of twin anemia-polycythemia sequence, and 5 cases (3.3%) of amniotic band syndrome. Cases with TTTS with early complications had a lower number of superficial arteriovenous vascular anastomoses and 1 or both fetus survival (70.2% vs 96.7%; P < .001), compared with no complications. Fetal survival was 238 of 307 cases (77.5%), with 1 or both twins surviving in 134 of 152 (88%) of pregnancies. Conclusion The incidence of early, late, and both early and late complications was 31%, 39%, and 10%, respectively. Close postoperative surveillance is important.
Objective We sought to evaluate amniotic fluid brain natriuretic peptide (BNP) levels as a biomarker of recipient twin (RT) cardiomyopathy (RTCM) in twin-twin transfusion syndrome. Study Design ...Amniotic fluid samples were obtained from 157 twin-twin transfusion syndrome RTs and from 6 singletons (controls) from 2007 through 2009. N-terminal prohormone BNP (NT-proBNP) levels were quantified by enzyme-linked immunosorbent assay. RTCM was classified as mild (IIIA), moderate (IIIB), or severe (IIIC) by fetal echocardiography. The relationship between NT-proBNP and RTCM was evaluated using analysis of variance. The ability of NT-proBNP to predict moderate or greater RTCM was evaluated by receiver operating characteristic analysis. Results There is a significant positive correlation between NT-proBNP levels and worsening RTCM (r = 0.33; P < .001). NT-proBNP thresholds of 569 fmol/mg and 369 fmol/mg had a sensitivity of 70% and 87%, and specificity of 67% and 42%, respectively, in predicting moderate or greater RTCM. Conclusion This is the first large case series that demonstrates a relationship between NT-proBNP and RTCM. This pathophysiologic insight supports ongoing efforts to develop screening biomarkers.
Abstract Background Anti-inflammatory cytokine interleukin (IL)-10 has been shown to induce regenerative healing in postnatal wounds. A viral homolog of IL-10 produced by human cytomegalovirus (CMV ...IL-10) similarly generates potent immunoregulatory effects, but its effects on wound healing have not been investigated. Currently, there are limited cost-effective methods of screening vulnerary therapeutics. Taken together, we aim to develop and validate a novel human ex vivo dermal wound model and hypothesize that CMV IL-10 will enhance dermal wound healing. Methods Full-thickness circular (6-mm) explants were taken from surgical skin samples and 3-mm full-thickness wounds were created. Explants were embedded in collagen I matrix and maintained in specially formulated media with the epidermis at air–liquid interface, and treated with human IL-10 or CMV IL-10 (200 ng/mL). The viability of cultured explants was validated by histology and lactate dehydrogenase (LDH) activity. Epithelial gap, epithelial height, basal keratinocyte migration, vascular endothelial growth factor levels, and neovascularization were measured at days 3 and 7 to determine IL-10 effects on wound healing. Results Culture explants at day 7 appeared similar to fresh skin in morphology, cell, and vessel density. By day 14, the epidermis separated from the dermis and the cell density diminished. Day 7 wounds appeared viable with advancing epithelial and basal keratinocyte migration with no evidence of necrosis. Cytotoxicity analysis via the quantification of LDH revealed no differences between controls and treated groups. There was a slight increase in the quantity of LDH in media at day 3; however, this decreased at day 5 and continued to decline up to day 21. CMV IL-10 treatment resulted in a significant decrease in the epithelial gap and an increase in epithelial height. There were no differences in the rates of basal keratinocyte migration at day 7 between treated and control groups. Interestingly, human IL-10 increased vascular endothelial growth factor expression and neovascularization compared with controls. Conclusions The human ex vivo wound model provides a simple and viable design to study dermal wound healing. Both IL-10 homologs demonstrate vulnerary effects. The viral homolog demonstrates enhanced effects on wound closure compared with human IL-10. These data represent a novel tool that can be used to screen therapeutics, such as CMV IL-10, before preclinical studies.
Objective The objective of the study was to review perinatal outcomes in pregnancies treated with intrafetal radiofrequency ablation (RFA) for twin reversed arterial perfusion (TRAP) sequence. Study ...Design Perinatal outcome data from a quaternary care referral center were abstracted from a chart review of pregnancies with TRAP sequence treated in the midtrimester with umbilical cord RFA of the perfused twin. Results Twenty-one pregnancies with TRAP sequence were evaluated. Two women had a pump twin demise prior to therapy, 1 with trisomy 21 declined treatment. Four of 20 were treated successfully with RFA but remain undelivered, and 1 was treated with fetoscopic cord coagulation. Twelve of 13 pump twins treated with RFA (94%) survived to 30 days of life. Mean preoperative cardiac combined cardiac output was 588 mL/kg and pump/twin ratio was 0.7 (range 0.4 to 1.1). The effect of RFA on postoperative cardiac output was variable (6-85%). The average gestational age at birth was 37 weeks (range 26-39 weeks). Conclusion Primary therapy with RFA is a successful modality for pregnancies complicated by TRAP sequence.
The aim of this study was to assess the relationship between cardiomyopathy and recipient twin (RT) outcome in twin-twin transfusion syndrome (TTTS).
Fetal echocardiography and outcomes data in 62 ...consecutive pregnancies with TTTS were reviewed. The primary outcome was neonatal RT survival. The severity of RT cardiomyopathy at presentation was assessed by the cardiovascular profile score (CVPS). RT outcomes and odds of survival were compared between groups stratified by CVPS.
Overall neonatal survival for all fetuses was 61% (76 of 124). RT survival was 58% (36 of 62). Grouped by CVPS, RT survival was greater (50%) for those with CVPS > or = 9 and even higher (74%) for CVPS of 10. Among the components of the CVPS, atrioventricular valve regurgitation was associated with negative RT outcome. Other factors at presentation were not predictive of RT outcome.
A normal CVPS in the RT in TTTS is predictive of improved survival compared with an abnormal CVPS, even in RTs with minor deductions. Standard clinical staging did not predict outcome. Cardiac assessment by CVPS may improve clinical decision making and the timing of fetal interventions.
Abstract Background Recent progress has been made in the care of infants with hypertrophic pyloric stenosis (HPS), including earlier operative intervention and shorter hospital length of stay (LOS), ...which is attributable to expedited postoperative feeding protocols developed and implemented by surgeons. We hypothesized that patients with HPS admitted to a unit that is co-managed by nonsurgeon providers postoperatively have a longer LOS than those on the surgical ward. Materials and methods We reviewed the medical records of infants who underwent pyloromyotomy for HPS at a single institution from April, 2009–July, 2013. Results A total of 259 patients underwent pyloromyotomy (35 female; 13.5%), 205 (79%) were admitted to the surgical ward; 46 had a planned neonatal intensive care unit (NICU) admission (18%) and were co-managed with the neonatology team. Eight (3%) had an unplanned NICU admission and were excluded from the analysis. The groups did not differ in terms of sex, age, serum electrolytes at presentation, or time between surgeon evaluation and operative intervention. Surgical ward patients had longer preoperative symptom duration. Operative time was longer in the NICU patients. Comparing the two groups, there was no difference in postoperative apnea, hypoxic, or bradycardic episodes. NICU patients achieved ad libitum feeds later than floor patients (2.0 versus 1.4 d; P = 0001) and had a longer postoperative LOS (2.2 versus 1.6 d; P = 0.0012). Conclusions Patients with HPS admitted to the NICU postoperatively had a longer time to full feeds and hospital LOS. The reduction in LOS between hospital wards may be improved with implementation of a hospital-wide postoperative protocol for patients with HPS.
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